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INTERLEUKIN 1 ALPHA
LATEST LITERATURE
1: Blood, 2010 Mar 3,
Platelet interleukin-1{alpha} drives cerebrovascular inflammation.
[Abstract]White blood cell infiltration across an activated brain endothelium contributes to neurological disease, including cerebral ischaemia and multiple sclerosis. Identifying mechanisms of cerebrovascular activation is therefore critical to our understanding of brain disease. Platelet accumulation in microvessels of ischaemic mouse brain was associated with endothelial activation in vivo. Mouse platelets expressed IL-1alpha(but not IL-1beta), induced endothelial cell adhesion molecule expression (ICAM-1 and VCAM-1) and enhanced the release of CXC chemokine CXCL1 when incubated with primary cultures of brain endothelial cells from wild type or IL-1alpha/beta-deficient mice. A neutralising antibody to IL-1alpha (but not IL-1beta) or application of IL-1 receptor antagonist inhibited platelet-induced endothelial activation by over 90 %. Platelets from IL-1alpha/beta-deficient mice did not induce expression of adhesion molecules in cerebrovascular endothelial cells and did not promote CXCL1 release in vitro. Conditioned medium from activated platelets induced an IL-1alpha-dependent activation of mouse brain endothelial cells and supported the transendothelial migration of neutrophils in vitro. Thus, we have identified platelets as a key source of IL-1alpha and propose that platelet activation of brain endothelium, via IL-1alpha is a critical step for the entry of white blood cells, major contributors to inflammation-mediated injury in the brain.
2: Infection and immunity, 2010 May, 78(5)
Listeriolysin O-dependent bacterial entry into the cytoplasm is required for calpain activation and interleukin-1 alpha secretion in macrophages infected with Listeria monocytogenes.
[Abstract]Listeriolysin O (LLO), an hly-encoded cytolysin of Listeria monocytogenes, plays an essential role in the entry of L. monocytogenes into the host cell cytoplasm. L. monocytogenes-infected macrophages produce various proinflammatory cytokines, including interleukin-1 alpha (IL-1 alpha), that contribute to the host immune response. In this study, we have examined IL-1 alpha production in macrophages infected with wild-type L. monocytogenes or a nonescaping mutant strain deficient for LLO (Delta hly). Expression of IL-1 alpha mRNA and accumulation of pro-IL-1 alpha in the cytoplasm were induced by both strains. In contrast, the secretion of the mature form of IL-1 alpha from infected macrophages was observed in infection with wild-type L. monocytogenes but not with the Delta hly mutant. A recovery of the ability to induce IL-1 alpha secretion was shown in a mutant strain complemented with the hly gene. The Toll-like receptor (TLR)/MyD88 signaling pathway was exclusively required for the expression of pro-IL-1 alpha, independently of LLO-mediated cytoplasmic entry of L. monocytogenes. The LLO-dependent secretion of mature IL-1 alpha was abolished by addition of calcium chelators, and only LLO-producing L. monocytogenes strains were able to induce elevation of the intracellular calcium level in infected macrophages. A calcium-dependent protease, calpain, was implicated in the maturation and secretion of IL-1 alpha induced by LLO-producing L. monocytogenes strains based on the effect of calpain inhibitor. Functional activation of calpain was detected in macrophages infected with LLO-producing L. monocytogenes strains but not with a mutant strain lacking LLO. These results clearly indicated that LLO-mediated cytoplasmic entry of bacteria could induce the activation of intracellular calcium signaling, which is essential for maturation and secretion of IL-1 alpha in macrophages during L. monocytogenes infection through activation of a calcium-dependent calpain protease. In addition, recombinant LLO, when added to macrophages infected with the Delta hly strain, could induce calcium influx and IL-1 alpha secretion at doses exhibiting cytolytic activity, suggesting that LLO produced by intracellular L. monocytogenes may be implicated in induction of calcium influx through pore formation.
3: Archives of otolaryngology--head & neck surgery, 2010 Feb, 136(2)
Association of IL1A, IL1B, and TNF Gene Polymorphisms With Chronic Rhinosinusitis With and Without Nasal Polyposis: A Replication Study.
[Abstract]OBJECTIVE: To replicate and extend recent findings in a Turkish population of associations between chronic rhinosinusitis (CRS) with nasal polyposis and single-nucleotide polymorphisms (SNPs) in the IL1A (rs17561 and Ser114Ala), IL1B (rs16944), and TNF (rs361525 and rs1800629) genes. DESIGN: In a case-control replication study, DNA samples were obtained from 206 patients with severe CRS (cases) and from 196 postal code-matched controls. For IL1A and TNF, the 3 reported SNPs were complemented with tagging SNPs using an International HapMap genotyping data set to ensure complete genetic coverage. For IL1B, only the single reported SNP was assessed. A total of 24 SNPs (7 in IL1A, 1 in IL1B, and 16 in TNF) were individually genotyped. The PLINK software package was used to perform genetic association tests. SETTING: Academic research. PATIENTS: Canadian population of individuals with severe CRS. MAIN OUTCOME MEASURES: Allelic differences between cases and controls. RESULTS: Significant allelic differences between cases and controls were obtained for IL1A rs17561 (odds ratio [OR], 1.48; P = .02). The following 3 additional SNPs in this gene were associated with CRS: rs2856838 (OR, 0.63; P = .003), rs2048874 (OR, 0.57; P = .01), and rs1800587 (OR, 1.49; P = .02). These 3 SNPs remained significant after correction for multiple testing. No association was found with IL1B or TNF. CONCLUSIONS: We replicated the previously reported association between the IL1A polymorphism and severe CRS and identified 3 potential new associations in the same gene. This further supports the potential contribution of IL1A to the development of CRS. We were unable to replicate previous reports of associations with IL1B or TNF.
4: Oncology reports, 2010 Mar, 23(3)
Multiplex genotyping of 1107 SNPs from 232 candidate genes identified an association between IL1A polymorphism and breast cancer risk.
[Abstract]We sought to identify genes and polymorphisms associated with breast cancer risk among Korean women using multiplex genotyping. The SNPs (n=1536) of 264 candidate genes were genotyped using the Illumina Golden Gate assay. These genes are involved in the pathways controlling apoptosis/anti-apoptosis, the immune and inflammatory responses, cytokines, DNA repair, cell adhesion, and cell cycle/proliferation. Breast cancer cases (n=209) were recruited from Seoul National University Hospital. Age-matched control subjects (n=209) were selected from a health examinees cohort. Gene-based and SNP-based tests were performed. The final analysis includes 117 cases and 164 controls with 1107 SNPs in 232 genes. Gene-based analyses showed that IL1A, TNFRSF10B, TNFRSF1B, ICAM, and TNFSF9 were significantly associated with breast cancer risk (p<0.01). IL1A was the most significant gene associated with breast cancer risk [p for likelihood ratio test, 1 degree of freedom (df)=6x10(-7); FDR-adjusted p-value, 1df=4x10(-4), 2df=0.0071, respectively]. Individual SNP-based analyses revealed that the rare allele of the IL1A SNP rs2856836, Ex7-592Tright curved arrow C, was strongly associated with breast cancer risk (FDR-adjusted p-value, 1df=0.0027, 2df=0.0162). This SNP was found to increase risk for breast cancer [odds ratio (OR)=2.88, 95% confidence interval (CI)=1.58-5.27 for heterozygote and OR=8.17, 95% CI=2.23-29.99 for rare homozygote]. In summary, we identified a common genetic variant in IL1A strongly associated with breast cancer risk.
5: Reproduction (Cambridge, England), 2009 Dec 23,
Is interleukin-1{alpha} a luteotrophic or luteolytic agent in cattle?
[Abstract]Cytokines are thought to regulate prostaglandin (PG)s secretion in the bovine endometrium. However, there is no consensus about the role of interleukin (IL)-1alpha on PG secretion. The objective of this study was to examine the influence of IL-1alpha on basal and interferon-tau (IFNtau)-regulated PG in vitro secretion, as well its effects on PG secretion, progesterone (P4) output and corpus luteum (CL) in vivo lifespan. Explants of bovine endometrium (Days 16-17 of the estrous cycle or early pregnancy) were stimulated with IL-1alpha (10 ng/ml), IFNtau (30 ng/ml) or IL-1alpha combined with IFNtau. IL-1alpha alone strongly stimulated luteotrophic PGE2 secretion by endometrial tissues of both pregnant and nonpregnant cows. IL-1alpha also stimulated luteolytic PGF2alpha output in the late luteal phase. IFNtau augmented the stimulatory effect of IL-1alpha on PGE2 secretion. In an in vivo experiment, saline or IL-1alpha at different doses (0.001-10 mug/per animal) were applied to the uterine lumen on Day 16 of the cycle. Only the highest dose of IL-1alpha caused a temporal increase in PGF2alpha secretion while it had no effect on P4 secretion or CL lifespan. Application of 0.1 and 1 mug IL-1alpha stimulated P4 and PGE2 output and prolonged the CL lifespan. Although IL-1alpha may stimulate in vitro luteolytic PGF2alpha secretion during the estrous cycle, it only acts as a luteotrophic factor in vivo. IL-1alpha increased luteotrophic PGE2 and P4 output, inhibiting spontaneous luteolysis. These luteotrophic effects may result in appropriate luteal development and function in the cow during the estrous cycle and early pregnancy.
6: European journal of orthodontics, 2009 Nov 16,
Emotional stress and orthodontic tooth movement: effects on apical root resorption, tooth movement, and dental tissue expression of interleukin-1 alpha and calcitonin gene-related peptide immunoreactive nerve fibres in rats.
[Abstract]The aim of the study was to investigate the effect of emotional stress on apical root resorption (ARR) and tooth displacement during orthodontic tooth movement in rats. A further area of interest was to evaluate if the expression of interleukin-1 alpha (IL-1alpha) as well as the density and distribution of peptidergic nerve fibres immunoreactive to calcitonin gene-related peptide (CGRP) in the periodontal ligament (PDL) are associated with possible stress-induced changes in root resorption and tooth movement. A total of 52 male Wistar rats, aged 6 weeks, were divided in three experimental and one control group (n = 4). Group 1 had orthodontic tooth movement and received foot shocks (OTMS; n = 16), group 2 had orthodontic tooth movement but received no foot shocks (OTMNS; n = 16), and group 3 had no orthodontic tooth movement and received foot shocks (NOTMS; n = 16). Each group was further divided into four subgroups (n = 4), corresponding to the period of the experiment, i.e. 3, 7, 13, and 21 days. At the end of each experimental period, the blood samples were taken, the animals were sacrificed, and the jaws excised, deminerialized, and processed for immunocytochemistry. One-way analysis of variance was used to detect inter-group differences for all investigated variables. CGRP immunopositive nerve fibres were evaluated qualitatively. All the experimental groups demonstrated higher corticosterone levels than the control group, suggesting a stress-induced experience by orthodontic treatment per se. The OTMS group had the least amount of cellular cementum throughout the experimental periods and showed significant reduction in tooth displacement, especially at 3 and 7 days. No obvious changes were observed in the dental tissue expression of IL-1alpha and CGRP immunoreactive nerve fibres between the stressed and non-stressed orthodontically treated groups.
7: Immunity, 2009 Jul 17, 31(1)
Virus binding to a plasma membrane receptor triggers interleukin-1 alpha-mediated proinflammatory macrophage response in vivo.
[Abstract]The recognition of viral components by host pattern-recognition receptors triggers the induction of the antiviral innate immune response. Toll-like receptor 9 (TLR9) and NLRP3 inflammasome were shown to be the principal specific sensors of viral double-stranded DNA. Here we present evidence that macrophages in vivo activated an innate immune response to a double-stranded DNA virus, adenovirus (Ad), independently of TLR9 or NLRP3 inflammasome. In response to Ad, macrophage-derived IL-1 alpha triggered IL-1RI-dependent production of a defined set of proinflammatory cytokines and chemokines. The IL-1 alpha-mediated response required a selective interaction of virus arginine-glycine-aspartic acid (RGD) motifs with macrophage beta(3) integrins. Thus, these data identify IL-1 alpha-IL-1RI as a key pathway allowing for the activation of proinflammatory responses to the virus, independently of its genomic nucleic acid recognition.
8: European journal of ophthalmology, 2009 Jul-Aug, 19(4)
Topical N-acetylcysteine reduces interleukin-1-alpha in tear fluid after laser subepithelial keratectomy.
[Abstract]PURPOSE: To evaluate the effect of topical N-acetylcysteine (NAC) on interleukin 1-alpha (IL-1alpha) levels in tear fluid after myopic laser subepithelial keratectomy (LASEK) and its possible role in modulating corneal wound healing. METHODS: Twenty-six eyes of 13 patients who underwent myopic LASEK were divided into 2 groups. Group 1 (n=10 eyes) was used as a control group. All patients received topical lomefloxacin and dexamethasone postoperatively. Additionally, patients in Group 2 received topical NAC for 1 month postoperatively. Tear fluid samples were collected with microcapillary tubes preoperatively, on the first and on the fifth postoperative day, and the release of IL-1alpha in tear fluid was calculated. Haze grading and confocal microscopic examination were performed at 1 and 3 months postoperatively. RESULTS: The mean IL-1-alpha release values were 0.285-/+0.159 pg/min in Group 1 and 0.235-/+0.142 pg/min in Group 2 preoperatively. In Group 1, the values were 0.243-/+0.155 pg/min on day 1 and 0.164-/+0.125 pg/min on day 5. In Group 2, the mean IL-1alpha release values were 0.220-/+0.200 pg/min on day 1 and 0.080-/+0.079 pg/min on day 5. The difference between the groups was significant only for day 5 (p<0.05). Mean corneal haze score and grey scale value in confocal microscopy were significantly higher (p<0.05) in Group 1 at 1 month. However, at 3 months there was no difference between groups (p>0.05). CONCLUSIONS: NAC seems to have an additive effect to steroids in suppressing IL-1alpha levels in tear fluid and may be clinically advantageous in modulating corneal wound healing during the early postoperative period after LASEK.
9: Endocrinology, 2009 Jan 22,
Opposite effects of interleukin -1{alpha} (IL-1{alpha}) and transforming growth factor-{beta}2 (TGF-{beta}2) induce stage-specific regulation of junctional adhesion molecule-B (JAM-B) gene in Sertoli cells.
[Abstract]In the mammalian testis, junctional adhesion molecule-B (JAM-B) is found at the blood-testis barrier (BTB) between Sertoli cells and the apical ectoplasmic specializations (ES) between Sertoli and germ cells. The expression of JAM-B is tightly regulated to allow the transit of developing germ cells across the BTB and the timely release of mature spermatids at stage VIII. In this study, the basal transcription of JAM-B in the mouse Sertoli cell line, MSC-1 cells, was examined. We found that the constitutive expression of JAM-B is carried out by the binding of Sp proteins, Elk-1, NRSF and E2F3 to various DNA motifs including TGIF, Elk-1, NRSF and pSp1+E2F1. We also investigated the effects of two cytokines IL-1alpha and TGF-beta2 on JAM-B expression. IL-1alpha promotes JAM-B expression by facilitating the binding of Elk-1 to TGIF and pSp1+E2F3 motifs in a p38-dependent manner, which leads to an additive effect on Sp1- and NRSF-mediated JAM-B transactivation. TGF-beta2 inhibits JAM-B transcription via the activation of Smad proteins and activated Smads compete with Sp proteins for the TGIF motif, resulting in JAM-B repression. IL-1alpha and Smad3 expression have been reported to be stage-specific. IL-1alpha is absent in the seminferous epithelium at stages VII-VIII, whereas high level of nuclear Smad3 level is found at the same stages. This study shows for the first time that IL-1alpha and TGF-beta2 regulate JAM-B expression in an opposite manner, and in vitro data obtained herein provides some clues on how junctions are regulated in the testis.
10: Reproduction in domestic animals = Zuchthygiene, 2009 Jan 8, 16(1)
Post-natal Changes in Testicular Concentrations of Interleukin-1 Alpha and Beta and Interleukin-6 during Sexual Maturation in Bulls.
[Abstract]Contents Based on observations in laboratory animals interleukins could be regulators of testicular development. The objects of this study were to see if interleukins (IL-1 and IL-6) are present in the developing bull testis and to establish the temporal patterns of concentrations of IL-1 and IL-6 in the bovine testis during development. Separate groups of six bull calves were castrated every 4 weeks from 5 to 33 weeks of age, and at 56 weeks of age. Mean testicular IL-1 alpha concentrations decreased (p < 0.01) from 5 to 9 weeks of age and 13 to 21 weeks of age. Mean testicular IL-1 beta concentrations decreased (p < 0.01) from 13 to 17 weeks of age and from 29 to 33 weeks of age. Mean IL-1 bioactivity increased from 13 to 17 weeks of age, decreased to 21 weeks, increased to 25 weeks, decreased to 29 weeks and decreased from 33 to 56 weeks of age (p < 0.05). Mean testicular IL-6 concentrations decreased (p < 0.05) from 9 to 13 weeks of age, increased (p < 0.05) to 21 weeks, decreased (p < 0.05) to 25 weeks, increased (p < 0.05) to 29 weeks and decreased (p < 0.01) to 56 weeks of age. In conclusion, testicular IL-1 alpha, IL-1 beta and IL-6 were found in the bovine testis and concentrations were age dependent. Testicular IL-1 alpha and IL-1 beta concentrations were highest in the early post-natal period; however, IL-1 bioactivity and IL-6 concentrations were greatest in the immediate pre-pubertal period. These findings suggest a functional role for interleukins in testicular development in the bull.
11: Frontiers in neuroendocrinology, 2009 Jan, 30(1)
Interleukin-1 (IL-1): a central regulator of stress responses.
[Abstract]Ample evidence demonstrates that the pro-inflammatory cytokine interleukin-1 (IL-1), produced following exposure to immunological and psychological challenges, plays an important role in the neuroendocrine and behavioral stress responses. Specifically, production of brain IL-1 is an important link in stress-induced activation of the hypothalamus-pituitary-adrenal axis and secretion of glucocorticoids, which mediate the effects of stress on memory functioning and neural plasticity, exerting beneficial effects at low levels and detrimental effects at high levels. Furthermore, IL-1 signaling and the resultant glucocorticoid secretion mediate the development of depressive symptoms associated with exposure to acute and chronic stressors, at least partly via suppression of hippocampal neurogenesis. These findings indicate that whereas under some physiological conditions low levels of IL-1 promote the adaptive stress responses necessary for efficient coping, under severe and chronic stress conditions blockade of IL-1 signaling can be used as a preventive and therapeutic procedure for alleviating stress-associated neuropathology and psychopathology.
12: Neuropsychobiology, 2008, 58(2)
Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and childhood-onset mood disorders.
[Abstract]BACKGROUND/AIMS: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. METHODS: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. RESULTS: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. CONCLUSION: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.
13: Head & neck, 2008 Dec, 30(12)
Regulation of IAPs gene family by interleukin-1 alpha and Epstein-Barr virus in nasopharyngeal carcinoma.
[Abstract]BACKGROUND: Inhibitors of apoptosis proteins (IAPs), which counteract apoptosis by potently inhibiting caspase activation, are promising targets of new anti-tumor therapy. However, their roles in the pathogenesis of nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated carcinoma, are not fully understood. Herein, we investigated the expression and regulation of IAPs in NPC. METHODS AND RESULTS: Using real-time quantitative polymerase chain reaction (PCR) analysis, we found that among the IAPs family only the transcription of survivin, HIAP-1, and HIAP-2 was consistently up-regulated in NPC and metastatic NPC tissues. Immunohistochemical staining showed that their proteins were more predominantly expressed in tumor cells nests. Noteworthy, these IAPs were upregulated by interleukin-1 alpha stimulation or EBV infection, and subsequently resulted in triggering rapid proliferation of NPC verified by strong Ki-67 staining. CONCLUSION: Survivin, HIAP-1, and HIAP-2 were distinctly upregulated in NPC, suggesting they may play significant roles in NPC tumorigenesis and serve as tumor markers with prognostic and therapeutic implications.
14: Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology, 2008 Oct, 37(9)
Immunohistochemical analysis of interleukin-1 alpha, its type I receptor and antagonist in keratocystic odontogenic tumors.
[Abstract]BACKGROUND: Interleukin-1 alpha (IL-1 alpha) is thought to play a crucial role in the growth of keratocystic odontogenic tumors (KCOTs) in the jaw. The function of IL-1 alpha is regulated by the local levels of IL-1 alpha, its receptor and receptor antagonist (IL-1Ra) in tissues. In this study, the expression of these proteins was investigated both before and after marsupialization in KCOTs. METHODS: The expression of IL-1 alpha, IL-1 receptor type I (IL-1RI) and IL-1Ra was detected immunohistochemically in 10 specimens of KCOTs. RESULTS: IL-1 alpha was intensively expressed throughout the epithelium in all cases, while mild expression of IL-1 alpha was detected in the subepithelial layer endothelial cells and fibroblasts. Mild or intensive immunoreactivity for IL-1RI was also observed in the epithelial cells in all cases, and in the endothelial cells and fibroblasts in five cases respectively. The expression of IL-1Ra was detected in the epithelial cells in five cases, and in the endothelial cells and fibroblasts in three cases. After marsupialization, the immunoreactivity for IL-1 alpha and IL-1RI in the epithelial cells decreased, while the immunoreactivity for IL-1Ra in the epithelial cells increased. However, the immunoreactivity for IL-1RI and IL-1Ra in endothelial cells and fibroblasts did not change significantly. CONCLUSION: The effects of IL-1 alpha on the epithelial cells might be downregulated after marsupialization by changing the expression levels of IL-1 alpha, IL-1RI and IL-1Ra in the epithelium of KCOTs.
15: Molecular and cellular neurosciences, 2008 Jun, 38(2)
Differential effects of interleukin-1 alpha and beta on interleukin-6 and chemokine synthesis in neurones.
[Abstract]Interleukin (IL)-1 is a key mediator of neuroinflammation via actions of two agonists IL-1alpha and beta that bind to the IL-1 type I receptor (IL-1RI), and are thought to trigger identical responses. However, evidence suggests that IL-1alpha and beta may have differential actions in the central nervous system (CNS). The objective of this study was to test the hypothesis that IL-1alpha and beta differentially regulate the expression of IL-6 and chemokines KC, IP-10 and MCP-1 in primary neurones. Here we demonstrate that, whilst IL-1beta induced significant synthesis of IL-6 in neurones, IL-1alpha had no effect. In contrast, IL-1alpha and beta induced strong synthesis and constitutive release of chemokines KC, IP-10 and MCP-1 from neurones, and these responses were IL-1RI-dependent. Whilst IL-1beta-induced IL-6 synthesis was dependent on the nSMase/Src kinase signalling cascade, specific inhibitors of nSMase (3-OMS) and Src kinase (PP2) failed to inhibit IL-1alpha- and IL-1beta-induced chemokines synthesis, suggesting the existence of alternative signalling pathway(s) in neurones.
16: Contact dermatitis, 2008 May, 58(5)
Polymorphisms in the interleukin-1 gene influence the stratum corneum interleukin-1 alpha concentration in uninvolved skin of patients with chronic irritant contact dermatitis.
[Abstract]BACKGROUND: Interleukin (IL)-1 alpha and its receptor antagonist IL-1 ra play a role in skin inflammation. Several polymorphisms in the IL1 gene cluster, coding for IL-1 alpha, IL-1 ra, and IL-1 beta, influence their protein expression. Within this cluster, strong linkage disequilibrium has been shown. OBJECTIVE: We studied the association between the polymorphisms IL1A-889 (C-->T) and IL1B-31 (T-->C) and the concentration of IL-1 alpha and IL-1 ra in the stratum corneum (SC). METHOD: In 124 patients with chronic irritant contact dermatitis, we genotyped the IL1A-889 and IL1B-31 polymorphisms and determined the amount of IL-1 alpha and IL-1 ra on tape strips obtained from uninvolved skin of the volar forearm. RESULTS: The SC IL-1 alpha concentration was 23% and 47% lower in subjects with IL1A-889 C/T genotype and T/T genotype, respectively, compared with wild-type genotype. In subjects with IL1B-31 C/C genotype, the IL-1 alpha concentration was 51% lower compared with C/T and T/T genotypes. The ratio IL-1 ra/IL-1 alpha increased twofold in IL1A-889 C/T genotype and threefold in T/T genotype compared with wild type. CONCLUSIONS: We have shown a clear effect of IL1 genotype on protein expression in the SC. This altered expression may be responsible for the interindividual differences in the inflammatory response of the skin.
17: Pain, 2008 Sep 15, 138(3)
Interleukin-1 alpha has antiallodynic and antihyperalgesic activities in a rat neuropathic pain model.
[Abstract]Nerve injury and the consequent release of interleukins (ILs) are processes implicated in pain transmission. To study the potential role of IL-1 in the pathogenesis of allodynia and hyperalgesia, IL-1alpha and comparative IL-1beta, IL-6, and IL-10 mRNA levels were quantified using competitive RT-PCR of the lumbar spinal cord and dorsal root ganglia (DRG; L5-L6) three and seven days after chronic constriction injury (CCI) in rats. Microglial and astroglial activation in the ipsilateral spinal cord and DRG were observed after injury. In naive and CCI-exposed rats, IL-1alpha mRNA and protein were not detected in the spinal cord. IL-1beta and IL-6 mRNAs were strongly ipsilaterally elevated on day seven after CCI. In the ipsilateral DRG, IL-1alpha, IL-6, and IL-10 mRNA levels were increased on days three and seven; IL-1beta was elevated only on day seven. Western blot analysis revealed both the presence of IL-1alpha proteins (45 and 31 kDa) in the DRG and the down-regulation of these proteins after CCI. Intrathecal administration of IL-1alpha (50-500 ng) in naive rats did not influence nociceptive transmission, but IL-1beta (50-500 ng) induced hyperalgesia. In rats exposed to CCI, an IL-1alpha or IL-1 receptor antagonist dose-dependently attenuated symptoms of neuropathic pain; however, no effect of IL-1beta was observed. In sum, the first days after CCI showed a high abundance of IL-1alpha in the DRG. Together with the antiallodynic and antihyperalgesic effects observed after IL-1alpha administration, this finding indicates an important role for IL-1alpha in the development of neuropathic pain symptoms.
18: Molecular cancer research : MCR, 2008 Jan, 6(1)
The osterix transcription factor down-regulates interleukin-1 alpha expression in mouse osteosarcoma cells.
[Abstract]K7M2 mouse osteosarcoma cells form lytic tumors and are deficient in osterix (Osx), a zinc finger-containing transcription factor required for osteoblast differentiation and bone formation. Our previous studies showed that replacement of Osx suppresses lytic bone destruction. Cytokines, including interleukin (IL)-1alpha, IL-6, IL-11, and prostaglandin E2, have been shown to stimulate osteoclast activity. We showed that IL-1alpha production by K7M2 cells was significantly suppressed following Osx transfection through a transcription-mediated mechanism. Osx had no effect on IL-6, IL-11, or prostaglandin E2. Site-directed mutagenesis and chromatin immunoprecipitation indicated that Osx down-regulated IL-1alpha through an Sp1-binding site on the IL-1alpha promoter. Inhibiting Osx by small interfering RNA in two cell lines (Dunn and DLM8) that expressed high levels of Osx led to enhanced IL-1alpha promoter activity and protein production and altered the phenotype from blastic to lytic. These data suggest that Osx down-regulates IL-1alpha expression in mouse osteosarcoma cells via transcriptional repression of IL-1alpha and this may in turn affect the lytic activity of the tumor cells.
19: Neuroscience, 2007 Nov 30, 150(1)
The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood-brain barrier of neonatal rats: a critical period for efficacy.
[Abstract]Proinflammatory cytokines circulating in the periphery of early postnatal animals exert marked influences on their subsequent cognitive and behavioral traits and are therefore implicated in developmental psychiatric diseases such as schizophrenia. Here we examined the relationship between the permeability of the blood-brain barrier to interleukin-1 alpha (IL-1 alpha) in neonatal and juvenile rats and their later behavioral performance. Following s.c. injection of IL-1 alpha into rat neonates, IL-1 alpha immunoreactivity was first detected in the choroid plexus, brain microvessels, and olfactory cortex, and later diffused to many brain regions such as neocortex and hippocampus. In agreement, IL-1 alpha administration to the periphery resulted in a marked increase in brain IL-1 alpha content of neonates. Repeatedly injecting IL-1 alpha to neonates triggered astrocyte proliferation and microglial activation, followed by behavioral abnormalities in startle response and putative prepulse inhibition at the adult stage. Analysis of covariance with a covariate of startle amplitude suggested that IL-1 alpha administration may influence prepulse inhibition. However, adult rats treated with IL-1 alpha as neonates exhibited normal learning ability as measured by contextual fear conditioning, two-way passive shock avoidance, and a radial maze task and had no apparent sign of structural abnormality in the brain. In comparison, when IL-1 alpha was administered to juveniles, the blood-brain barrier permeation was limited. The increases in brain IL-1 alpha content and immunoreactivity were less pronounced following IL-1 alpha administration and behavioral abnormalities were not manifested at the adult stage. During early development, therefore, circulating IL-1 alpha efficiently crosses the blood-brain barrier to induce inflammatory reactions in the brain and influences later behavioral traits.