interleukin 1 beta

C Subfamily
CC Subfamily
CXC Subfamily
CX3C Subfamily

Chemokines

gp130 (IL6ST) shared
IL13RA1 shared
IL3RB (CSF2RB) shared
ILRG shared

interleukin 18
interleukin 18 proprotein
interleukin 1 alpha
interleukin 1, alpha proprotein
interleukin 1 beta
interleukin 1, beta proprotein

interleukin 17
interleukin 17b
interleukin 17E
interleukin 17E isoform 1

IL-1 Family /IL-17 Family

interleukin 10
interleukin 19
interleukin 19 isoform 2
interleukin 20
interleukin 22
interleukin 24
interleukin 24 isoform 1
interleukin 28A
interleukin 28B
interleukin 29

IL-10 Family

interferon alpha family, gene 1
interferon, alpha 1
interferon beta
interferon, beta 1
interferon epsilon 1
interferon, epsilon 1
interferon gamma
interferon, gamma
interferon kappa
interferon, kappa
interferon, omega 1

Interferon Family

CSF1 Egf Flt3l
FLT3LG HGF Kitl
KITLG Pdgfa PDGFB
PDGFC Pdgfd PLEKHQ1
VEGF Vegfa VEGFB
VEGFC

PDGF Family

AMH Bmp2 Bmp7
GDF5 Inhba INHBB
INHBC INHBE Tgfb1
TGFB2 TGFB3

TGF-β Family

CD40LG Eda Fasl
FASLG Lta LTB
TNF Tnfsf10 Tnfsf11
TNFSF12 Tnfsf13 TNFSF13B
Tnfsf14 TNFSF18 TNFSF4
TNFSF7 TNFSF8 TNFSF9

TNF Family

INTERLEUKIN 1 BETA

LATEST LITERATURE

1: The Journal of biological chemistry, 2010 Aug 11, 411(19-20)
CCAAT/enhancer-binding protein {beta} (C/EBP{beta}) and nuclear factor kappa B (NF-{kappa}B) mediate high level expression of chemokine genes CCL3 and CCL4 by human chondrocytes in response to interleukin-1{beta} (IL-1{beta}).

[Abstract]A large set of chemokines is highly up-regulated in human chondrocytes in response to IL-1beta (Sandell, L.J. et al. 2008. Osteoarthritis Cartilage 16, 1560-1571). To investigate the mechanism of transcriptional regulation, deletion constructs of selected chemokine gene promoters, the human CCL3 (MIP-1alpha) and CCL4 (MIP-1beta), were transfected into human chondrocytes with or without IL-1beta. The results show that an IL-1beta-responsive element is located between -300 to -140bp of CCL3 promoter, and -222 to -100bp of CCL4 promoter. As both of these elements contain C/EBPbeta motifs, the function of C/EBPbeta was examined. IL-1beta stimulated the expression of C/EBPbeta, and the direct binding of C/EBPbeta to the C/EBPbeta motif was confirmed by EMSA and ChIP analyses. The -300bp CCL3 promoter and -222bp CCL4 promoter were strongly up-regulated by co-transfection with C/EBPbeta expression vector. Mutation of the C/EBPbeta motif and reduction of C/EBPbeta expression by siRNA decreased the up-regulation. Additionally, another cytokine-related transcriptional factor, NF-kappaB, was also shown to be involved in the up-regulation of chemokines in response to IL-1beta and the binding site was identified. The regulation of C/EBPbeta and NF-kappaB was confirmed by the inhibition by C/EBPbeta and NF-kappaB and by transfection with C/EBPbeta and NF-kappaB expression vectors in the presence or absence of IL-1beta. Taken together, our results suggest that C/EBPbeta and NF-kappaB are both involved in the IL-1beta-responsive up-regulation of chemokine genes in human chondrocytes. Time course experiments indicated that C/EBPbeta gradually and steadily induces chemokine up-regulation, whereas the NF-kappaB activity was highest at the early stage of chemokine up-regulation.

2: Peptides, 2010 Aug 2, 411(19-20)
alpha-melanocyte-stimulating hormone (alpha-MSH) reverses impairment of memory reconsolidation induced by Interleukin-1 beta (IL-1 beta) hippocampal infusions.

[Abstract]Interleukin-1beta (IL-1beta) significantly influences cognitive processes. Treatments which raise the level of IL-1beta in the brain impair memory consolidation in contextual fear conditioning. However, the effect of IL-1beta on memory reconsolidation has not yet been established. The melanocortin alpha-melanocyte-stimulating hormone (alpha-MSH) exerts potent anti-inflammatory actions by antagonizing the effect of pro-inflammatory cytokines. Five subtypes of melanocortin receptors (MC1R-MC5R) have been identified, of which MC3R and MC4R are predominant in the central nervous system. The present experiments show that the injection of IL-1beta (5ng/0.25ul) in dorsal hippocampus up to 30min after re-exposition to the context decreases freezing during the contextual fear test. Impairment of memory reconsolidation was reversed by treatment with alpha-MSH (0.05ug/0.25ul). Administration of the MC4 receptor antagonist HS014 (0.5ug/0.25ul) blocked the effect of alpha-MSH. These results suggest that IL-1beta may influence memory reconsolidation and that activation of central MC4R could lead to improve cognitive performance.

3: Innate immunity, 2010 Aug 3, 411(19-20)
Distinct regulation by lipopolysaccharides of the expression of interleukin-1{beta} by murine macrophages and salivary glands.

[Abstract]The regulation of interleukin (IL)-1 expression and secretion by salivary glands and macrophages in response to lipopolysaccharides (LPS) was compared. In wild-type mice, injection of LPS significantly decreased the volume of saliva stimulated by pilocarpine and increased its protein and amylase concentration. It did not modify the salivary concentration of IL-1beta. The cytokine was expressed by submandibular acini and ducts. Macrophages also expressed IL-1beta but at lower concentration than salivary glands. The pre-incubation of macrophages with LPS increased the phosphorylation of IkappaB and the expression of IL-1beta. Adenosine triphosphate also promoted the secretion of the cytokine by these cells. These responses were absent in submandibular gland cells. These glands expressed CD14, TLR4 and MyD88. P2X7-KO mice secreted a lower volume of saliva which contained less proteins and amylase. In conclusion, IL-1beta is constitutively expressed by submandibular glands and its secretion is not regulated by a P2X7 agonist. In these cells, LPS do not activate the nuclear factor-kappaB-pro-IL-1beta axis in spite of the expression of the proteins involved in their recognition.

4: Endocrinology, 2010 Jul 21, 33(4)
Interleukin-1{beta} May Mediate Insulin Resistance in Liver-Derived Cells in Response to Adipocyte Inflammation.

[Abstract]Central obesity is frequently associated with adipose tissue inflammation and hepatic insulin resistance. To identify potential individual mediators in this process, we used in vitro systems and assessed if insulin resistance in liver cells could be induced by secreted products from adipocytes preexposed to an inflammatory stimulus. Conditioned medium from 3T3-L1 adipocytes pretreated without (CM) or with TNFalpha (CM-TNFalpha) was used to treat Fao hepatoma cells. ELISAs were used to assess the concentration of several inflammatory mediators in CM-TNFalpha. CM-TNFalpha-treated Fao cells exhibited about 45% diminution in insulin-stimulated phosphorylation of insulin receptor, insulin receptor substrate proteins, protein kinase B, and glycogen synthase kinase-3 as compared with CM-treated cells, without changes in the total abundance of these protein. Insulin increased glycogenesis by 2-fold in CM-treated Fao cells but not in cells exposed to CM-TNFalpha. Expression of IL-1beta mRNA was elevated 3-fold in TNFalpha-treated adipocytes, and CM-TNFalpha had 10-fold higher concentrations of IL-1beta but not TNFalpha or IL-1alpha. IL-1beta directly induced insulin resistance in Fao, HepG2, and in primary rat hepatocytes. Moreover, when TNFalpha-induced secretion/production of IL-1beta from adipocytes was inhibited by the IL-1 converting enzyme (ICE-1) inhibitor II (Ac-YVAD-CMK), insulin resistance was prevented. Furthermore, liver-derived cells treated with IL-1 receptor antagonist were protected against insulin resistance induced by CM-TNFalpha. Finally, IL-1beta secretion from human omental fat explants correlated with body mass index (R(2) = 0.639, P < 0.01), and the resulting CM induced insulin resistance in HepG2 cells, inhibitable by IL-1 receptor antagonist. Our results suggest that adipocyte-derived IL-1beta may constitute a mediator in the perturbed cross talk between adipocytes and liver cells in response to adipose tissue inflammation.

5: Human reproduction (Oxford, England), 2010 Jun 24, 285(26)
Cytokine and hormonal profile in serum samples of patients undergoing controlled ovarian stimulation: interleukin-1{beta} predicts ongoing pregnancy.

[Abstract]BACKGROUND Changes in the endometrium are not regulated exclusively by ovarian hormones; the immune system has also been implicated in normal endometrial function, similar to processes taking place during inflammatory and reparative path. Many cytokines are crucially important for reproductive processes, and the role of cytokines in the female reproductive system function has been broadly investigated during controlled ovarian stimulation (COS) for IVF attempts. The aim of this study was to evaluate the levels of serum cytokines and hormones, and the clinical outcomes of women who underwent COS and ICSI procedures. METHODS The study prospectively included 96 patients (aged 22-43 years, unexplained or male infertility, n = 61; female infertility factors, n = 35) who underwent ICSI cycles. Serum levels of interleukin (IL-8, IL-6, IL-1beta, IL-10, IL-12), tumour necrosis factor and leukaemia-inhibitory factor (LIF) and the hormones FSH, estradiol, progesterone, anti-Mullerian hormone and Inhibin-B were measured on the day of oocyte retrieval. RESULTS The ongoing pregnancy rate was 25.3%. The presence of serum IL-1beta positively affected the implantation rate (P = 0.004) and increased the chance of becoming pregnant by 15 fold. Furthermore, the percentage of patients with detectable serum IL-1beta levels who conceived (62.5%) was higher than those who failed to conceive (37.5%; P = 0.019). The LIF was undetectable in all serum samples, and no other factors influenced the clinical outcomes of patients undergoing ICSI cycles. CONCLUSIONS Our findings revealed that detectable serum levels of IL-1beta on the day of oocyte retrieval in patients undergoing COS and ICSI are predictive of successful implantation and ongoing pregnancy.

6: European journal of orthodontics, 2010 Jun 9, 44(3)
Interleukin-1{beta} levels, pain intensity, and tooth movement using two different magnitudes of continuous orthodontic force.

[Abstract]This study aimed to determine the optimum orthodontic force from a broader perspective. Interleukin (IL)-1beta levels in human gingival crevicular fluid (GCF), pain intensity, and the amount of tooth movement were measured during canine retraction using different magnitudes of continuous orthodontic force. Sixteen subjects (two males and 14 females), aged 18-24 years, diagnosed with Class I bimaxillary protrusion and treated with first premolar extractions participated in this study. The upper canines were retracted with continuous forces of 50 or 150 g using nickel-titanium coil springs on segmented archwires. One of the lower canines was used as a control. GCF was collected from the distal site of each tooth at specific time points. IL-1beta concentrations, pain intensity, using the visual analogue scale (VAS), and the amount of tooth movement were evaluated. One-way analysis of variance, Friedman, and paired t-tests were used for comparisons of IL-1beta in GCF, the plaque and gingival indices, and the efficiency of tooth movement on pain perception, respectively. IL-1beta concentration in the 150 g group showed the highest level at 24 hours and 2 months with significant differences compared with the control group (P < 0.05). The mean VAS score of pain intensity from the 150 g force was significantly greater than from the 50 g force at 24 hours (P < 0.01). However, no significant difference in the amount of tooth movement was found between these two different magnitudes of continuous force at 2 months. A 50 g force could effectively induce tooth movement similar to 150 g with less pain and less inflammation.

7: Clinica chimica acta; international journal of clinical chemistry, 2010 Jun 4, 44(3)
Influence of interleukin-1 beta genetic polymorphism, smoking and alcohol drinking on the risk of non-small cell lung cancer.

[Abstract]BACKGROUND: Non-small cell cancer (NSCLC) accounts for approximately 80% of all lung cancers. Reports suggested an association between the interleukin-1beta (IL1beta) -31 and -511 gene loci and NSCLC, but few studies took into account the effect of smoking and/or alcohol drinking on the association. METHODS: Two-hundred thirteen cases of NSCLC (aged 58.2+/-10.1) and 213 controls (aged 59.4+/-10.3 y) were included in this research. Information about the smoking and drinking behaviors, dietary customs, and anamnesis were obtained from all subjects by questionnaires, and genomic DNA was extracted. IL1beta -31 and -511 gene polymorphisms were detected using PCR-RFLP. The interactions between the genotypes and alcohol drinking/smoking were analyzed using multivariate logistic regression models. RESULTS: (The T/T genotype and the T allele of the IL1beta -31 gene were associated with higher incidence of NSCLC (P<0.05). For the IL1beta -511 locus, no difference was found in different genotypes between the NSCLC and control groups. After the adjustment of confounding variables, such as age and gender, the binary logistic analysis showed a significant gene-environment interaction (P<0.05). CONCLUSIONS: The IL1beta -31T allele was positively associated with a risk of NSCLC, and the carriers of IL1beta -31T/T or -511C/C would have higher risk of suffering from NSCLC if they drank alcohol or smoke heavily.

8: Journal of clinical periodontology, 2010 Aug 1, 37(8)
Interleukin-1 beta levels in gingival crevicular fluid and serum under naturally occurring and experimentally induced gingivitis.

[Abstract]AIMS: To evaluate the interleukin-1 beta (IL-1 beta) levels in gingival crevicular fluid (GCF) and serum in either naturally occurring (N-O) or experimentally induced (E-I) plaque-associated gingivitis. MATERIAL AND METHODS: Thirty-seven periodontally healthy subjects were evaluated in real life conditions (N-O gingivitis) as well as after 21 days of experimental gingivitis trial (E-I gingivitis). During the experimental gingivitis trial, in one maxillary quadrant (test quadrant), gingival inflammation was induced by oral hygiene abstention, while in the contralateral (control) quadrant, oral hygiene was routinely continued. IL-1 beta concentrations in N-O and E-I gingivitis were investigated for IL-1B(+3954) and IL-1B(-511) gene polymorphisms. RESULTS: (i) GCF IL-1 beta concentrations in E-I gingivitis were significantly higher compared with N-O gingivitis; (ii) an intra-individual correlation between GCF concentrations of IL-1 beta detected in N-O and E-I gingivitis was observed in control quadrants, but not in test quadrants; (iii) IL-1 beta concentration in GCF was associated with IL-1B(+3954) genotype only at test quadrants; (iv) IL-1 beta was detectable in serum only at low levels in a limited number of subjects, without difference between gingivitis conditions. CONCLUSIONS: Aspects of the bacterial challenge to the gingival tissues, such as the amount of plaque deposits and plaque accumulation rate, appear to affect the IL-1 beta levels in GCF in subjects with a specific IL-1B genotype.

9: Plastic and reconstructive surgery, 2010 Jun, 125(6)
Effects of pulsed electromagnetic fields on interleukin-1 beta and postoperative pain: a double-blind, placebo-controlled, pilot study in breast reduction patients.

[Abstract]BACKGROUND: Surgeons seek new methods of pain control to reduce side effects and speed postoperative recovery. Pulsed electromagnetic fields are effective for bone and wound repair and pain and edema reduction. This study examined whether the effect of pulsed electromagnetic fields on postoperative pain was associated with differences in levels of cytokines and angiogenic factors in the wound bed. METHODS: In this double-blind, placebo-controlled, randomized study, 24 patients, undergoing breast reduction for symptomatic macromastia received pulsed electromagnetic field therapy configured to modulate the calmodulin-dependent nitric oxide signaling pathway. Pain levels were measured by a visual analogue scale, and narcotic use was recorded. Wound exudates were analyzed for interleukin (IL)-1 beta, tumor necrosis factor-alpha, vascular endothelial growth factor, and fibroblast growth factor-2. RESULTS: Pulsed electromagnetic fields produced a 57 percent decrease in mean pain scores at 1 hour (p < 0.01) and a 300 percent decrease at 5 hours (p < 0.001), persisting to 48 hours postoperatively in the active versus the control group, along with a concomitant 2.2-fold reduction in narcotic use in active patients (p = 0.002). Mean IL-1 beta concentration in the wound exudates of treated patients was 275 percent lower (p < 0.001). There were no significant differences found for tumor necrosis factor-alpha, vascular endothelial growth factor, or fibroblast growth factor-2 concentrations. CONCLUSIONS: Pulsed electromagnetic field therapy significantly reduced postoperative pain and narcotic use in the immediate postoperative period. The reduction of IL-1 beta in the wound exudate supports a mechanism that may involve manipulation of the dynamics of endogenous IL-1 beta in the wound bed by means of a pulsed electromagnetic field effect on nitric oxide signaling, which could impact the speed and quality of wound repair.

10: Expert opinion on pharmacotherapy, 2010 Jun 2, 44(3)
Clinical findings and gingival crevicular fluid prostaglandin E2 and interleukin-1-beta levels following initial periodontal treatment and short-term meloxicam administration.

[Abstract]Objective: To evaluate the effects of adjunctive meloxicam administration on clinical periodontal measurements and gingival crevicular fluid (GCF) prostaglandin E(2) (PGE(2)) and interleukin-1-beta (IL-1beta) levels in chronic periodontitis. Methods: Forty chronic periodontitis patients were randomized to receive either meloxicam 7.5 mg or placebo tablets for 10 days with scaling and root planing (SRP). GCF levels of PGE(2) and IL-1beta at baseline, day 10 of drug intake and 4 weeks after SRP were determined by enzyme-linked immunosorbent assay. Demographic, clinical periodontal data were analyzed using a repeated measures ANOVA and Bonferroni analysis. GCF PGE(2) and IL-1beta levels were compared between different evaluation times using the Friedman test. The Mann-Whitney test was used to compare biochemical data between the study groups. Pearson correlation analysis was used to relate clinical and biochemical data. Results: Study groups showed significant reductions in all clinical periodontal measurements and GCF volume (p < 0.05). In both groups, IL-1beta was reduced significantly on day 10 and at week 4 compared with baseline (p < 0.01) without significant changes in PGE(2) levels (p > 0.05). No significant differences were found between study groups in GCF IL-1beta or PGE(2) levels (p > 0.05). Conclusion: Adjunctive meloxicam does not seem to provide additional improvement in clinical parameters or GCF PGE(2) and IL-1beta levels. Larger-scale studies may better clarify potential usage of anti-inflammatory agents in periodontal therapy.

11: Plastic and reconstructive surgery, 2010 Jun, 125(6)
Discussion. Effects of pulsed electromagnetic fields on interleukin-1 beta and postoperative pain: a double-blind, placebo-controlled, pilot study in breast reduction patients.

[Abstract]To explore whether or not the umbilical blood levels of cytokines can be used to indicate the adverse outcomes of hypoxic-ischemic encephalopathy (HIE) patients. Umbilical artery blood and peripheral venous blood samples were collected on the 1st, 3rd and 7th days after birth to detect the levels of IL-1 beta, IL-8 and TNF-alpha. Neurological examination and Denver developmental screening test (DDST-II) were performed at the 6 and 12 months evaluations to detect any neurodevelopmental abnormalities. The results showed: (i) the serum concentrations of IL-1 beta, IL-8 and TNF-alpha in umbilical and peripheral blood were significantly higher in HIE patients than control groups; (ii) the umbilical blood concentrations of IL-1 beta exhibited the best positive correlation with HIE grades, when compared with IL-8 and TNF-alpha; and (iii) abnormal neurological outcomes at 6 and 12 months of age were best predicted by umbilical levels of IL-1 beta. Thus, umbilical concentrations of IL-1 beta were associated with the grades and adverse outcomes of HIE.

12: Biocell : official journal of the Sociedades Latinoamericanas de Microscop��a Electronica ... et. al, 2010 Apr, 34(1)
Interleukin-1 beta regulates metalloproteinase activity and leptin secretion in a cytotrophoblast model.

[Abstract]Implantation is one of the most regulated processes in human reproduction, by endocrine and immunological systems. Cytokines are involved in embryo-maternal communication and an impaired balance could result in pregnancy loss. Here we investigated the effect of interleukin 1-beta on the activity of two important metalloproteinases (MMP-2 and MMP-9) that are involved in extracellular matrix remodeling as well as the secretion of leptin, one of the reproductive hormones actively regulating their activity and secretion. We found that IL-1 beta activates matrix metalloproteinase activity as well as increases leptin secretion. We propose that this interleukin, through the regulation of leptin, in turn activates matrix metalloproteinases which results in an increased cytotrophoblast invasion.

13: The Journal of biological chemistry, 2010 Jul 23, 285(30)
Temporal Interleukin-1{beta} Secretion from Primary Human Peripheral Blood Monocytes by P2X7-independent and P2X7-dependent Mechanisms.

[Abstract]The processing and regulated secretion of IL-1beta are critical points of control of the biological activity of this important pro-inflammatory cytokine. IL-1beta is produced by both monocytes and macrophages, but the rate and mechanism of release differ according to the differentiation status and the origin of these cells. We aimed to study the control of processing and release in human blood monocytes and human monocyte-derived macrophages. Toll-like receptor (TLR)-induced IL-1beta production and release were investigated for dependence upon caspase-1, P2X7 receptor activation, and loss of membrane asymmetry associated with microvesicle shedding. TLR agonists induced P2X7 receptor-dependent IL-1beta release in both monocytes and macrophages; however, only monocytes also showed P2X7 receptor-independent release of mature IL-1beta. Furthermore, in monocytes ATP-mediated PS exposure could be activated independently of IL-1beta production. Release of IL-1beta from monocytes showed selectivity for specific TLR agonists and was accelerated by P2X7 receptor activation. Human monocytes released more IL-1beta/cell than macrophages. These data have important implications for inflammatory diseases that involve monocyte activation and IL-1 release.

14: Investigative ophthalmology & visual science, 2010 Apr 30,
Up-regulation of matrix metalloproteinase expression by poly(I:C) in corneal fibroblasts: role of NF-{kappa}B and interleukin-1{beta}

[Abstract]Purpose: To characterize the mechanism of corneal ulceration associated with viral keratitis, we investigated the effects of polyinosinic-polycytidylic acid [poly(I:C)], asynthetic analog of viral double-stranded RNA, on the expression of matrix metalloproteinases (MMPs) in human corneal fibroblasts. Methods: The expression of MMPs in human corneal fibroblasts cultured in the absence or presence of poly(I:C) was examined by immunoblot analysis, gelatin zymography, and quantitative reverse transcription-polymerase chain reaction analysis. The phosphorylation of the NF-kappaB inhibitor protein IkappaB-alpha was assessed by immunoblot analysis, and the concentration of interleukin (IL)-1beta in culture supernatants was measured by enzyme-linked immunosorbent assay. Results: Poly(I:C) increased the expression of MMP-1 and MMP-3 in corneal fibroblasts at the mRNA and protein levels. It also induced the phosphorylation of IkappaB-alpha as well as IL-1beta secretion in these cells. The poly(I:C)-induced expression of MMP-1 and MMP-3 was attenuated by a synthetic inhibitor of NF-kappaB signaling as well as by IL-1 receptor antagonist, the latter of which also inhibited poly(I:C)-induced phosphorylation of IkappaB-alpha. Conclusions: Poly(I:C) induces the expression of MMP-1 and MMP-3 in human corneal fibroblasts in a manner dependent on activation of the transcription factor NF-kappaB and on IL-1beta secretion. These effects may play an important role in corneal ulceration associated with viral keratitis.

15: The Journal of biological chemistry, 2010 Jun 25, 285(26)
Regulation of CCAAT/enhancer-binding protein homologous protein (CHOP) expression by interleukin-1 beta in pancreatic beta cells.

[Abstract]Apoptosis contributes to immune-mediated pancreatic beta cell destruction in type I diabetes. Exposure of beta cells to interleukin-1beta (IL-1beta) causes endoplasmic reticulum stress and activates proapoptotic networks. Here, we show that nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signaling pathways regulate the expression of CCAAT/enhancer-binding protein homologous protein (CHOP), which mediates endoplasmic reticulum stress-induced apoptosis. Both CHOP mRNA and protein increase in beta cells treated with IL-1beta. In addition, prolonged exposure to high glucose further increases IL-1beta-triggered CHOP expression. IL-1beta also causes increased expression of C/EBP-beta and a reduction of MafA, NFATc2, and Pdx-1 expression in beta cells. Inhibition of the NF-kappaB and MAPK signaling pathways differentially attenuates CHOP expression. Knocking down CHOP by RNA interference protects beta cells from IL-1beta-induced apoptosis. These studies provide direct mechanistic links between cytokine-induced signaling pathways and CHOP-mediated apoptosis of beta cells.

16: The Journal of biological chemistry, 2010 Apr 21,
A kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1 beta (IL-1{beta}) activity.

[Abstract]Many therapeutic antibodies act as antagonists to competitively block cellular signaling pathways. We describe here an approach for the therapeutic use of monoclonal antibodies based on context-dependent attenuation to reduce pathologically high activity while allowing homeostatic signaling in biologically important pathways. Such attenuation is achieved by modulating the kinetics of a ligand binding to its various receptors and regulatory proteins rather than by complete blockade of signaling pathways. The anti-Interleukin-1beta (IL-1beta) antibody XOMA 052 is a potent inhibitor of IL-1beta activity that reduces the affinity of IL-1beta for its signaling receptor and co-receptor, but not for its decoy and soluble inhibitory receptors. This mechanism shifts the effective dose-response of the cytokine so that the potency of IL-1beta bound by XOMA 052 is 20-to 100-fold lower than that of IL-1beta in the absence of antibody in a variety of in vitro cell-based assays. We propose that by decreasing potency of IL-1beta while allowing binding to its clearance and inhibitory receptors, XOMA 052 treatment will attenuate IL-1beta activity in concert with endogenous regulatory mechanisms. Furthermore, the ability to bind the decoy receptor may reduce the potential for accumulation of antibody-IL-1beta complexes. Regulatory antibodies like XOMA 052, which selectively modulate signaling pathways, may represent a new mechanistic class of therapeutic antibodies.

17: Molecular and cellular neurosciences, 2010 Apr 7,
Adhesion to the extracellular matrix is required for interleukin-1 beta actions leading to reactive phenotype in rat astrocytes.

[Abstract]The extracellular matrix (ECM) of the brain is essential for homeostasis and normal functions, but is rapidly remodelled during acute brain injury alongside the development of an inflammatory response driven by the cytokine interleukin (IL)-1. Whether the ECM regulates IL-1 actions in astrocytes is completely unknown. The aim of this study was to test the hypothesis that cellular attachment to the ECM is a critical mediator of IL-1beta-induced signalling pathways and development of reactive phenotype in astrocytes. Primary rat astrocytes adhered to fibronectin, laminin and fibrillin-1 in an integrin-dependent manner. Attachment to these ECM molecules significantly increased IL-1beta-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and inhibition of RhoA and Rho kinase (ROCK), coincident with loss of focal adhesions and cellular morphological changes. Our data demonstrate that the ECM regulates IL-1 actions in astrocytes via cross-talk mechanisms between ERK1/2 and RhoA/ROCK, which could have important implications in brain inflammatory disorders.

18: Investigative ophthalmology & visual science, 2010 Apr 7,
Localisation and gene expression of Human {beta}-defensin 9 at the human ocular surface epithelium in response to pathogen-associated molecular patterns (PAMPs) and Interleukin-1 beta.

[Abstract]Purpose. Antimicrobial peptides (AMPs) are multi-functional host defence molecules. Human beta-defensin 9 (HBD9) has previously been shown to be down-regulated during ocular surface (OS) infection or inflammation. Here, we aimed to study a) localisation of HBD9 protein in different OS regions and b) determine the role of Toll-like receptors (TLRs), Nucleotide Oligomerisation Domain (NOD)-like receptors and pro-inflammatory cytokines in HBD9 expression. Methods. Immuno-localisation of HBD9 protein was carried out on the normal human OS regions (cornea, limbus and conjunctiva). Quantitative PCR analysis of HBD9 mRNA was performed in SV40-transformed human corneal epithelial cell line (hCECs) treated for different durations with synthetic pathogen-associated molecular patterns (PAMPs) and recombinant cytokines. Results. HBD9 protein was constitutively expressed on OS epithelia. Corneal and limbal epithelia and corneal stroma demonstrated modest levels of HBD9, whereas conjunctival epithelium demonstrated high levels of HBD9 protein. TLR02, 03, 04 and 05 were shown to modulate HBD9 mRNA in hCECs. Similarly, NOD2 and IL-1beta were also shown to alter HBD9 in a time-dependent manner. In response to infection related PAMPs and inflammatory cytokines, an initial increase in HBD9 mRNA levels was noted followed by a significant down-regulation. Conclusions. To our knowledge, this is the first demonstration of HBD9 protein expression at different OS regions. We have also determined the role of various innate immune receptors in HBD9 mRNA modulation. Further understanding of the signalling mechanisms involved in the initial response of HBD9 to infection or inflammation is likely to indicate future therapeutic directions with this AMP.

19: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2010 Apr 1, 38(4)
Two haplotypes of the P2X7 receptor containing the Ala-348 to Thr polymorphism exhibit a gain-of-function effect and enhanced interleukin-1{beta} secretion.

[Abstract]The P2X7 receptor is an ATP-gated cation channel expressed in immune cells and plays a role in proinflammatory cytokine release from monocytes and macrophages. This study investigated the coinheritance of 12 functionally relevant single nucleotide polymorphisms (SNPs) in the human P2X7 gene (P2RX7), and the functional effect of each singly and in combination was assessed by measurements of ATP-induced currents and ethidium(+) uptake. Genotyping of 3430 Caucasian subjects identified 4 common haplotypes in addition to the common (wild-type) P2X7-1. Two haplotypes (denoted P2X7-2 and P2X7-4) contained various combinations of gain-of-function SNPs. P2X7-4 was identified uniquely by the Gln-460 to Arg polymorphism (rs2230912). When expressed in HEK-293 cells, recombinant P2X7-2, and P2X7-4 haplotypes displayed a 3-fold and 5-fold increase, respectively, in receptor function compared to the wild-type P2X7-1. Both P2X7 haplotypes contained the Ala-348>Thr polymorphism (rs1718119), and this mutation was critical for the gain-of-function effect. Peripheral blood monocytes and erythrocytes from subjects homozygous for gain-of-function P2X7 haplotypes exhibited increased ATP-induced ethidium(+) uptake and (86)Rb(+) efflux, respectively, and this correlated with increased IL-1beta secretion from LPS-primed monocytes. Inheritance of these P2X7 haplotypes predisposing to increased proinflammatory cytokine secretion may be important in genetic association studies of inflammatory, infectious, and psychiatric disorders.-Stokes, L., Fuller, S. J., Sluyter, R., Skarratt, K. K., Gu, B. J., Wiley, J. S. Two haplotypes of the P2X7 receptor containing the Ala-348 to Thr polymorphism exhibit a gain-of-function effect and enhanced interleukin-1beta secretion.

20: Journal of periodontal research, 2010 Jun, 45(3)
Major surface protein complex of Treponema denticola induces the production of tumor necrosis factor alpha, interleukin-1 beta, interleukin-6 and matrix metalloproteinase 9 by primary human peripheral blood monocytes.

[Abstract]BACKGROUND AND OBJECTIVE: Treponema denticola is a micro-organism that is involved in the pathogenesis of periodontitis. Major surface protein complex (MSPc), which is expressed on the envelope of this treponeme, plays a key role in the interaction between T. denticola and gingival cells. The peptidoglycan extracted from T. denticola induces the production of a large variety of inflammatory mediators by macrophage-like cells, suggesting that individual components of T. denticola cells induce the inflammatory response during periodontal disease. This study was designed to demonstrate that MSPc of T. denticola stimulates release of proinflammatory mediators in primary human monocytes. MATERIAL AND METHODS: Primary human monocytes were separated from the blood of healthy donors and incubated for up to 24 h with varying concentrations of MSPc. The production of tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and matrix metalloproteinase 9 (MMP-9) was measured at different time points with commercially available enzyme-linked immunosorbent assays. RESULTS: T. denticola MSPc induced the synthesis of TNF-alpha, IL-1 beta, IL-6 and MMP-9 in a dose- and time-dependent manner. Similar patterns of TNF-alpha, IL-1 beta and IL-6 release were observed when cells were stimulated with 100 and 1000 ng/mL of MSPc. The production of MMP-9 was significant only when cells were treated with 1000 ng/mL of MSPc. CONCLUSION: These results indicate that T. denticola MSPc, at concentrations ranging from 100 ng/mL to 1.0 microg/mL, activates a proinflammatory response in primary human monocytes.

21: Journal of periodontal research, 2010 Aug, 45(4)
Flutamide inhibits nifedipine- and interleukin-1 beta-induced collagen overproduction in gingival fibroblasts.

[Abstract]BACKGROUND AND OBJECTIVE: To understand the role of the androgen receptor in gingival overgrowth, the effects of flutamide on interleukin-1 beta- and nifedipine-induced gene expression of connective tissue growth factor (CTGF/CCN2) and collagen production in gingival fibroblasts were examined. MATERIAL AND METHODS: Gingival fibroblasts from healthy subjects and patients with dihydropyridine-induced gingival overgrowth (DIGO) were used. Confluent cells were treated with nifedipine, interleukin-1 beta or both. The mRNA expression was examined using real-time polymerase chain reaction, and the concentration of total soluble collagen in conditioned media was analysed by Sircol Collagen Assay. In addition, the protein expressions of androgen receptor, CTGF/CCN2 and type I collagen in gingival tissue were determined by western blot. RESULTS: Interleukin-1 beta was more potent than nifedipine in stimulating CTGF/CCN2 and procollagen alpha1(I) mRNA expression, and there was an additive effect of the two drugs. Healthy cells exhibited an equal or stronger response of procollagen alpha1(I) than those with DIGO, but DIGO cells displayed a stronger response in the secretion of soluble collagen in the same conditions. Flutamide, an androgen receptor antagonist, inhibited stimulation by nifedipine or interleukin-1 beta. Additionally, the protein expressions of androgen receptor and type I collagen were higher in DIGO gingival tissue than those in healthy gingival tissue. CONCLUSION: The data suggest that both nifedipine and interleukin-1 beta play an important role in DIGO via androgen receptor upregulation and that gingival overgrowth is mainly due to collagen accumulation. Flutamide decreases the gene expression and protein production of collagen from dihydropyridine-induced overgrowth cells.

22: European journal of heart failure : journal of the Working Group on Heart Failure of the European Society of Cardiology, 2010 Apr, 12(4)
Interleukin-1{beta} modulation using a genetically engineered antibody prevents adverse cardiac remodelling following acute myocardial infarction in the mouse.

[Abstract]Hyaluronan (HA) plays a crucial role in the lubricating and buffering properties of synovial fluid. The purpose of this study was to examine the effects of interleukin (IL)-1beta on HA degradation in cultured synovial membrane cells. The rabbit synovial membrane cell line HIG-82 was cultured with and without IL-1beta. The amounts of HA of varying molecular weights in the medium were analyzed using high-performance liquid chromatography, the mRNA levels of HA synthase (HAS) and hyaluronidase (HYAL) were analyzed by means of real-time PCR, and HYAL activity was analyzed by HA zymography. The amounts of HA with a molecular weight lower than 300 kDa, and between 300 and 1900 kDa, in the culture medium of HIG-82 cells were significantly higher in the presence of IL-1beta. However, the amount of HA with a molecular weight greater than 1900 kDa was significantly lower in the presence of IL-1beta. Both HAS2 and HAS3 mRNA levels were upregulated by treatment with IL-1beta. So, too, were the levels of HYAL1 and HYAL2 mRNA, which resulted in enhanced HYAL activity. However, HYAL activity was inhibited by transfection of HYAL2-siRNA. Our results suggest that IL-1beta is a crucial factor in the fragmentation of HA in inflammatory joints.

23: The Journal of veterinary medical science / the Japanese Society of Veterinary Science, 2010 Jun, 72(6)
Angiotensin II Enhances Interleukin-1 beta-Induced MMP-9 Secretion in Adult Rat Cardiac Fibroblasts.

[Abstract]Cardiac fibroblasts play important roles during the cardiac remodeling through the secretion of matrix metalloproteinase (MMP)-9. Inflammatory cytokine, interleukin (IL)-1beta induces MMP-9 secretion in cultured cardiac fibroblasts. Angiotensin II is well known to play pivotal roles in cardiac remodeling, but the effect of angiotensin II on MMP-9 secretion in cardiac fibroblasts has not been fully clarified. In the present study, we investigated the effect of angiotensin II on basal and IL-1beta-induced MMP-9 secretion in adult rat cardiac fibroblasts. MMP-9 protein secreted into culture medium, and phosphorylation of nuclear factor (NF)-kappaB, c-Jun NH(2)-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) in cell lysates were measured by Western blotting. Angiotensin II (1 nM, 24 hr) alone-treatment did not induce MMP-9 secretion. However, angiotensin II significantly enhanced IL-1beta (4 ng/ml, 24 hr)-induced MMP-9 secretion. Telmisartan (10 nM), an angiotensin II type 1 receptor (AT1R) antagonist, significantly suppressed the enhancement of IL-1beta-induced MMP-9 secretion by angiotensin II, whereas PD123319 (10 nM), an angiotensin II type 2 receptor antagonist, was ineffective. IL-1beta (4 ng/ml, 10 min) induced phosphorylation of NF-kappaB, JNK, and ERK. Angiotensin II augmented the IL-1beta-induced phosphorylation of ERK but not NF-kappaB and JNK. PD98059 (50 microM), a selective inhibitor of ERK pathway, inhibited the angiotensin II enhancement of IL-1beta-induced MMP-9 secretion. These results suggest that angiotensin II enhances IL-1beta-induced MMP-9 secretion through the augmentation of ERK phosphorylation via AT1R in adult rat cardiac fibroblasts.

24: American journal of veterinary research, 2010 Feb, 71(2)
Effects of glucocorticoids and interleukin-1 beta on expression and activity of aggrecanases in equine chondrocytes.

[Abstract]OBJECTIVE: To determine effects of interleukin (IL)-1 beta and glucocorticoids on total glycosaminoglycan (GAG) loss and aggrecanase-mediated matrix degradation in equine cartilage. SAMPLE POPULATION: Cartilage from 24 equine cadavers free of sepsis and musculoskeletal disease. PROCEDURES: Effects of IL-1 beta, IL-1 beta with glucocorticoids (dexamethasone and triamcinolone, 10(-6) and 10(-7)M), and glucocorticoids alone on degradation of equine articular and nasal cartilage explants were assessed by measuring GAG release in media and GAG content in cartilage. Aggrecanase-mediated cleavage within the interglobular domain at Glu373-Ala374 was evaluated via western blot analysis and ELISAs. Steady-state mRNA concentrations of matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)4, and ADAMTS5 were assessed by use of real-time reverse transcriptase PCR assay (cartilage explants) and northern blot analysis (cell culture). RESULTS: IL-1 beta increased GAG release and aggrecanase activity (11-fold). The MMP-3, MMP-13, and ADAMTS4 mRNA were upregulated with IL-1 beta, whereas ADAMTS5 mRNA was increased (13-fold), but significantly less than ADAMTS4 mRNA (27-fold), suggesting a role for both ADAMTS4 and ADAMTS5 in degradation of cytokine-stimulated cartilage. Despite downregulation of MMP-3 and MMP-13 mRNA, glucocorticoids did not alter GAG degradation. A further increase in aggrecanase activity was detected with ELISAs and western blot analysis, whereas ADAMTS4 mRNA was downregulated and ADAMTS5 mRNA was maintained or upregulated. CONCLUSIONS AND CLINICAL RELEVANCE: MMP-3, MMP-13, and ADAMTS4 were regulated differently than ADAMTS5. Glucocorticoids increased aggrecanase activity despite down-regulation of ADAMTS4 mRNA, suggesting a major role of ADAMTS5. Effects of glucocorticoids on aggrecanase activity have important implications in terms of treatment.

25: Annals of biomedical engineering, 2010 Jan 23, 17(2)
Modulation of Hyaluronan Fragmentation by Interleukin-1 Beta in Synovial Membrane Cells.

[Abstract]Hyaluronan (HA) plays a crucial role in the lubricating and buffering properties of synovial fluid. The purpose of this study was to examine the effects of interleukin (IL)-1beta on HA degradation in cultured synovial membrane cells. The rabbit synovial membrane cell line HIG-82 was cultured with and without IL-1beta. The amounts of HA of varying molecular weights in the medium were analyzed using high-performance liquid chromatography, the mRNA levels of HA synthase (HAS) and hyaluronidase (HYAL) were analyzed by means of real-time PCR, and HYAL activity was analyzed by HA zymography. The amounts of HA with a molecular weight lower than 300 kDa, and between 300 and 1900 kDa, in the culture medium of HIG-82 cells were significantly higher in the presence of IL-1beta. However, the amount of HA with a molecular weight greater than 1900 kDa was significantly lower in the presence of IL-1beta. Both HAS2 and HAS3 mRNA levels were upregulated by treatment with IL-1beta. So, too, were the levels of HYAL1 and HYAL2 mRNA, which resulted in enhanced HYAL activity. However, HYAL activity was inhibited by transfection of HYAL2-siRNA. Our results suggest that IL-1beta is a crucial factor in the fragmentation of HA in inflammatory joints.

26: Inflammation, 2010 Aug, 33(4)
Gender-related distribution of the interleukin-1 beta and interleukin-1 receptor antagonist gene polymorphisms in patients with end-stage liver disease.

[Abstract]Interleukin-1 beta (IL-1 beta) genetic polymorphisms and IL-1 receptor antagonist (IL1RN) variable number tandem repeat (VNTR) seem to be related with the occurrence of chronic diseases. This study aimed to verify whether IL-1 beta -511>C/T, -31>T/C, +3953>C/T and IL1RN VNTR were associated to the development of liver cirrhosis. Two hundred forty cirrhotic patients were involved in the study. A significant trend was detected, for increasing cirrhosis frequencies, grouping the patients as follows: females and males carrying neither the IL-1 beta (-511 -31) T-C/T-C or T-C/(T-T or C-C) diplotypes nor any IL1RN A2 allele (138/292), males carrying either the IL-1 beta T-C/T-C or T-C/(T-T or C-C) diplotypes or at least one IL1RN A2 allele (74/147) and males carrying either the IL-1 beta T-C/T-C or T-C/(T-T or C-C) diplotypes and at least one IL1RN A2 allele (28/37) (p < 0.01). IL-1 beta polymorphisms are associated with the occurrence of end stage liver disease. IL-1 beta inflammatory activity appears more pronounced in males.

27: Neuroscience letters, 2010 Mar 3, 471(2)
Levetiracetam inhibits interleukin-1 beta inflammatory responses in the hippocampus and piriform cortex of epileptic rats.

[Abstract]Levetiracetam (LEV, 2S-(oxo-1-pyrrolidinyl)butanamide, Keppra, UCB Pharma) is a new anti-epileptic drug used to treat certain types of seizures in epilepsy patients. However, the pharmacodynamics of LEV is still controversial. Recently, interleukin-1 beta (IL-1 beta) has been reported to involve in epileptic phenomena. Therefore, we investigated the effects of LEV on IL-1 beta system in the hippocampus and piriform cortex of chronic epileptic rats. As compared to controls, typical reactive astrogliosis and microgliosis were observed in the hippocampus and piriform cortex of epileptic animals. In addition, both reactive astrocytes and reactive microglia showed strong IL-1 beta and interleukin-1 receptor subtype 1 (IL-1R1) immunoreactivities. LEV reduced reactive gliosis and expression levels of IL-1 beta system in the hippocampus and the piriform cortex, while valproic acid did not. These findings suggest that the LEV may have, at least in part, anti-inflammatory effect, particularly against IL-1 beta system in neuroglia within epileptic brains.

28: Biological psychiatry, 2009 Dec 29, 11(1)
The Interleukin 1 Beta (IL1B) Gene Is Associated with Failure to Achieve Remission and Impaired Emotion Processing in Major Depression.

[Abstract]BACKGROUND: Accumulating evidence suggests the involvement of inflammatory processes and cytokines in particular in the pathophysiology of major depression (MDD) and resistance to antidepressant treatment. Furthermore, amygdala and anterior cingulate cortex (ACC) responsiveness to emotional stimuli has been suggested as a predictor of treatment response. This study investigated the association between genetic variants of the interleukin 1 beta (IL1B) gene and amygdala and ACC responsiveness to emotional stimuli and response to antidepressant treatment. METHODS: In this analysis, 256 Caucasian patients with MDD (145 women, 111 men) were genotyped for variants rs16944, rs1143643, and rs1143634 in the IL1B gene (2q14). Response to antidepressant treatment over 6 weeks was defined as remission (50% decrease on Hamilton Rating Scale for Depression-21-question). Brain activity under visual presentation of emotional faces was assessed in a subsample of 32 depressed patients by means of functional magnetic resonance imaging at 3 T. RESULTS: Pharmacogenetic analyses show significant associations of the GG genotypes of single nucleotide polymorphisms (SNPs) rs16944 (odds ratio = 1.74; 95% confidence interval 1.2-4.3) and rs1143643 (odds ratio = 3.1; 95% confidence interval 1.3-7.8) (compared with the AA genotype) with nonremission after 6 weeks. The imaging analyses show that the number of G-alleles in both SNPs (rs16944 and rs1143643) was associated with reduced responsiveness of the amygdala and ACC to emotional stimulation. CONCLUSIONS: The present study suggests a negative effect of the IL1B gene on pharmacological response and amygdala and ACC function involving the same genotypes of two SNPs (rs16944, rs116343), which taken together increase the risk of nonremission over 6 weeks of antidepressant treatment in MDD.

29: The Journal of biological chemistry, 2009 Dec 28, 11(1)
Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1{beta}

[Abstract]Interleukin-1beta (IL-1beta) is a pleiotropic cytokine promoting inflammation, angiogenesis and tissue remodeling as well as regulation of immune responses. Although IL-1beta contributes to growth and metastatic spread in experimental and human cancers, the molecular mechanisms regulating the conversion of the inactive IL-1beta precursor to a secreted and active cytokine remains unclear. Here we demonstrate that NALP3 inflammasome is constitutively assembled and activated with cleavage of caspase-1 in human melanoma cells. Late stage human melanoma cells spontaneously secrete active IL-1beta via constitutive activation of the NALP3 inflammasome and IL-1 receptor signaling, exhibiting a feature of autoinflammatory diseases. Unlike human blood monocytes, these melanoma cells require no exogenous stimulation. In contrast, NALP3 functionality in intermediate stage melanoma cells requires activation of the IL-1 receptor to secrete active IL-1beta; cells from early stage of melanoma require stimulation of the IL-1 receptor plus the co-stimulant muramyl dipeptide. The spontaneous secretion of IL-1beta from melanoma cells was reduced by inhibition of caspase-1 or the use of siRNA directed against ASC. Supernatants from melanoma cell cultures enhanced macrophage chemotaxis and promoted in vitro angiogenesis, both prevented by pretreating melanoma cells with inhibitors of caspases-1 and -5 or IL-1 receptor blockade. These findings implicate IL-1-mediated autoinflammation as contributing to the development and progression of human melanoma, and suggest that inhibiting the inflammasome pathway or reducing IL-1 activity can be a therapeutic option for melanoma patients.

30: The Journal of biological chemistry, 2009 Dec 28, 11(1)
Lysine 63-linked polyubiquitination of transforming growth factor-[beta]-activated kinase 1 at lysine 158 is required for tumor necrosis factor [alpha] and interleukin-1 [beta]-induced I[kappa]B kinase/nuclear factor-[kappa]B and c-JUN N-terminal kinase/

[Abstract]Transforming growth factor-[beta]-activated kinase 1 (TAK1) plays an essential role in Tumor necrosis factor [alpha] (TNF[alpha]) and Interleukin-1 [beta] (IL-1[beta])-induced I[kappa]B kinase (IKK)/nuclear factor-[kappa]B (NF-[kappa]B) and c-Jun N-terminal kinase (JNK)/ activator protein 1 (AP-1) activation. Here we report that TNF[alpha] and IL-1[beta] induce K63-linked TAK1 polyubiquitination at the Lys-158 residue within the kinase domain. Tumor necrosis factor receptor-associated factor (TRAF) 2 and 6 act as the ubiquitin E3 ligases to mediate K63-linked TAK1 polyubiquitination at Lys-158 residue in vivo and in vitro. K63-linked TAK1 polyubiquitination at Lys-158 residue is required for TAK1-mediated IKK complex recruitment. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with TAK1 wild-type or a TAK1 mutant containing a lysine 158 to arginine mutation revealed the importance of this site in TNF[alpha] and IL-1[beta]-mediated IKK/NF-[kappa]B and JNK/AP-1 activation as well as IL-6 gene expression. Our findings demonstrate that K63-linked polyubiquitination of TAK1 at Lys-158 is essential for its own kinase activation and its ability to mediate its downstream signal transduction pathways in response to TNF[alpha] and IL-1[beta] stimulation.

31: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2009 Dec 23, 11(1)
IL1B rs1143634 Polymorphism, Cigarette Smoking, Alcohol Use, and Lung Cancer Risk in a Japanese Population.

[Abstract]BACKGROUND:: Interleukin 1B (IL1B) is involved in pulmonary inflammation induced by environmental or occupational toxins. Chronic inflammation has been implicated in the development of lung cancer. METHODS:: We evaluated the role of IL1B (rs1143634, 3954C>T) in a case-control study comprised of 462 lung cancer cases and 379 controls in a Japanese population. Logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS AND DISCUSSION:: Individuals with a history of smoking and at least one T allele (adjusted OR = 5.45, 95% CI = 2.75-4.42, p < 0.01) presented a higher risk of lung cancer than those with the CC genotype (adjusted OR = 2.86, 95% CI = 2.02-4.05, p < 0.01) as compared with never smokers with the CC genotype (reference). The adjusted attributable proportion because of interaction between the IL1B rs1143634 genotypes and smoking was estimated to be 0.45 (95% CI = 0.08-0.83, p = 0.02), indicating that 45% of the excess risk for lung cancer in ever smokers with at least one T allele was due to additive interaction. Subjects with excessive alcohol intake and at least one T allele had a significantly higher risk (OR = 2.48, 95% CI =1.36-4.54, p < 0.01) than drinkers with appropriate intake and the CC genotype. There was no interaction between the polymorphism and alcohol intake. CONCLUSIONS:: Our findings indicate the possible association of the T allele carriers of the IL1B rs1143634 polymorphism with higher risk of lung cancer especially among smokers. Additional studies are warranted to confirm the IL1B rs1143634-smoking interaction suggested in this study.

32: Arteriosclerosis, thrombosis, and vascular biology, 2009 Dec 17, 314(1)
Phosphorylation and Acetylation of Histone H3 and Autoregulation by Early Growth Response 1 Mediate Interleukin 1{beta} Induction of Early Growth Response 1 Transcription.

[Abstract]Background and Purpose-The transcription factor early growth response (EGR) 1 has been implicated as a key vascular phenotypic switch through its control of inducible transcription. EGR-1 autoregulation and histone modification in the EGR-1 promoter represent key regulatory steps but have not been investigated in any cell type. METHODS AND RESULTS: We demonstrate that EGR-1 regulates its own transcription and that this involves histone H3 phosphorylation and acetylation. EGR-1 transactivates its promoter in smooth muscle cells exposed to interleukin (IL) 1beta through a novel cis-acting element (-211/-203). PD98059, which inhibits MEK/extracellular signal-regulated kinase 1/2, attenuates IL-1beta-inducible phosphorylation of extracellular signal-regulated kinase 1/2 and mitogen and stress-activated protein kinases 1/2; and reduces levels of phosphorylated and acetylated histone H3. Histone deacetylase inhibition enhances EGR-1 transcription in response to cytokine. Conversely, suppression of histone modification with mitogen and stress-activated protein kinase 1/2 short interfering RNA, or the histone H3 acetyltransferase inhibitor Garcinol, inhibits IL-1beta-inducible EGR-1 transcription. EGR-1 interacts with the acetyltransferase p300. Acetylated H3 and phosphorylated H3 are enriched at the promoter of EGR-1; and EGR-1 is enriched at the promoters of tissue factor and plasminogen activator inhibitor 1 in response to IL-1beta, and attenuated by PD98059, Garcinol, and mitogen and stress-activated protein kinase 1/2 short interfering RNA. CONCLUSIONS: IL-1beta induction of EGR-1 transcription involves histone H3 phosphorylation, acetylation, and autoregulation by EGR-1.

33: Shock (Augusta, Ga.), 2009 Dec 15, 314(1)
Polymorphisms in PARP, IL1B, IL4, IL10, C1INH, DEFB1 and DEFA4 in meningococcal disease in three populations.

[Abstract]OBJECTIVE: The pathogenesis of meningococcal infections involves activation of the complement system, pro- and anti-inflammatory mediators, antimicrobial peptides and apoptosis. We hypothesized that variations in genes encoding these products are involved in the susceptibility to and severity of pediatric meningococcal infections. STUDY DESIGN: Polymorphisms in PARP, C1INH, IL4, IL10 and IL1B, DEFA4 and DEFB1 were analyzed in two independent Caucasian case control cohorts from the UK and the Netherlands and in a family based TDT cohort from the UK RESULTS: In the UK case control cohort the DEFB1 -44 G/G homozygous genotype was overrepresented in patients with meningococcal disease compared to the G/C and C/C genotypes when combined (OR 1.57, 95% CI 1.12-2.20). The TDT analysis did not confirm this, but did find an association and linkage of the IL4 -524 and the C1INH 480 polymorphisms with susceptibility to meningococcal infection. Hematological failure was present more often in UK patients with the DEFB1 -44 G/G genotype compared to the C allele carriers (OR 2.17, 95% CI 1.22-3.85). CONCLUSIONS: Additional studies are necessary to elucidate the conflicting results obtained for the DEFB1, IL4 and C1INH polymorphisms and their role in susceptibility to and severity of meningococcal disease.

34: Journal of periodontology, 2009 Dec, 80(12)
Gingival inflammation and interleukin-1 Beta and tumor necrosis factor-alpha levels in gingival crevicular fluid during the menstrual cycle.

[Abstract]BACKGROUND: Hormonal changes during puberty, pregnancy, and menopause may impact periodontal tissues by altering the host response. There are only a few studies that examined gingival changes during the menstrual cycle. This longitudinal and prospective study aims to investigate clinical and laboratory markers of gingival inflammation in women at different phases during their menstrual cycles. METHODS: Twenty-seven females were included in this study. Subjects were given oral hygiene instructions before the study, and their plaque index scores were recorded once a week for 2 months. The duration and regularity of the menstrual cycle were also checked at the same time. The gingival index and bleeding on probing (BOP) were recorded. Probing depths were measured to assess the periodontal condition of the subjects. Gingival crevicular fluid (GCF) was collected to analyze the levels of interleukin (IL)-1beta and tumor necrosis factor-alpha on the first menstruation day (MD), estimated ovulation day (OD), and estimated predominant progesterone secretion day (PgD). These exact menstrual cycle days were determined according to serum progesterone and estradiol levels. RESULTS: BOP and IL-1beta levels in GCF showed significant increases from the MD to PgD under optimal plaque control. Among the 12 subjects that had premenstrual symptoms, six subjects reported oral complaints during the premenstrual period, whereas apthous lesions were more frequent during the menstruation period. CONCLUSION: These results demonstrate that the fluctuation of sex steroid hormones impact gingival inflammation during menstruation.

35: Journal of applied oral science : revista FOB, 2009 Sep-Oct, 17(5)
Interleukin-1 beta and interleukin-8 in healthy and inflamed dental pulps.

[Abstract]After aggression to the dental pulp, some cells produce cytokines in order to start and control the inflammatory process. Among these cytokines, interleukin-1 beta (IL-1beta) and interleukin-8 (IL-8) emerge as important ones. OBJECTIVE: The purpose of this study was to analyze the location, distribution and concentration of these cytokines in healthy and inflamed dental pulps. MATERIAL AND METHODS: Twenty pulps, obtained from healthy third molars (n=10) and from pulpectomies (n=10) were used for the study, with half of each group used for immunohistochemistry and half for protein extraction and ELISA assays. Fibroblasts obtained from healthy dental pulps, stimulated or not by Escherichia coli lipopolysaccharide (LPS), in order to simulate aggression on the cell cultures, were also used and analyzed by ELISA for IL-1beta and IL-8 as complementary information. Data obtained from immunohistochemistry were qualitatively analyzed. Data obtained from ELISA assays (tissue and cells) were statistically treated by the t-test (p<0.05). RESULTS: Immunohistochemically, it was observed that inflamed pulps were strongly stained for both cytokines in inflammatory cells, while healthy pulps were not immunolabeled. ELISA from tissues quantitatively confirmed the higher presence of both cytokines. Additionally, cultured pulp fibroblasts stimulated by LPS also produce more cytokines than the control cells. CONCLUSIONS: It may be concluded that inflamed pulps present higher amounts of IL-1beta and IL-8 than healthy pulps and that pulp fibroblasts stimulated by bacterial LPS produce higher levels of IL-1beta and IL-8 than the control group.

36: Pediatrics international : official journal of the Japan Pediatric Society, 2009 Nov 16, 44(6)
Surfactant lavage decreases systemic interleukin-1 beta production in meconium aspiration syndrome.

[Abstract]Background: Surfactant lavage has been used to remove meconium debris in meconium aspiration syndrome (MAS), but the influence of surfactant lavage on pro-inflammatory cytokines and cellular apoptosis are unclear. This study was aimed to investigate the response of pro-inflammatory cytokine and influence on alveolar cellular apoptosis using therapeutic bronchoalveolar lavage (BAL) with diluted surfactant to treat MAS. Methods: Twelve newborn piglets were anesthetized, intubated via tracheostomy, and artificially ventilated. MAS was induced by intratracheal instillation of 3-5 mL/kg of 20% human meconium. The piglets were then randomly assigned to a surfactant lavage group (n = 6) or a control group (n = 6). Piglets in the lavage group received BAL with 30 mL/kg diluted surfactant (5 mg/mL) in 2 aliquots. Cardiopulmonary parameters were monitored continuously. Serum was obtained hourly to measure concentrations of pro-inflammatory cytokines, including interleukin (IL)-I beta, IL-6, and tumor necrosis factor (TNF) alpha. Lung tissue was histologically examined after experiments, and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay for apoptotic cell death was also performed. Results: The animals in the lavage group displayed significantly better gas exchange and lower serum concentrations of IL-1 beta than the animals in the control group (P < 0.05). The numbers of apoptotic cells in lung tissues was significantly lower in lavage than control group, and also in nondependent than dependent site. Conclusion: Therapeutic surfactant lavage improves oxygenation, decreases production of systemic pro-inflammatory cytokine IL-1 beta, and alleviate the severity of lung cell apoptosis in newborn piglets with experimentally induced MAS.

37: Nature immunology, 2010 Jan, 11(1)
Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production.

[Abstract]Interleukin 1 beta (IL-1 beta) is a potent proinflammatory factor during viral infection. Its production is tightly controlled by transcription of Il1b dependent on the transcription factor NF-kappaB and subsequent processing of pro-IL-1 beta by an inflammasome. However, the sensors and mechanisms that facilitate RNA virus-induced production of IL-1 beta are not well defined. Here we report a dual role for the RNA helicase RIG-I in RNA virus-induced proinflammatory responses. Whereas RIG-I-mediated activation of NF-kappaB required the signaling adaptor MAVS and a complex of the adaptors CARD9 and Bcl-10, RIG-I also bound to the adaptor ASC to trigger caspase-1-dependent inflammasome activation by a mechanism independent of MAVS, CARD9 and the Nod-like receptor protein NLRP3. Our results identify the CARD9-Bcl-10 module as an essential component of the RIG-I-dependent proinflammatory response and establish RIG-I as a sensor able to activate the inflammasome in response to certain RNA viruses.

38: Annals of the rheumatic diseases, 2009 Nov 12, 44(6)
HES1, a new target for interleukin-1{beta} in chondrocytes.

[Abstract]OBJECTIVES: To investigate the effects of interleukin 1beta (IL-1beta) treatment on the Notch1/Hes1 pathway in chondrocytes in vitro. METHODS: Mouse articular chondrocytes in primary culture were challenged with IL-1beta, alone or combined with Notch1 and IL-beta pathways inhibitors. Notch1 and Hes1 expressions were investigated by immunocytochemistry, western blot and real-time qPCR. IL-beta-responsive genes were assessed by real-time qPCR and a specific siRNA against Hes1 was used to identify Hes1 target genes. RESULTS: Notch1 labeling remained nuclear and stable in intensity irrespective of treatment, suggesting a steady-state activation of this pathway in our model. IL-1beta transiently increased Hes1 mRNA (2.5-fold) and protein expression in treated versus naive chondrocytes. Hes1 mRNA level then decreased below control and its cyclic pattern of expression was lost. This was associated with nuclear translocation of the cytoplasmic Hes1 protein. IL-1beta induced increase in Hes1 mRNA was transcriptional, occurred through NF-kappaB activation and appeared to be associated with down-regulation by its own protein. Hes1 induction was insensitive to the gamma-secretase inhibitor DAPT which suggested its independence from novel Notch1 activation. Hes1 expression was efficiently silenced by a specific siRNA. This experiment revealed that Hes1 did not mediate IL-1beta-induced down-regulation of Sox9, type II collagen and aggrecan transcription but mediated IL-1beta induction of MMP-13 and ADAMTS-5. The Hes1-related repressor Hey1 was expressed at a very low level and was not inducible by IL-1beta. CONCLUSION: Hes1 is a novel IL-1beta target gene in chondrocytes which influences a discrete subset of genes linked to cartilage matrix remodeling and/or degradation.

39: American journal of reproductive immunology (New York, N.Y. : 1989), 2009 Dec, 62(6)
Increased expression of glutathione by estradiol, tumor necrosis factor-alpha, and interleukin 1-beta in endometrial stromal cells.

[Abstract]PROBLEM: The intracellular antioxidant system, based on glutathione (GSH), plays a key role in endometrial detoxification reactions and has been proposed to be involved in the pathogenesis endometriosis. This study was designed to evaluate whether estradiol (E(2)) and proinflammatory cytokines have any effects on expression of glutathione in endometrial stromal cells (ESCs). METHOD OF STUDY: Glutathione levels were measured utilizing high-performance liquid chromatography following in vitro culture and treatment of ESCs with estradiol, tumor necrosis factor-alpha (TNF-alpha) and interleukin 1-beta (IL-1beta). RESULTS: The GSH level in E(2) (10(-8) m) treatment group was significantly higher than in the control group at 48 h (P < 0.05). In vitro treatment of ESCs with TNF-alpha 10 ng/mL as well as E(2) (10(-8) m) plus TNF-alpha 10 ng/mL for 48 hr also led to a significant increase in GSH level (P < 0.05; P < 0.05, respectively). Both IL-1beta 10 ng/mL and E(2) (10(-8) m) plus IL-1beta 10 ng/mL for 48 hr increased GSH level significantly (P < 0.05; P < 0.05, respectively) as well. CONCLUSIONS: These findings might suggest that increased production of estradiol and proinflammatory cytokines in the peritoneal cavity possibly leads to the establishment of endometriosis through increased level of GSH.

40: Arthritis and rheumatism, 2009 Oct 29, 60(11)
DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes.

[Abstract]OBJECTIVE: To determine whether changes in the DNA methylation status in the promoter region of the gene encoding interleukin-1beta (IL-1beta) account for expression of IL1B messenger RNA (mRNA) after long-term treatment of human articular chondrocytes with inflammatory cytokines. METHODS: IL-1beta, tumor necrosis factor alpha (TNFalpha) plus oncostatin M (OSM), or 5-azadeoxycytidine (5-aza-dC) was added twice weekly for 4-5 weeks to primary cultures of normal human articular chondrocytes derived from the femoral head cartilage of patients with a fracture of the femoral neck. Expression of MMP13, IL1B, TNFA, and DNMT1 was determined by SYBR Green-based quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of genomic DNA and total RNA extracted from the same sample before and after culture. Bisulfite modification was used to identify which CpG sites in the IL1B promoter showed differential methylation between IL1B-expressing and IL1B-nonexpressing cells. The percentages of cells that were methylated at that critical CpG site (-299 bp) were quantified by a method that depended on methylation-sensitive restriction enzymes and real-time RT-PCR. Secretion of IL-1beta into the culture media was assessed by enzyme-linked immunosorbent assay. RESULTS: Healthy chondrocytes did not express IL1B mRNA, but the levels were increased 5-fold by treatment with 5-aza-dC and were increased 100-1,000-fold by treatment with TNFalpha/OSM. The percentage CpG methylation was decreased by 5-aza-dC treatment but was reduced considerably more by IL-1beta and was almost abolished by TNFalpha/OSM. The mRNA was translated into protein in cytokine-treated chondrocytes. CONCLUSION: These novel findings indicate that inflammatory cytokines can change the DNA methylation status at key CpG sites, resulting in long-term induction of IL1B in human articular chondrocytes.

41: Thorax, 2010 Mar, 65(3)
Diagnostic importance of pulmonary interleukin-1{beta} and interleukin-8 in ventilator-associated pneumonia.

[Abstract]Background Ventilator-associated pneumonia (VAP) is the most commonly fatal nosocomial infection. Clinical diagnosis of VAP remains notoriously inaccurate. The hypothesis was tested that significantly augmented inflammatory markers distinguish VAP from conditions closely mimicking VAP. Methods A prospective, observational cohort study was carried out in two university hospital intensive care units recruiting 73 patients with clinically suspected VAP, and a semi-urban primary care practice recruiting a reference group of 21 age- and sex-matched volunteers. Growth of pathogens at >10(4) colony-forming units (cfu)/ml of bronchoalveolar lavage fluid (BALF) distinguished VAP from "non-VAP". Inflammatory mediators were quantified in BALF and serum. Mediators showing significant differences between patients with and without VAP were analysed for diagnostic utility by receiver operator characteristic (ROC) curves. Results Seventy-two patients had recoverable lavage-24% had VAP. BALF interleukin-1beta (IL-1beta), IL-8, granulocyte colony-stimulating factor and macrophage inflammatory protein-1alpha were significantly higher in the VAP group (all p<0.005). Using a cut-off of 10 pg/ml, BALF IL-1beta generated negative likelihood ratios for VAP of 0.09. In patients with BALF IL-1beta <10 pg/ml the post-test probability of VAP was 2.8%. Using a cut-off value for IL-8 of 2 ng/ml, the positive likelihood ratio was 5.03. There was no difference in cytokine levels between patients with sterile BALF and those with growth of <10(4) cfu/ml. Conclusions BALF IL-1beta and IL-8 are amongst the strongest markers yet identified for accurately demarcating VAP within the larger population of patients with suspected VAP. These findings have potential implications for reduction in unnecessary antibiotic use but require further validation in larger populations.

42: Journal of tropical pediatrics, 2009 Oct 12, 41(2)
Increased Umbilical Cord Plasma Interleukin-1{beta} Levels was Correlated with Adverse Outcomes of Neonatal Hypoxic-ischemic Encephalopathy.

[Abstract]To explore whether or not the umbilical blood levels of cytokines can be used to indicate the adverse outcomes of hypoxic-ischemic encephalopathy (HIE) patients. Umbilical artery blood and peripheral venous blood samples were collected on the 1st, 3rd and 7th days after birth to detect the levels of IL-1beta, IL-8 and TNF-alpha. Neurological examination and Denver developmental screening test (DDST-II) were performed at the 6 and 12 months evaluations to detect any neurodevelopmental abnormalities. The results showed: (i) the serum concentrations of IL-1beta, IL-8 and TNF-alpha in umbilical and peripheral blood were significantly higher in HIE patients than control groups; (ii) the umbilical blood concentrations of IL-1beta exhibited the best positive correlation with HIE grades, when compared with IL-8 and TNF-alpha; and (iii) abnormal neurological outcomes at 6 and 12 months of age were best predicted by umbilical levels of IL-1beta. Thus, umbilical concentrations of IL-1beta were associated with the grades and adverse outcomes of HIE.

43: Infection and immunity, 2009 Sep 8, 240(1)
Bacillus anthracis capsule Activates Caspase-1/ICE and Induces Interleukin-1{beta} release from Differentiated THP-1 and Human Monocyte-derived Dendritic cells.

[Abstract]The poly-gamma-D-glutamic acid (PGA) capsule is one of the major virulence factors of Bacillus anthracis, which causes a highly lethal infection. The antiphagocytic PGA capsule disguises the bacilli from immune surveillance and allows unimpeded growth of bacilli in the host. Recently, efforts have been made to include PGA as a component of anthrax vaccine; however, the innate immune response of PGA itself has been poorly investigated. In this study, we characterized the innate immune response elicited by PGA in the human monocytic cell line THP-1, which was differentiated into macrophages with phorbol 12-myristate 13-acetate (PMA) and human monocyte-derived dendritic cells (hMoDCs). PGA capsules were isolated from the culture supernatant of either the pXO1-cured strain of B. anthracis H9401 or B. licheniformis ATCC 9945a. PGA treatment of differentiated THP-1 cells and hMoDCs led to the specific extracellular release of interleukin (IL)-1beta in a dose-dependent manner. Evaluation of IL-1beta processing by Western blot revealed that cleaved IL-1beta increased in THP-1 cells and hMoDCs after PGA treatment. Enhanced processing of IL-1beta directly correlated with increased activation of its upstream regulator, Caspase-1/ICE. The extracellular release of IL-1beta in response to PGA was ICE dependent, as the administration of an ICE inhibitor prior to PGA treatment blocked induction of IL-1beta. These results demonstrate that B. anthracis PGA elicits IL-1beta production through activation of ICE in PMA-differentiated THP-1 cells and hMoDCs, suggesting the potential for PGA as a therapeutic target for anthrax.

44: American journal of rhinology & allergy, 2009 Jul-Aug, 23(4)
[6]-Gingerol suppresses interleukin-1 beta-induced MUC5AC gene expression in human airway epithelial cells.

[Abstract]BACKGROUND: [6]-Gingerol is a major active component of ginger and a natural polyphenol compound. The present study investigated whether [6]-gingerol suppresses interleukin (IL)-1 beta-induced MUC5AC gene expression in human airway epithelial cells and, if so, examined whether the suppression of MUC5AC gene expression is mediated via the mitogen-activated protein kinase (MAPK) signal transduction pathway. METHODS: MUC5AC mRNA and protein were measured using reverse transcription-polymerase chain reaction (PCR), real-time PCR, and Western blot analysis in cultured NCI-H292 human airway epithelial cells. Extracellular signal-regulated kinase (ERK) and p38 MAPK protein levels were analyzed by Western blot. RESULTS: Expression of MUC5AC mRNA increased in NCI-H292 cells upon treatment with 10 ng/mL of IL-1 beta for 24 hours. When the cells were pretreated with 10 microM of [6]-gingerol, expression of IL-1 beta-induced MUC5AC mRNA and protein was significantly suppressed. Suppression of IL-1 beta-induced MUC5AC mRNA was also observed in cells pretreated with ERK- or p38 MAPK-specific inhibitors, suggesting that [6]-gingerol-mediated suppression of IL-1 beta-induced MUC5AC mRNA operated via the ERK- and p38 MAPK-dependent pathways. CONCLUSIONS: [6]-Gingerol suppresses IL-1 beta -induced MUC5AC gene expression in human airway epithelial cells via the ERK- and p38 MAPK-dependent pathways; therefore, [6]-gingerol may be considered a possible anti-hypersecretory agent.

45: Molecular and cellular endocrinology, 2010 Jan 15, 314(1)
Association between interleukin-1 beta polymorphism (+3953) and obesity.

[Abstract]It now appears that obesity is associated with a low-grade inflammation of white adipose tissue resulting from chronic activation of the innate immune system as interleukin-1 beta (IL-1). Previous investigations have described a positive association between IL-1 beta +3953 (C>T) gene polymorphism (rs 1143634) and obesity, suggesting functional effects on fat mass, fat metabolism and body mass. However, it is necessary to determine if these results occur in other populations and if they are influenced by sex and age. Therefore, we performed a case-control study using 880 Caucasian subjects (59.7+/-11.9 years old) from the Brazilian Aging Research Program (non-overweight=283, overweight=334, obese=263) previously investigated in genetic studies, in whom we analyzed the IL-1 beta +3953C/T polymorphism. We observed higher T allele (CT/TT) frequency in non-overweight than overweight and obese groups. The odds ratio showed 1.340 (95% CI: 1.119-1.605) times more chance of the obese group being CC carriers compared to non-overweight group independent of sex and age. This study corroborates the idea that the IL-1 system is linked to the development of obesity.

46: Neuromolecular medicine, 2009 Jul 24, 330(2)
Interleukin-1 Beta -511C/T Genetic Polymorphism is Associated with Age of Onset of Geriatric Depression.

[Abstract]The pro-inflammatory cytokine interleukin-1 beta has been implicated in the pathogenesis of major depressive disorder and in cognitive function decline in the elderly. This study tests the hypothesis that a biallelic functional polymorphism in the promoter region of the interleukin-1 beta gene (IL1B -511C/T) affects vulnerability to geriatric depression and its manifestations, including age of onset, depression severity, and cognitive function. We genotyped the IL1B -511C/T polymorphism in 125 elderly inpatients diagnosed with major depression and 282 normal elderly controls. The depressed patients were evaluated at baseline after admission using the Hamilton Rating Scale for Depression (HAM-D) for depression severity and the Mini-Mental Status Examination (MMSE) for cognitive function; depression age of onset was evaluated by interview and medical records. We found no association between IL1B -511C/T genotypes and geriatric depression susceptibility (P = 0.213), depression severity (HAM-D scores; P = 0.766) or cognitive function (MMSE scores; P = 0.827); however, compared with depressed subjects carrying the -511C allele, depressed subjects who were -511T homozygotes showed a significantly later depression age of onset of 7 years (P = 0.021). Our findings suggest that the IL1B -511C/T polymorphism may be related to age at manifestation among individuals vulnerable to depression, but they do not affect the basic vulnerability to or severity of depression in elderly Chinese adults. Further study is warranted to confirm this finding and to assess its generalization to other ethnic groups.

47: American journal of reproductive immunology (New York, N.Y. : 1989), 2009 Aug, 62(2)
Uterine leiomyoma is associated with a polymorphism in the interleukin 1-beta gene.

[Abstract]PROBLEM: To investigate whether polymorphisms in the interleukin-1beta (IL-1beta) gene are associated with uterine leiomyoma. METHOD OF STUDY: Case-control study in a collective of 131 patients and 280 controls. Genotyping of the IL-1beta-511 and IL-1beta-3954 polymorphism was performed by PCR amplification and subsequent RFLP analysis. RESULTS: A significant difference in the allele frequencies of the IL-1beta-511 C48: Journal of periodontal research, 2009 Dec, 44(6)
Expression of matrix metalloproteinase-1, matrix metalloproteinase-2 and extracellular metalloproteinase inducer in human periodontal ligament cells stimulated with interleukin-1 beta.

[Abstract]BACKGROUND AND OBJECTIVES: Matrix metalloproteinases (MMPs), produced by both infiltrating and resident cells of the periodontium, play important roles in physiologic and pathologic events. Both interleukin-1 beta and extracellular MMP inducer can stimulate the expression of MMPs, which in turn leads to breakdown of the periodontium. However, it is currently unknown whether interleukin-1 beta up-regulates MMPs through stimulating the expression of extracellular MMP inducer. The aims of this study were to investigate the effect of interleukin-1 beta on the expression of MMP-1, MMP-2 and extracellular MMP inducer in human periodontal ligament cells and to evaluate whether the regulation of MMP-1 and MMP-2 by this cytokine occurred through an effect on extracellular MMP inducer expression. MATERIAL AND METHODS: Cultured human periodontal ligament cells were treated with varying concentrations (0.01-10 ng/mL) of interleukin-1 beta at for 6, 12 and 24 h. Reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, gelatin zymography and western blotting were performed to measure the mRNA and protein levels of MMP-1, MMP-2 and extracellular MMP inducer. RESULTS: Basal levels of mRNA and protein for MMP-1, MMP-2 and extracellular MMP inducer were detected in untreated human periodontal ligament cells. Interleukin-1 beta significantly up-regulated the expression of MMP-1 and MMP-2 mRNA and protein (p < 0.05); however, the levels of mRNA and protein for extracellular MMP inducer were not significantly different (p > 0.05). In the culture medium, the concentration of MMP-1 was also increased significantly, but the concentration of MMP-1 was not related to the concentration of extracellular MMP inducer (R(2) = 0.2538, p > 0.05). CONCLUSION: Interleukin-1 beta up-regulated the levels of MMP-1 and MMP-2, but it did not alter the expression of extracellular MMP inducer. Expression of MMP-1 and MMP-2 might be elevated by interleukin-1 beta and extracellular MMP inducer via two different signal pathways.

49: Toxicology and applied pharmacology, 2009 Oct 1, 240(1)
Signal-transducing mechanisms of ketamine-caused inhibition of interleukin-1 beta gene expression in lipopolysaccharide-stimulated murine macrophage-like Raw 264.7 cells.

[Abstract]Ketamine may affect the host immunity. Interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) are pivotal cytokines produced by macrophages. This study aimed to evaluate the effects of ketamine on the regulation of inflammatory cytokine gene expression, especially IL-1 beta, in lipopolysaccharide (LPS)-activated murine macrophage-like Raw 264.7 cells and its possible signal-transducing mechanisms. Administration of Raw 264.7 cells with a therapeutic concentration of ketamine (100 microM), LPS, or a combination of ketamine and LPS for 1, 6, and 24 h was not cytotoxic to macrophages. Exposure to 100 microM ketamine decreased the binding affinity of LPS and LPS-binding protein but did not affect LPS-induced RNA and protein synthesis of TLR4. Treatment with LPS significantly increased IL-1 beta, IL-6, and TNF-alpha gene expressions in Raw 264.7 cells. Ketamine at a clinically relevant concentration did not affect the synthesis of these inflammatory cytokines, but significantly decreased LPS-caused increases in these cytokines. Immunoblot analyses, an electrophoretic mobility shift assay, and a reporter luciferase activity assay revealed that ketamine significantly decreased LPS-induced translocation and DNA binding activity of nuclear factor-kappa B (NF kappaB). Administration of LPS sequentially increased the phosphorylations of Ras, Raf, MEK1/2, ERK1/2, and IKK. However, a therapeutic concentration of ketamine alleviated such augmentations. Application of toll-like receptor 4 (TLR4) small interfering (si)RNA reduced cellular TLR4 amounts and ameliorated LPS-induced RAS activation and IL-1 beta synthesis. Co-treatment with ketamine and TLR4 siRNA synergistically ameliorated LPS-caused enhancement of IL-1 beta production. Results of this study show that a therapeutic concentration of ketamine can inhibit gene expression of IL-1 beta possibly through suppressing TLR4-mediated signal-transducing phosphorylations of Ras, Raf, MEK1/2, ERK1/2, and IKK and subsequent translocation and transactivation of NF kappaB.

50: The Journal of pharmacology and experimental therapeutics, 2009 Aug, 330(2)
Regulation of tristetraprolin expression by interleukin-1 beta and dexamethasone in human pulmonary epithelial cells: roles for nuclear factor-kappa B and p38 mitogen-activated protein kinase.

[Abstract]The mRNA-destabilizing protein tristetraprolin (TTP) negatively regulates adenine- and uridine-rich element (ARE)-containing mRNAs. In A549 pulmonary cells, TTP mRNA and both a approximately 40- and a approximately 45-kDa phosphorylated version of TTP protein were rapidly induced in response to interleukin (IL)-1beta. Analysis with IkappaBalphaDeltaN, a dominant version of inhibitor of kappaBalpha (IkappaBalpha), as well as dominant-negative and small-molecule IkappaB kinase (IKK) inhibitors demonstrated that IL-1beta-induced TTP is nuclear factor-kappaB (NF-kappaB)-dependent. Likewise, TTP expression and formation of the approximately 45-kDa phosphorylated form of TTP are blocked by the p38 mitogen-activated protein kinase (MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). By contrast, and despite a 3- to 4-fold induction of TTP mRNA, the anti-inflammatory glucocorticoid dexamethasone only modestly induced expression of the approximately 40-kDa form of TTP. In the context of IL-1beta, dexamethasone exerted a marginal repressive effect on TTP mRNA expression and more considerably reduced TTP protein. Given a requirement for p38 MAPK in the induction of TTP by IL-1beta, this repressive effect may be explained by repression of the p38 MAPK pathway by dexamethasone. Knockdown of TTP protein by siRNA elevated IL-1beta-induced expression of granulocyte macrophage-colony-stimulating factor (GM-CSF) and IL-8, demonstrating a role for TTP in feedback control. Likewise, knockdown of TTP increased GM-CSF expression in the presence of IL-1beta plus dexamethasone, suggesting that feedback control by TTP also occurs in the context of IL-1beta plus dexamethasone. Taken together, our data demonstrate that NF-kappaB and p38 MAPK are critical to the induction of TTP by IL-1beta and that TTP induction provides feedback control of the ARE-containing genes GM-CSF and IL-8.

51: Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2009 Oct, 58(10)
Interleukin-1 beta and tumor necrosis factor-alpha increase ABCG2 expression in MCF-7 breast carcinoma cell line and its mitoxantrone-resistant derivative, MCF-7/MX.

[Abstract]OBJECTIVE: In this study, we aimed to evaluate the influence of proinflammatory cytokines on ABCG2 expression and function in human MCF-7 breast cancer cell line and its mitoxantrone-resistant derivative MCF-7/MX. METHODS: The effects of proinflammatory cytokines on ABCG2 mRNA expression were studied using real-time PCR method. Cytokine-mediated modification of ABCG2 protein expression and function was investigated by means of flow cytometry. RESULTS: Significant inductions in the ABCG2 mRNA levels, protein expression, and activity were observed in IL-1 beta and TNF-alpha-treated MCF-7 cells. IL-6 increased ABCG2 protein, but had no effects on ABCG2 mRNA and function in MCF-7 cells. Although IL-1 beta did not alter mRNA and protein levels of the transporter in MCF-7/MX cells, ABCG2-mediated efflux was significantly increased in IL-1 beta-treated MCF-7/MX cells. TNF-alpha-treated MCF-7/MX cells also demonstrated greater ABCG2 protein expression and function without any changes in mRNA levels of the transporter. Neither ABCG2 mRNA nor its protein expression and function were affected by IL-6 in MCF-7/MX cells. CONCLUSION: IL-1 beta and TNF-alpha induce ABCG2 mRNA and protein expression and increase its activity in breast cancer cell line MCF-7. In MCF-7/MX cells these cytokines modulate ABCG2 protein expression and/or function, but they have no influence on the transporter mRNA levels.

52: Cytokine, 2009 Feb 27,
Interleukin 1 beta gene promoter SNPs are associated with risk of pancreatic cancer.

[Abstract]Epidemiological and experimental data demonstrate, that inflammation contributes significantly to pancreatic carcinogenesis. IL1beta, a pleiotropic cytokine produced by inflammatory cells and tumor cells, promotes cancer progression. Single nucleotide polymorphisms (SNPs) of the IL1beta promoter were found to be associated with an increased risk for certain cancers. In this case-control study we determined IL1beta promoter SNPs in 73 patients with pancreatic cancer and 235 controls. We found that the IL1beta -511CT/-31TC genotype was significantly associated with an increased risk for pancreatic cancer (OR 1.42, p=0.0456). Among pancreatic cancer cases, patients with the -511CT/-31TC genotype had less frequently resectable disease than patients with other IL1beta -511/-31 genotypes (p=0.0323). Furthermore, the IL1beta -511CT/-31TC genotype was more frequent observed in UICC stage IV (p=0.039) and undifferentiated tumors (G3) (p=0.019). In addition, we found that the proinflammatory IL1beta -511CT/-31TC alleles define an IL1beta secretory phenotype in pancreatic cancer cell lines in vitro. These findings provide a first evidence for an association of the IL1beta gene promoter SNPs with risk for pancreatic cancer.

53: Molecular and cellular neurosciences, 2009 Feb 26,
Adhesion to fibronectin regulates interleukin-1 beta expression in microglial cells.

[Abstract]The extracellular matrix (ECM) of the central nervous system (CNS) is rapidly degraded following acute brain injury, leading to inflammation and neuronal death. Under these conditions, the pro-inflammatory cytokine interleukin-1beta (IL-1beta) is primarily produced by microglial cells and is a key mediator of neuroinflammation, but whether the ECM regulates microglial IL-1 synthesis after CNS injury remains unknown. This study aimed to investigate whether cell attachment to ECM molecules modulated IL-1beta production in activated microglia in vitro. We found adhesion to fibronectin, fibrillin-1 and laminin promoted microglial cell adhesion and spreading, potentiated by bacterial lipopolysaccharide (LPS) treatment. Adhesion to fibronectin (but not fibrillin-1 or laminin) regulated IL-1beta expression via a cell density-dependent mechanism, whereby fibronectin-induced cell proliferation resulted in less IL-1beta being produced. These data suggest an important regulatory mechanism of IL-1 production, associated with microglial migration and proliferation, driven by ECM degradation and/or synthesis in an injured brain.

54: Investigaci��n cl��nica, 2008 Dec, 49(4)
[Increase of interleukin-1 beta, gamma interferon and tumor necrosis factor alpha in serum and brain of mice infected with the Venezuelan Equine Encephalitis virus]

[Abstract]Considerable efforts have been directed to clarify the main protective and recovery mechanisms in acute viral infections and, the possible role of the cytokines involved in the primary immune response induced by an epizootic strain of the Venezuelan Equine Encephalitis (VEE) virus. This study examined the levels of TH1 cytokines Interleukin-2 (IL-2) and Interferon-gamma (IFN-gamma), TH2 cytokines Interleukin-4 (IL-4) and proinflammatory cytokines (IL-1beta, TNF-alpha) in serum and brain of mice infected with the VEE virus during different post infection periods. NMRI albino male mice infected with a suspension (10 DL50) of the Guajira strain of the VEE virus, and a control group (without infection) were used. At one, 3 and 5 days post-infection, whole blood and brains were extracted to obtain sera and brain homogenates, respectively. IL-2, IFN-gamma, IL-4, IL-beta and TNF-alpha were determined by ELISA. A significant increment in the levels of IL-1beta, IFN-gamma and TNF-alpha was observed (p<0.01) in serum and brain homogenates at 1, 3 and 5 day post-infection, when compared with the control group. The levels of IL-2 and IL-4 did not show any significant statistical difference when compared to the controls. These results suggest that IL-1beta, IFN-gamma and TNF-alpha, could be involved in the early immunitary response to VEE virus during the primary infection.

55: Mayo Clinic proceedings. Mayo Clinic, 2009 Feb, 84(2)
Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component.

[Abstract]OBJECTIVE: To conduct in vitro studies as well as a phase 2 clinical trial in patients with smoldering or indolent multiple myeloma to determine if interleukin 1 (IL-1) inhibitors can delay or prevent active myeloma. PATIENTS AND METHODS: Stromal cells were cocultured with IL-1beta-expressing myeloma cells in the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of interleukin 6 (IL-6) and of apoptosis were also quantified. Between November 19, 2002, and May 24, 2007, 47 patients were enrolled in the study and subsequently treated with IL-1Ra. In 25 (53%) of the 47 study patients, low-dose dexamethasone (20 mg/wk) was added. The primary end point was progression-free survival (PFS). RESULTS: In vitro, IL-1Ra was superior to dexamethasone at inhibiting IL-6 production; maximal IL-6 inhibition and apoptosis induction were achieved by addition of both IL-1Ra and dexamethasone. In the clinical trial, 3 patients achieved a minor response to IL-1Ra alone; 5 patients achieved a partial response and 4 patients a minor response after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index that paralleled a decrease in high-sensitivity C-reactive protein (hs-CRP) levels. The median overall PFS was 37.5 months. The median PFS for patients without (n=12) or with (n=35) a greater than 15% decrease in 6-month vs baseline hs-CRP levels was 6 months and more than 3 years, respectively (P=.002). Disease stability was maintained in 8 patients who received therapy for more than 4 years. CONCLUSION: In patients with smoldering or indolent multiple myeloma who were at risk of progression to active myeloma, treatment with IL-1 inhibitors decreased the myeloma proliferative rate and hs-CRP levels in those who responded, leading to a chronic disease state and an improved PFS. Trial Registration: clinicaltrials.gov identifier: NCT00635154.

56: Mayo Clinic proceedings. Mayo Clinic, 2009 Feb, 84(2)
Targeting the pathogenic role of interleukin 1{beta} in the progression of smoldering/indolent myeloma to active disease.

[Abstract]OBJECTIVE: To conduct in vitro studies as well as a phase 2 clinical trial in patients with smoldering or indolent multiple myeloma to determine if interleukin 1 (IL-1) inhibitors can delay or prevent active myeloma. PATIENTS AND METHODS: Stromal cells were cocultured with IL-1beta-expressing myeloma cells in the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of interleukin 6 (IL-6) and of apoptosis were also quantified. Between November 19, 2002, and May 24, 2007, 47 patients were enrolled in the study and subsequently treated with IL-1Ra. In 25 (53%) of the 47 study patients, low-dose dexamethasone (20 mg/wk) was added. The primary end point was progression-free survival (PFS). RESULTS: In vitro, IL-1Ra was superior to dexamethasone at inhibiting IL-6 production; maximal IL-6 inhibition and apoptosis induction were achieved by addition of both IL-1Ra and dexamethasone. In the clinical trial, 3 patients achieved a minor response to IL-1Ra alone; 5 patients achieved a partial response and 4 patients a minor response after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index that paralleled a decrease in high-sensitivity C-reactive protein (hs-CRP) levels. The median overall PFS was 37.5 months. The median PFS for patients without (n=12) or with (n=35) a greater than 15% decrease in 6-month vs baseline hs-CRP levels was 6 months and more than 3 years, respectively (P=.002). Disease stability was maintained in 8 patients who received therapy for more than 4 years. CONCLUSION: In patients with smoldering or indolent multiple myeloma who were at risk of progression to active myeloma, treatment with IL-1 inhibitors decreased the myeloma proliferative rate and hs-CRP levels in those who responded, leading to a chronic disease state and an improved PFS. Trial Registration: clinicaltrials.gov identifier: NCT00635154.


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