|
|
| Cytokine Database |
|
INTERLEUKIN 4 ISOFORM 1
LATEST LITERATURE
1: European journal of immunology, 2010 Aug 3, 5(8)
DX5(+)CD4(+) T cells modulate cytokine production by CD4(+) T cells towards IL-10 via the production of IL-4.
[Abstract]CD4(+) Th cells play a critical role in orchestrating the adaptive immune response. Uncontrolled Th1 responses are implicated in the pathogenesis of autoimmune diseases. T cells with immune-modulatory properties are beneficial for inhibiting such inflammatory responses. Previously we demonstrated that repetitive injections of immature DC induce expansion of DX5(+)CD4(+) T cells, which upon adoptive transfer show potent regulatory properties in murine collagen-induced arthritis as well as in delayed-hypersensitivity models. However, their regulatory mechanism remains to be defined. Here, we analyzed the effect of DX5(+)CD4(+) T cells on other CD4(+) T cells in vitro. Although proliferation of na?ve CD4(+) T cells upon antigenic triggering was not altered in the presence of DX5(+)CD4(+) T cells, there was a striking difference in cytokine production. In the presence of DX5(+)CD4(+) T cells, an IL-10-producing CD4(+) T-cell response was induced instead of a predominant IFN-gamma-producing Th1 response. This modulation did not require cell-cell contact. Instead, IL-4 produced by DX5(+)CD4(+) T cells was primarily involved in the inhibition of IFN-gamma and promotion of IL-10 production by CD4(+) T cells. Together, our data indicate that DX5(+)CD4(+) T cells modulate the outcome of Th-responses by diverting Th1-induction into Th responses characterized by the production of IL-10.
2: PloS one, 2010, 5(8)
Fatty Acid Amide Hydrolase in Prostate Cancer: Association with Disease Severity and Outcome, CB(1) Receptor Expression and Regulation by IL-4.
[Abstract]BACKGROUND: Recent data have indicated that there may be a dysregulation of endocannabinoid metabolism in cancer. Here we have investigated the expression of the endocannabinoid metabolising enzyme fatty acid amide hydrolase (FAAH) in a well characterised tissue microarray from patients diagnosed with prostate cancer at transurethral resection for voiding problems. METHODOLOGY/PRINCIPAL FINDINGS: FAAH immunoreactivity (FAAH-IR) was assessed in formalin-fixed paraffin-embedded non-malignant and tumour cores from 412 patients with prostate cancer. CB(1) receptor immunoreactivity (CB(1)IR) scores were available for this dataset. FAAH-IR was seen in epithelial cells and blood vessel walls but not in the stroma. Tumour epithelial FAAH-IR was positively correlated with the disease severity at diagnosis (Gleason score, tumour stage, % of the specimen that contained tumour) for cases with mid-range CB(1)IR scores, but not for those with high CB(1)IR scores. For the 281 cases who only received palliative therapy at the end stages of the disease, a high tumour epithelial FAAH-IR was associated with a poor disease-specific survival. Multivariate Cox proportional-hazards regression analyses indicated that FAAH-IR gave additional prognostic information to that provided by CB(1)IR when a midrange, but not a high CB(1)IR cutoff value was used. Interleukin-4 (IL-4) receptor IR was found on tumour epithelial cells and incubation of prostate cancer PC-3 and R3327 AT1 cells with IL-4 increased their FAAH activity. CONCLUSIONS/SIGNIFICANCE: Tumour epithelial FAAH-IR is associated with prostate cancer severity and outcome at mid-range, but not high, CB(1)IR scores. The correlation with CB(1)IR in the tumour tissue may be related to a common local dysregulation by a component of the tumour microenvironment.
3: Recent patents on inflammation & allergy drug discovery, 2010 Aug 31, 49(9)
Current Prospective of Anti-IL-4, -IL-9, and -IL-13 Therapies in Allergic Disease.
[Abstract]While the incidence of allergy and allergic diseases continues to increase, new drugs to treat these disorders have not been forthcoming. The mainstay of therapy continues to be inhaled steroids, leukotriene receptor antagonists, antihistamines and immunotherapy. Even though these drugs work for many patients there remains a group of individuals who fail to improve with these treatments. With the exception of immunotherapy, these drugs improve symptoms, but do not do anything to alter the course of disease. This review will cover recent patents and new drugs that target IL-4, IL-13 and IL-9, molecules involved not only in inflammation associated with disease, but also with the development of the immune repertoire necessary for the perpetuation of disease. Inhibition of these cytokines may lead to true immunomodulation of disease and finally give us drugs that cure the disease rather than just treat symptoms.
4: Human immunology, 2010 Aug 21, 49(9)
Association of STR Polymorphisms in CMA1 and IL-4 with Asthma and Atopy: the SAPALDIA Cohort.
[Abstract]BACKGROUND:: Asthma is a chronic pulmonary disorder which is characterized by airway inflammation and bronchial hyperreactivity. Several genetic loci have been associated with asthma and some of these associations have been replicated in independent studies. However, larger population-based replication studies for the association of short tandem repeat (STR) polymorphisms with asthma are limited. METHODS:: Investigation of the association of STR polymorphisms in genes encoding mast cell chymase (CMA1), uteroglobin (UGB), tumor necrosis factor alpha (TNF-alpha) and interleukin 4 (IL-4) with asthma and atopic phenotypes in the large population-based Swiss Cohort Study SAPALDIA. RESULTS:: We show that the STR polymorphism in the CMA1 gene is associated with asthma and that this association is even stronger with atopic asthma. Similarly, we observed a weak association of the IL-4 2-allele with asthma which tended to be stronger for atopic asthma than for non-atopic asthma. This minor IL-4 2-allele was also associated with higher IgE levels, with a higher risk for a positive skin prick test and with a trend for a higher risk for bronchial hyperresponsivenes. CONCLUSIONS:: These results support previous findings suggesting a role for CMA1 and IL-4 in atopic asthma and for IL-4 in atopy in general.
5: American journal of physiology. Lung cellular and molecular physiology, 2010 Aug 20, 49(9)
Expression of IL-4/IL-13 Receptors in Differentiating Human Airway Epithelial Cells.
[Abstract]Interleukin (IL)-4 and IL-13 elicit several important responses in airway epithelium, including chemokine secretion and mucous secretion that may contribute to airway inflammation, cell migration and differentiation. These cytokines have overlapping but not identical effector profiles likely due to shared subunits in their receptor complexes. These receptors are variably described in epithelial cells, and the relative expression, localization and function of these recep-tors in differentiated and repairing epithelial cells are not clear. We examined IL-4/IL-13 recep-tor expression and localization in primary airway epithelial cells collected from normal human lungs and grown under conditions yielding both undifferentiated and differentiated cells inclu-sive of basal, goblet and ciliated cell phenotypes. Gene expression of the IL-4Ralpha, IL-2Rgammac, IL-13Ralpha1, and IL-13Ralpha2 receptor subunits increased with differentiation, but different patterns of localization and protein abundance were seen for each subunit based on both differentiation and the cell subtypes present. Increased expression of receptor subunits observed in more differenti-ated cells was associated with more substantial functional responses to IL-4 stimulation includ-ing increased eotaxin-3 expression and accelerated migration after injury. We demonstrate sub-stantial differences in IL-4/IL-13 receptor subunit expression and responsiveness to IL-4 based on the extent of airway epithelial cell differentiation, and suggest that these differences may have functional consequences in airway inflammation.
6: Brain, behavior, and immunity, 2010 May 31, 32(6)
Epinephrine-primed murine bone marrow-derived dendritic cells facilitate production of IL-17A and IL-4 but not IFN-gamma by CD4(+) T cells.
[Abstract]Sympathetic activation leading to the release of epinephrine and norepinephrine, is known as an important regulatory circuit related to immune-mediated diseases. However, questions still remain on the behavior of antigen presenting cells (APC) dictated by stress-induced sympathetic neurotransmitters. The purpose of this study was to examine the fate of bone marrow-derived dendritic cell (BMDC)-associated influences on resting CD4(+) T cell activation. We hypothesize that pre-exposure of dendritic cells (DCs) can modify the intensity of cytokine production, leading to preference in resting CD4(+) T cell activation. BMDCs were pre-treated with epinephrine for 2h followed by subsequent treatment of lipopolysaccharide (LPS). Subsequently, BMDCs were cocultured with purified CD4(+) T cells from mouse spleen in the absence or presence of anti-CD3 stimulation in epinephrine-free media. Epinephrine pre-treatment enhanced surface expression of MHCII, CD80 and CD86. Quantitative RT-PCR showed that epinephrine pre-treatment induced a significant transcriptional decrease of IL-12p40 and a significant increase of IL-12p35 and IL-23p19. In addition, beta2-adrenergic-blockade was shown to reverse these effects. Epinephrine pre-treatment also induced a significant decrease of IL-12p70 and a significant increase of IL-23 and IL-10 cytokine production. Importantly, these changes corresponded with increased IL-4 and IL-17A, but not IFN-g cytokine production by CD4(+) T cells in a b2-adrenergic receptor-dependent manner. These results suggest that exposure to stress-derived epinephrine dictates dendritic cells to generate a dominant Th2/Th17 phenotype in the context of subsequent exposure to a pathogenic stimulus.
7: International journal of immunogenetics, 2010 Jul 2, 185(2)
Association of IL-4 -590 T>C polymorphism and risk of renal cell carcinoma in a Chinese population.
[Abstract]Summary Interleukin 4 (IL-4) is a typical pleiotropic T helper 2 (Th2) cytokine. This cytokine is a critical mediator of the Th1/Th2 balance and apoptosis potential and involved in the process of inflammation-mediated carcinogenesis in human organs, including renal cell carcinoma (RCC). The effects of functional promoter polymorphism of the IL-4 gene on risk of RCC in Chinese are still unknown. In this study, we genotyped functional polymorphism in IL-4-590 T>C in a hospital-based case-control study of 340 patients with diagnosed RCC and 342 cancer-free controls in a Chinese population. Compared with IL-4-590 TT genotype, the CC genotype had a significantly decreased RCC risk [adjusted odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.22-0.89]. Furthermore, a significant decreased risk of RCC was found in the combined variant genotypes CT + CC compared with the TT genotype (adjusted OR = 0.68, 95% CI = 0.50-0.93). The IL-4 C allele frequency was 0.178 among the cases and 0.237 among the controls, and the difference was statistically significant (P = 0.007). These results suggest that the IL-4-590 T>C polymorphism is involved in susceptibility to developing RCC in Chinese populations. Larger studies are warranted to validate our findings.
8: Veterinary immunology and immunopathology, 2010 Jun 17, 34(1)
Effect of IL-12 on canine dendritic cell maturation following differentiation induced by granulocyte-macrophage CSF and IL-4.
[Abstract]IL-12 is a cytokine produced by dendritic cells (DC) and activates cytotoxic T cells and NK cells against tumors. We investigated the effect of IL-12 on DC. When peripheral blood monocytes were incubated with canine granulocyte-macrophage (GM)-CSF and IL-4, expression of MHC class II, CD1a, CD80 and CD86 was significantly elevated, but the cell morphology was that of immature DC. By adding canine IL-12 to the DC-inducing culture, expression of CD80 and CD1a was significantly enhanced, and the cell morphology shifted to that of mature DC. T cell stimulation by cultured cells was also significantly enhanced by the presence of IL-12. These results show that IL-12 significantly promotes the maturation and activation of canine DC following the induction of differentiation by GM-CSF and IL-4.
9: The Journal of allergy and clinical immunology, 2010 Jun 23, 34(1)
Expression of IL-4 receptor alpha on smooth muscle cells is not necessary for development of experimental allergic asthma.
[Abstract]BACKGROUND: Airflow in the lungs of patients with allergic asthma is impaired by excessive mucus production and airway smooth muscle contractions. Elevated levels of the cytokines IL-4 and IL-13 are associated with this pathology. In vitro studies have suggested that IL-4 receptor alpha (IL-4Ralpha) signaling on smooth muscle cells is critical for airway inflammation and airway hyperresponsiveness. OBJECTIVE: To define the contribution of IL-4 and IL-13 to the onset of asthmatic pathology, the role of their key receptor IL-4Ralpha in smooth muscle cells was examined in vivo. METHODS: By using transgenic smooth muscle myosin heavy chain(cre)IL-4Ralpha(-/lox) mice deficient in IL-4Ralpha in smooth muscle cells, in vivo effects of impaired IL-4Ralpha signaling in smooth muscle cells on the outcome of asthmatic disease were investigated for the first time. Allergic asthma was introduced in mice by repeated sensitization with ovalbumin/aluminum hydroxide on days 0, 7, and 14, followed by intranasal allergen challenge on days 21 to 23. Mice were investigated for the presence of airway hyperresponsiveness, airway inflammation, allergen-specific antibody production, T(h)2-type cytokine responses, and lung pathology. RESULTS: Airway hyperresponsiveness, airway inflammation, mucus production, T(h)2 cytokine production, and specific antibody responses were unaffected in smooth muscle myosin heavy chain(cre)IL-4Ralpha(-/lox) mice compared with control animals. CONCLUSION: The impairment of IL-4Ralpha on smooth muscle cells had no effect on major etiologic markers of allergic asthma. These findings suggest that IL-4Ralpha responsiveness in airway smooth muscle cells during the early phase of allergic asthma is not, as suggested, necessary for the outcome of the disease.
10: Lung, 2010 Jun 4,
Association of IL-4 and ADAM33 Gene Polymorphisms with Asthma in an Indian Population.
[Abstract]There are more than 100 candidate genes of asthma located on 23 human chromosomes. Interleukin-4 (IL-4), located on chromosome 5q31, and ADAM33, located on chromosome 20p13, and some single nucleotide polymorphisms (SNPs) of these genes have been shown to be associated with asthma and its manifestations in different populations. The most prominent SNPs of IL-4 and ADAM33 are 589C>T and 400A>G, respectively. There are also controversial reports on the association of these SNPs with asthma. In the present study, we analyzed these two SNPs in 100 patients with asthma and 50 controls through PCR amplification and restriction digestion to evaluate association of these two SNPs with asthma. The nonsignificant differences were observed for the IL-4 promoter polymorphism C589T and the ADAM33 T1 polymorphism between asthmatic patients and controls (P = 0.638 and 0.943, respectively). Our data revealed that there is no association of these SNPs with asthma indicating that other SNPs of these genes or other genes might be involved in the manifestation of asthma.
11: Journal of pediatric ophthalmology and strabismus, 2010 May 28, 32(6)
Infantile Aphakic Glaucoma: A Proposed Etiologic Role of IL-4 and VEGF.
[Abstract]PURPOSE:To identify the factors secreted by lens epithelial cells (LECs) responsible for the altered trabecular meshwork (TM) cells and to compare their effect on monocultured TM cells with that of TM cells co-cultured with LECs. METHODS:Such factors were isolated using cytokine antibody array membranes, and their effect on TM cells was assessed by analyzing changes in morphology and gene expression. In addition, inhibition of the isolated factors was performed in the co-culture model by adding specific antibodies to the cell culture media. RESULTS:Transforming growth factor beta-2, interleukin-4 (IL-4), and vascular endothelial growth factor (VEGF) are presented as candidate cytokines responsible for the observed changes in LEC-TM co-cultures. Culturing TM cells in the presence of VEGF and IL-4 triggered alterations closely reflecting those observed in the LEC-TM co-culture model, where their inhibition significantly hindered the alteration of the TM cells. CONCLUSION:These findings suggest a possible explanation for the development of infantile aphakic glaucoma, based on residual LECs secreting IL-4 and VEGF after removal of congenital cataract, which then alter trabecular meshwork cell morphology and gene expression.
12: Journal of immunotherapy (Hagerstown, Md. : 1997), 2010 May 11, 47(10)
Alternatively Activated Macrophage Possess Antitumor Cytotoxicity That Is Induced by IL-4 and Mediated by Arginase-1.
[Abstract]Earlier studies have shown that the adoptive transfer of Th2-polarized CD4 T cells can clear established tumors from mice in an antigen-specific manner. Although eosinophils were implicated in this process, the exact mechanism of tumor clearance and which immune effector cells were involved, remain to be defined. Consequently, experiments were undertaken to elucidate the mechanism of Th2-mediated destruction of B16-F1 melanoma cells by examining the in vitro antitumor activity of leukocytes within a type-2 inflammatory infiltrate. The experimental data show that activation of alternatively activated macrophages (aaMacs) within type-2 infiltrates by IL-4 or IL-13 can inhibit B16-F1 melanoma cell proliferation through a mechanism that is dependent on arginase-1 depletion of L-arginine within the tumor cell microenvironment. Interestingly, whilst at higher E:T ratios aaMac exhibited antitumor activity, at lower E:T ratios aaMacs were observed to enhance rather than inhibit B16-F1 melanoma cell growth. This highlights the fine balance between stimulating the antitumorigenic and protumorigenic properties of aaMacs in tumor immunotherapy protocols.
13: Rheumatology (Oxford, England), 2010 May 5, 47(10)
IgG4-positive multi-organ lymphoproliferative syndrome manifesting as chronic symmetrical sclerosing dacryo-sialadenitis with subsequent secondary portal hypertension and remarkable IgG4-linked IL-4 elevation.
[Abstract]While IL-4 directs CD4 T cells to produce Th2 cytokines (including IL-4, IL-13, IL-5) in vitro it has been shown that production of these cytokines can be induced in vivo in the absence of IL-4/IL-13/STAT-6 signaling. The present report shows that CD8 as well as CD4 T cells activated through their TCR, in vitro upregulate the Th2-features - IL-4, IL-13, IL-5, and GATA-3. However, in vivo while alum-precipitated antigen strongly and selectively induces these Th2-features in CD4 T cells, CD8 T cells mount a markedly different response to this antigen. This CD8 response is associated with strong proliferation and production of IFN-gamma, but no Th2-features are induced. Alum-protein formulations are widely used in human vaccines and typically induce strong antibody responses characterized by the differentiation of IL-4-producing CD4 T cells and immunoglobulin class switching to IgG1. Nevertheless, the mechanism responsible for CD4 Th2 and follicular helper T cell commitment triggered by these alum-protein vaccines is still poorly understood. Analysis of the in vivo response to alum-precipitated protein shows that while subsets of CD4 T cells strongly upregulate Th2 and follicular helper T cell features including the surface markers OX40, CXCR5, PD-1, IL-17RB and the transcription factor c-Maf, CD8 T cells do not. These discrete differences between responding CD4 and CD8 T cells provide further insight into the differences between Th2 polarization of CD4 T cells directed by IL-4 in vitro and the induction of IL-4 production by CD4 T cells in vivo in response to alum-precipitated protein.
14: Carcinogenesis, 2010 Apr 19, 184(9)
Comprehensive analysis of the cytokine rich chromosome 5q31.1 region suggests a role for IL-4 gene variants in prostate cancer risk.
[Abstract]While inflammation is emerging as a candidate prostate cancer risk factor, the T-helper cytokine-rich (IL-5, IL-13 and IL-4) chromosomal region at 5q31.1 has been implicated in prostate cancer pathogenesis. In particular, IL-4 has been associated with prostate cancer progression, while the IL-4 -589C>T (rs2243250) promoter variant has been associated with differential gene expression. We genotyped rs2243250 and 11 tagSNPs spanning 200 kb across the 5q31.1 region on 825 cases and 732 controls from the Risk Factors for Prostate Cancer Study. The minor alleles of rs2243250 and an IL-4 tagSNP rs2227284 were associated with a small increase in prostate cancer risk. Per allele ORs are 1.32 (95% CI 1.08-1.61, P=0.006) and 1.26 (95% CI 1.07-1.48, P=0.005), respectively. Although these associations were not replicated in an analysis of the Melbourne Collaborative Cohort Study, including 810 cases and 1733 controls, no clinicopathological characteristic was implicated for this divergence. Correlating rs2243250 genotypes to IL-4 gene transcript levels and circulating IL-4 plasma levels, we observe in contrast to previous reports, a non-significant trend towards the minor T-allele decreasing the likelihood of IL-4 activity. From our observed association between a low IL-4 producing promoter T-allele and prostate cancer risk, our study suggests an anti-tumor role for IL-4 in prostate cancer. While we saw no association for IL-5 or IL-13 gene variants and prostate cancer risk, our findings call for further evaluation of IL-4 as a contributor to prostate cancer susceptibility.
15: Molecular systems biology, 2010 Apr 13, 6(38)
Short-term memory in gene induction reveals the regulatory principle behind stochastic IL-4 expression.
[Abstract]Although cell-to-cell variability has been recognized as an unavoidable consequence of stochasticity in gene expression, it may also serve a functional role for tuning physiological responses within a cell population. In the immune system, remarkably large variability in the expression of cytokine genes has been observed in homogeneous populations of lymphocytes, but the underlying molecular mechanisms are incompletely understood. Here, we study the interleukin-4 gene (il4) in T-helper lymphocytes, combining mathematical modeling with the experimental quantification of expression variability and critical parameters. We show that a stochastic rate-limiting step upstream of transcription initiation, but acting at the level of an individual allele, controls il4 expression. Only a fraction of cells reaches an active, transcription-competent state in the transient time window determined by antigen stimulation. We support this finding by experimental evidence of a previously unknown short-term memory that was predicted by the model to arise from the long lifetime of the active state. Our analysis shows how a stochastic mechanism acting at the chromatin level can be integrated with transcriptional regulation to quantitatively control cell-to-cell variability.
16: Journal of visualized experiments : JoVE, 2010, 184(38)
Using an automated cell counter to simplify gene expression studies: siRNA knockdown of IL-4 dependent gene expression in Namalwa cells.
[Abstract]The use of siRNA mediated gene knockdown is continuing to be an important tool in studies of gene expression. siRNA studies are being conducted not only to study the effects of downregulating single genes, but also to interrogate signaling pathways and other complex interaction networks. These pathway analyses require both the use of relevant cellular models and methods that cause less perturbation to the cellular physiology. Electroporation is increasingly being used as an effective way to introduce siRNA and other nucleic acids into difficult to transfect cell lines and primary cells without altering the signaling pathway under investigation. There are multiple critical steps to a successful siRNA experiment, and there are ways to simplify the work while improving the data quality at several experimental stages. To help you get started with your siRNA mediated gene knockdown project, we will demonstrate how to perform a pathway study complete from collecting and counting the cells prior to electroporation through post transfection real-time PCR gene expression analysis. The following study investigates the role of the transcriptional activator STAT6 in IL-4 dependant gene expression of CCL17 in a Burkitt lymphoma cell line (Namalwa). The techniques demonstrated are useful for a wide range of siRNA-based experiments on both adherent and suspension cells. We will also show how to streamline cell counting with the TC10 automated cell counter, how to electroporate multiple samples simultaneously using the MXcell electroporation system, and how to simultaneously assess RNA quality and quantity with the Experion automated electrophoresis system.
17: Molecular immunology, 2010 Apr 12, 6(38)
IL-4 directs both CD4 and CD8 T cells to produce Th2 cytokines in vitro, but only CD4 T cells produce these cytokines in response to alum-precipitated protein in vivo.
[Abstract]While IL-4 directs CD4 T cells to produce Th2 cytokines (including IL-4, IL-13, IL-5) in vitro it has been shown that production of these cytokines can be induced in vivo in the absence of IL-4/IL-13/STAT-6 signaling. The present report shows that CD8 as well as CD4 T cells activated through their TCR, in vitro upregulate the Th2-features - IL-4, IL-13, IL-5, and GATA-3. However, in vivo while alum-precipitated antigen strongly and selectively induces these Th2-features in CD4 T cells, CD8 T cells mount a markedly different response to this antigen. This CD8 response is associated with strong proliferation and production of IFN-gamma, but no Th2-features are induced. Alum-protein formulations are widely used in human vaccines and typically induce strong antibody responses characterized by the differentiation of IL-4-producing CD4 T cells and immunoglobulin class switching to IgG1. Nevertheless, the mechanism responsible for CD4 Th2 and follicular helper T cell commitment triggered by these alum-protein vaccines is still poorly understood. Analysis of the in vivo response to alum-precipitated protein shows that while subsets of CD4 T cells strongly upregulate Th2 and follicular helper T cell features including the surface markers OX40, CXCR5, PD-1, IL-17RB and the transcription factor c-Maf, CD8 T cells do not. These discrete differences between responding CD4 and CD8 T cells provide further insight into the differences between Th2 polarization of CD4 T cells directed by IL-4 in vitro and the induction of IL-4 production by CD4 T cells in vivo in response to alum-precipitated protein.
18: The Journal of allergy and clinical immunology, 2010 Apr 12, 6(38)
In vivo regulation of the allergic response by the IL-4 receptor alpha chain immunoreceptor tyrosine-based inhibitory motif.
[Abstract]BACKGROUND: Signaling by IL-4 and IL-13 through the IL-4 receptor alpha chain (IL-4Ralpha) plays a critical role in the pathology of allergic diseases. The IL-4Ralpha is endowed with an immunoreceptor tyrosine-based inhibitory motif (ITIM) centered on tyrosine 709 (Y709) in the cytoplasmic domain that binds a number of regulatory phosphatases. The function of the ITIM in the in vivo regulation of IL-4 receptor signaling remains unknown. OBJECTIVE: We sought to determine the in vivo function of the IL-4Ralpha ITIM by using mice in which the ITIM was inactivated by mutagenesis of the tyrosine Y709 residue into phenylalanine (F709). METHODS: F709 ITIM mutant mice were derived by means of knock-in mutagenesis. Activation of intracellular signaling cascades by IL-4 and IL-13 was assessed by means of intracellular staining of phosphorylated signaling intermediates and gene expression analysis. In vivo responses to allergic sensitization were assessed by using models of allergic airway inflammation. RESULTS: The F709 mutation increased signal transducer and activator of transcription 6 phosphorylation by IL-4 and, disproportionately, by IL-13. This was associated with exaggerated T(H)2 polarization, enhanced alternative macrophage activation by IL-13, augmented basal and antigen-induced IgE responses, and intensified allergen-induced eosinophilic airway inflammation and hyperreactivity. CONCLUSIONS: These results point to a physiologic negative regulatory role for the Y709 ITIM in signaling through IL-4Ralpha, especially by IL-13.
19: Journal of immunology (Baltimore, Md. : 1950), 2010 Mar 10, 184(6)
T Cell Ig Domain and Mucin Domain 1 Engagement on Invariant NKT Cells in the Presence of TCR Stimulation Enhances IL-4 Production but Inhibits IFN-{gamma} Production.
[Abstract]The T cell Ig domain and mucin domain (TIM)1 protein expressed on the surface of Th2 cells regulates the immune response by modulating cytokine production. However, the functional roles of TIM1 have not been examined in NKT cells. Therefore, we investigated the immunologic effects of TIM1 on NKT cells. We found that mouse NK1.1(+)TCR-beta(+), alpha-galactosyl ceramide/CD1d dimer(+) NKT, and NKT hybridoma (DN32.D3) cells constitutively express TIM1 and TIM4 on their surface. Engagement of TIM1 on NKT cells by any of several anti-TIM1 mAbs suppressed the production of IFN-gamma in the presence of TCR stimulation in vitro and in vivo, whereas the effects of such engagement on Th2 cytokine production by the NKT cells varied with the particular anti-TIM1 Ab clone. Moreover, in DN32.D3 TIM4-knockdown NKT hybridoma cells, TIM1 engagement by rTIM1 or TIM4 enhanced IL-4 production while inhibiting IFN-gamma production in the presence of alpha-galactosyl ceramide stimulation. TIM1 engagement increased GATA-3 expression but reduced T-bet expression in NKT cells in the presence of TCR engagement. The adoptive transfer of NKT cells preincubated with anti-TIM1 mAbs into Jalpha18(-/-) mice aggravated bleomycin-induced pulmonary fibrosis by suppressing IFN-gamma production. Taken together, these results suggest that TIM1 costimulation on NKT cells enhances the cellular production of IL-4 while inhibiting the production of IFN-gamma. Thus, as a differential regulator of the immune response, TIM1 on NKT cells may be a useful therapeutic target for immune diseases.
20: Chest, 2010 Feb 5, 30(3)
Airway wall expression of OX40/OX40L and IL-4 in Asthma.
[Abstract]BACKGROUND: The co-stimulatory molecules OX40 and OX40 ligand (L) mediate key aspects of allergic airway inflammation in animal models of asthma including eosinophilic airway inflammation, airway hyperresponsiveness and Th2 polarization. We sought to examine OX40/OX40L and IL-4 expression in asthma across severities. METHODS: Bronchial biopsies were obtained from 27 subjects with asthma (mild GINA 1 [n=10], moderate GINA 2-3 [n=7] and severe GINA 4-5 [n=10]) and 13 healthy controls. The number of OX40+, OX40L+, IL-4+, and IL-4Ralpha+ cells in the lamina propria and airway smooth muscle (ASM) bundle and the intensity of IL-4Ralpha+ expression by the ASM was assessed. RESULTS: The number of OX40+, OX40L+, and IL-4+ cells in the lamina propria and OX40+ and IL-4+ cells in the ASM-bundle was significantly increased in subjects with mild asthma, but not in those with moderate or severe asthma, compared to healthy controls. In the subjects with asthma OX40/OX40L expression was positively correlated with the number of eosinophils and IL-4+ cells in the lamina propria. The number of IL-4Ralpha+ cells in the lamina propria was significantly increased in moderate to severe disease, but not mild asthma, compared to controls. IL-4Ralpha expression by the ASM-bundle was not different between groups. CONCLUSION: OX40/OX40L expression is increased in the bronchial submucosa in mild asthma, but not in moderate to severe disease and is related to the degree of tissue eosinophilia and IL-4 expression. Whether these co-stimulatory molecules have a role as targets for asthma requires further investigation.
21: Brain, behavior, and immunity, 2010 Feb 4, 30(3)
Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization.
[Abstract]Peripheral activation of the immune system by infectious agents triggers the brain-cytokine system causing sickness behaviors which profoundly impact well-being. Dietary fiber is a beneficial foodstuff that, from a gastrointestinal tract perspective, exists in both insoluble and soluble forms. We show that a diet rich in soluble fiber protects mice from endotoxin-induced sickness behavior by polarizing mice Th2 when compared to a diet containing only insoluble fiber. Mice fed soluble fiber became less sick and recovered faster from endotoxin-induced sickness behaviors than mice fed insoluble fiber. In response to intraperitoneal endotoxin, mice fed soluble fiber had up-regulated IL-1RA and reduced IL-1beta and TNF-alpha in the brain as compared to mice fed insoluble fiber. Importantly, mice fed soluble fiber had a basal increase in IL-4 in the ileum and spleen which was absent in MyD88 knockout mice. Con A stimulated splenocytes from mice fed soluble fiber showed increased IL-4 and IL-5 and decreased IL-2, IL-12 and IFN-gamma when compared to mice fed insoluble fiber. Likewise, endotoxin-stimulated macrophages from mice fed soluble fiber demonstrated decreased IL-1beta, TNF-alpha, IFN-gamma, IL-12 and nitrate and increased IL-1RA, arginase 1 and Ym1 when compared to mice fed insoluble fiber. Finally, the behavioral protection afforded by feeding mice soluble fiber was reduced in IL-4 knockout mice, as was the impact of soluble fiber on Con A stimulated splenocytes and endotoxin activated macrophages. These data show that a diet rich in soluble fiber protects against endotoxin-induced sickness behavior by polarizing mice Th2 and promoting alternative activation of macrophages.
22: Immunological investigations, 2010 Jan, 39(2)
Phytoglycoprotein (75 kDa) Suppresses Release of Histamine and Expression of IL-4 and IFN- gamma in BPA-treated RBL-2H3 Cells.
[Abstract]The current study investigated whether the phytoglycoprotein (75 kDa) isolated from Cudrania tricuspidata Bureau (CTB glycoprotein) has anti-allergic inflammatory potential. Bisphenol A (BPA) is well known to promote development of allergy-related immune dysfunction. This experiment evaluated the release of histamine, increased intracellular Ca(2+) level, and the activities of protein kinase C alpha (PKC alpha), transcription factors NFkappaB and cytokines (IL-4, and IFN-gamma) in BPA-treated RBL-2H3 cells. The results in this study showed that the phytoglycoprotein (75 kDa) inhibits the intracellular Ca(2+) level, translocation of PKC alpha from cytosol to membrane and the translocation of NF-kappaB in cells. We also found that the phytoglycoprotein (75 kDa) inhibits the release of histamine, and the expressions of cytokines (IL-4 and IFN-gamma) in the presence of BPA in RBL-2H3 cells. The results obtained from these experiments indicated that the phytoglycoprotein (75 kDa) inhibits release of histamine and expressions of IL-4, and IFN-gamma via down regulations of Ca(2+)/PKCalpha and NF-kappaB on the stage of degranulation induced by BPA. From point of view, we speculated that the phytoglycoprotein (75 kDa) is one of natural compounds that can block allergic-inflammation caused by BPA.
23: European journal of immunology, 2010 Apr, 40(4)
SUMOylation attenuates c-Maf-dependent IL-4 expression.
[Abstract]The function of transcription factors can be critically regulated by SUMOylation. c-Maf, the cellular counterpart of v-maf oncogene, is a potent transactivator of the IL-4 gene in Th2 cells. We found in a yeast two-hybrid screen that c-Maf can interact with Ubc9 and PIAS1, two key enzymes of the SUMOylation pathway. In this study, we report that c-Maf co-localized with these two SUMO (small ubiquitin-like modifier) ligases in the nucleus and that c-Maf can be SUMOylated in vitro and also in primary Th2 cells. We also demonstrated that lysine-33 is the dominant, if not the only, SUMO acceptor site of c-Maf. SUMOylation of c-Maf attenuated its transcriptional activity. Reciprocally, a SUMOylation resistant c-Maf was more potent than WT-c-Maf in driving IL-4 production in c-Maf-deficient Th2 cells. Furthermore, we showed that ablation of the SUMO site did not alter the subcellular localization or the stability of c-Maf protein but instead enhanced its recruitment to the Il4-promoter. We conclude that SUMOylation at lysine-33 is a functionally critical post-translational modification event of c-Maf in Th cells.
24: The Journal of allergy and clinical immunology, 2010 Jan, 125(1)
Identification of a novel subset of human circulating memory CD4(+) T cells that produce both IL-17A and IL-4.
[Abstract]BACKGROUND: IL-17A has been suggested to play a pathogenic role in bronchial asthma and other allergic disorders. OBJECTIVE: Study of the relationship between human IL-17A-producing CD4(+) T(H) cells (T(H)17) and IL-4-producing CD4(+) T(H) (T(H)2) cells. METHODS: T-cell clones generated from the CCR6(+)CD161(+) fraction of human circulating CD4(+) T cells, which contains virtually all T(H)17 cells, as well as circulating CD4(+) T cells from both healthy subjects and patients with asthma, were assessed by flow cytometry for their cytokine production profile. RESULTS: A small proportion of CCR6(+)CD161(+)CD4(+) T-cell clones showed the ability to produce both IL-17A and IL-4 (T(H)17/T(H)2). T(H)17/T(H)2 clones also produced IL-5, IL-8, IL-9, IL-13, IL-21, and IL-22 and displayed the ability to induce the in vitro secretion of IgE. A very few T(H)17/T(H)2 cells were found among circulating CD4(+) T cells from normal subjects, but their proportions were significantly increased in the circulation of patients with chronic asthma. T(H)17/T(H)2 cells could not be derived from naive umbilical cord blood CD4(+) T cells under any experimental condition. However, when circulating memory CCR6(+)CD161(+)CD4(+) T cells were cloned under appropriate polarizing conditions, T(H)17/T(H)2 clones originated in the presence of IL-4, suggesting that an IL-4-rich microenvironment may induce the shifting of memory T(H)17 cells into T(H)17/T(H)2 cells. CONCLUSION: Because of its peculiar functional properties and the increased numbers in the circulation of patients with bronchial asthma, this previously unknown population of T(H)17/T(H)2 cells may play some role in the pathogenesis of this disease.
25: Cellular immunology, 2010 Jan 4, 107(2)
Role of IL-4 in aversion induced by food allergy in mice.
[Abstract]To ascertain the role of IL-4 in aversion to antigen induced by food allergy, wild type and IL-4 deficient BALB/c mice were sensitized with ovalbumin and challenged orally with egg white. Sensitized wild type mice had increased production of IL-4 by spleen and mesenteric lymph node cells in vitro, higher levels of serum anti-ovalbumin IgE and IgG1, aversion to ingestion of the antigen and loss of body weight after continuous oral challenge. Intestinal changes in wild type sensitized mice included eosinophil infiltration and increased mucus production. The IL-4 deficiency impaired the development of food allergy and the aversion to antigen, suggesting the involvement of the antigen specific antibodies. When IL-4 deficient mice received serum from sensitized wild type donors, the aversion was restored. These results indicate that production of IL-4 and specific IgE/IgG1 antibodies correlate with aversion to antigen induced by food allergy in mice.
26: The Journal of veterinary medical science / the Japanese Society of Veterinary Science, 2009 Dec, 71(12)
Molecular cloning and sequencing of the cDNAs encoding the bat interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12p40, and tumor necrosis factor-alpha.
[Abstract]This is the first report on the cDNA sequences of bat interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12 p40, and tumor necrosis factor (TNF)-alpha. The cDNAs of bat IL-2, IL-4, IL-6, IL-10, IL-12 p40, and TNF-alpha comprise 459, 405, 624, 537, 990, and 699 base pairs respectively. Moreover, each of the cDNAs of bat IL-2, IL-4, IL-6, IL-10, IL-12 p40, and TNF-alpha contain a single open reading frames encoding 152, 134, 207, 178, 329, and 232 amino acids, respectively. The comparison of bat cytokines with Perrissodactyla (horse), Carnivora (dog and cat), and Cetartiodactyla (cattle and pig) orthologs revealed a high degree of homology. Although the N-terminal amino acids and cysteine residues are highly conserved in each mature cytokine, the deduced N-linked glycosylation sites vary across species.
27: Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology, 2009 Dec, 17(6)
[Influence of Intra-bone Marrow Infusion of Donor Lymphocytes on Development of Graft-Versus-Host Disease and Level of IL-4 and IFN-gamma in Peripheral Blood.]
[Abstract]To investigate the effect of donor lymphocyte infusion (DLI) by intra-bone marrow (IBM) routes on the incidence of graft-versus-host disease(GVHD), level of IL-4 and IFN-gamma after allogeneic peripheral hematopoietic stem cell transplantation (allo-PBSCT). Female C57BL/6 mice as recipients received total body irradiation (TBI) on day 0, followed by injection of peripheral hematopoietic stem cells from mobilized donor of male BALB/c with the granulocyte-colony stimulating factor (rhG-CSF), and DLI was performed via ether IV or IBM routes. The severity of GVHD was compared in recipients received allogeneic IBM-DLI with those mice received IV-DLI; at 14 days after DLI, the levels of IL-4 and interferon (IFN)-gamma were tested by ELISA. The results showed that as compared with IV-DLI group the frequency and severity of GVHD were reduced in IBM-DLI (p < 0.01); the level of IL-4 significantly increased, while the level of IFN-gamma decreased in group IV-DLI (p < 0.01). It is concluded that IBM-DLI declines the incidence and severity of GVHD after allo-PBSCT.
28: Cryobiology, 2009 Sep 18, 206(10)
Effect of cryopreservation on IL-4, IFNgamma and IL-6 production of porcine peripheral blood lymphocytes.
[Abstract]Cryopreservation of animal or human peripheral blood mononuclear cells (PBMC) is a commonly used technique. Effects of cryopreservation on functional capacity, especially the cytokine production of human PBMCs, have been extensively defined. However, certain animals, such as livestock, are a shortage of these information. Here we investigated the effects of cryopreservation on cytokine (IL-4, IFNgamma and IL-6) production of porcine PBMC. The porcine PBMCs were cryopreserved at -196 degrees C for a variety time periods for 2, 5, 25 and 50days. Viability and cytokine production of the porcine PBMCs were measured before and after cryopreservation. The results showed that about 90% cell recovery rate was obtained at each storage time, indicating that about 10% loss of PBMCs in this short-term cryopreservation was due to the freezing process rather than the duration of cryopreservation. The fresh or frozen resting porcine PBMCs produced little cytokines in the absence of stimulation. However, three cytokines were apparently increased after PMA stimulation in both fresh and frozen porcine PBMCs. The sensitivity of frozen cells to PMA simulation for IFNgamma and IL-6 production was different from that of the fresh ones. IFNgamma production from the frozen PBMCs was significantly higher than that from the fresh ones (P<0.01). In contrast, IL-6 level from the frozen sample was significantly lower than that from the fresh one (P<0.05). Those results indicate that cryopreservation can increase the sensitivity of porcine PBMCs stimulated by PMA for IFNgamma production but not for IL-6 production. There was no significant difference of IL-4 production between fresh and frozen cells either stimulated (P>0.05) or un-stimulated (P>0.05).
29: Blood, 2009 Sep 17, 206(10)
GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF-{alpha} converting enzyme (TACE).
[Abstract]Monocytes give rise to macrophages, osteoclasts (OCs), and dendritic cells (DCs). M-CSF and RANK ligand induce OC differentiation from monocytes, while GM-CSF and IL-4 trigger monocytic differentiation into DCs. These two differentiation pathways occur in a mutually exclusive manner. However, regulatory mechanisms for the polarization of monocytic differentiation are still unclear. The present study was undertaken to clarify the mechanism of triggering the deflection of OC and DC differentiation from monocytes. GM-CSF and IL-4 abolished monocytic differentiation into OCs while inducing DC differentiation even in the presence of M-CSF and RANK ligand. GM-CSF and IL-4 in combination potently up-regulate TNF-alpha converting enzyme (TACE) expression and activity in monocytes, causing ectodomain shedding of the membrane-bound M-CSF receptor, resulting in the disruption of its phosphorylation by M-CSF as well as the induction of osteoclastogenesis from monocytes by M-CSF and RANK ligand. Interestingly, TACE inhibition robustly causes the resumption of the surface expression of M-CSF receptors on monocytes, which facilitates M-CSF-mediated phosphorylation of M-CSF receptors and macrophage/OC differentiation while impairing GM-CSF and IL-4-mediated DC differentiation from monocytes. These results reveal a novel proteolytic regulation of M-CSF receptor expression in monocytes to control M-CSF signaling and monocytic differentiation into macrophage/OC-lineage cells or DCs.
30: Blood, 2009 Nov 19, 114(21)
Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes.
[Abstract]Alternatively activated macrophages (AAMs), triggered by interleukin-4 (IL-4) and IL-13, play a modulating role during Th2 cytokine-driven pathologies, but their molecular armament remains poorly characterized. Here, we established E-cadherin (Cdh1) as a selective marker for IL-4/IL-13-exposed mouse and human macrophages, which is STAT6-dependently induced during polarized Th2 responses associated with Taenia crassiceps helminth infections or allergic airway inflammation. The IL-4-dependent, arginase-1/ornithine decarboxylase-mediated production of polyamines is important for maximal Cdh1 induction, unveiling a novel mechanism for IL-4-dependent gene transcription. At the macrophage surface, E-cadherin forms a functional complex with the catenins that accumulates at sites of cell contact. Macrophage-specific deletion of the Cdh1 gene illustrates the implication of E-cadherin in IL-4-driven macrophage fusion and heterotypic interactions with CD103(+) and KLRG1(+) T cells. This study identifies the E-cadherin/catenin complex as a discriminative, partly polyamine-regulated feature of IL-4/IL-13-exposed alternatively activated macrophages that contributes to homotypic and heterotypic cellular interactions.
31: Journal of leukocyte biology, 2009 Feb 19,
Endogenous suppression of mast cell development and survival by IL-4 and IL-10.
[Abstract]Mast cell development is an important component of atopic and chronic inflammatory diseases such as asthma, multiple sclerosis, rheumatoid arthritis, and atherosclerosis. In this study, we found that IL-4 and IL-10 were produced constitutively in cultures of developing mast cells, correlating with mast cell purity. Deletion of either gene increased mast cell numbers and FcepsilonRI expression during culture in IL-3 + stem cell factor (SCF). By adding exogenous IL-4 and IL-10 to bone marrow (BM) cultures containing IL-3 + SCF, we found that IL-4 + IL-10 suppressed mast cell development through mechanisms not used by either cytokine alone. IL-4 + IL-10 elicited a rapid cell death coincidental with reduced Kit receptor expression and signaling and enhanced mitochondrial damage and caspase activation. IL-4 or IL-10 costimulation, unlike either cytokine alone, altered mast cell ontogeny to yield predominantly macrophages in cultures that typically produce mast cells. This effect was observed consistently with unseparated BM cells, purified mouse BM stem cells, and erythrocyte-depleted human umbilical cord blood cells. These experiments demonstrated a major role for Stat6 and Stat3, but not the Stat3-induced transcriptional repressor Ets variant gene 3. Genetic background was also a critical factor, as BALB/c-derived BM cells were completely resistant to IL-10-mediated killing and expressed lower levels of IL-10R. Collectively, these results support the theory that IL-4 and IL-10 function as endogenous regulators of mast cell progenitor development, consistent with a role in immune homeostasis. Loss of this homeostasis, perhaps via genetic polymorphism, could contribute to the etiology of mast cell-associated disease.
32: Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 2009 Feb, 11(2)
[Effects of montelukast and BCG-PSN on the expression of STAT5b mRNA and IL-4 mRNA in blood mononuclearcells of rats with asthma.]
[Abstract]OBJECTIVE: To study the expression of signal transducer and activator of transcription 5b (STAT5b) mRNA and interleukin-4 (IL-4) mRNA in blood mononuclearcells in a rat model of asthma and the effect of montelukast (MK) and BCG-polysaccharide and nucleic acid injection (BCG-PSN) on STAT5b mRNA and IL-4 mRNA expression. METHODS: Fifty-two male Sprague-Dawley rats (weight:140-200 g) were randomly divided into four groups¨²asthma, MKjtreated and BCG-PSN-treated and control groups. Rat model of asthma was prepared by ovalbumin (OVA) sensitization. The rats were sacrificed 24 hrs after the last sensitization. Blood eosinophils (EOS) were counted?Plasma contens of IL-4 and interferon-gamma (IFN-gamma) were measured using ELISA. Expression of STAT5b mRNA and IL-4 mRNA in blood mononuclearcells was detected with SYBR GREEN I fluorescent quantitation PCR method. RESULTS: Blood contents of STAT5b mRNA and IL-4 mRNA in the untreated asthma group were significantly higher than those in the other three groups (<0.01). Blood EOS count and plasma IL-4 contents in the untreated asthma group significantly increased, while plasma IFN-gamma contents significantly decreased compared with the other three groups (<0.01). There were no significant differences in the parameters measured among the MK-treated, the BCG-PSNjtreated and the control groups. STAT5b mRNA expression was positively correlated to IL-4 mRNA expression, IL-4 content and EOS count (r=0.730,0.650, 0.664, respectively; <0.01), but negatively correlated to IFN-gamma content (r=-0.798; <0.01). CONCLUSIONS: STAT5b mRNA and IL-4 mRNA were strongly expressed in blood mononuclearcells in rats with asthma, and there was a positive correlation between them?MK and BCG-PSN had inhibitory effects on the expression of STAT5b mRNA and IL-4 mRNA, which might be contributed to suppression of airway inflammation in asthma.
33: Blood, 2009 Feb 12, 11(2)
Host natural killer T cells induce an IL-4 dependent expansion of donor CD4+CD25+Foxp3+ Tregs that protects against graft-versus-host disease.
[Abstract]Though CD4(+)CD25(+) T cells (Tregs) and natural killer T cells (NKT cells) each protect against graft-versus-host disease (GVHD), interactions between these two regulatory cell populations after allogeneic bone marrow transplantation (BMT) have not been studied. We show that host NKT cells can induce an in vivo expansion of donor Tregs that prevents lethal GVHD in mice after conditioning with fractionated lymphoid irradiation (TLI) and anti-T cell antibodies, a regimen which models human GVHD-protective non-myeloablative protocols using TLI and anti-thymocyte globulin (ATG) followed by allogeneic hematopoietic cell transplantation (HCT). GVHD protection was lost in NKT cell-deficient Jalpha18(-/-) hosts and IL-4(-/-) hosts, or when the donor transplant was Treg-depleted. Add-back of donor Tregs or wild-type host NKT cells restored GVHD protection. Donor Treg proliferation was lost in IL-4(-/-) hosts or when IL-4(-/-) mice were used as the source of NKT cells for adoptive transfer, indicating that host NKT cell augmentation of donor Treg proliferation after TLI/ATS is IL-4-dependent. Our results demonstrate that host NK T cells and donor Tregs can act synergistically after BMT, and provide a mechanism by which strategies designed to preserve host regulatory cells can augment in vivo donor Treg expansion to regulate GVHD after allogeneic HCT.
34: Molecular immunology, 2009 Feb 2, 182(4)
IL-4 increases CD21-dependent infection of pulmonary alveolar epithelial type II cells by EBV.
[Abstract]EBV infection has been implicated in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). Viral infection may occur from the early or late stage in IPF development. Whether alveolar epithelial cells, AECs, normally express EBV main receptor, CD21, remains uncertain. Such situations prompted us to exploit an efficient direct infection system to investigate EBV receptor repertoire in primary human AECs. Using human primary type 2 AECs, which have been grown in basal medium supplemented with 10ng/ml Keratinocyte Growth Factor, and type 1 AECs, supplemented with Epithelial Growth Factor, both AEC lines express CD21 mRNA and protein with a significant increase in type 2 cells. Type 2 AECs have been exposed to TGFbeta1 and IL-4, whose expression is associated with IPF development. CD21 is highly expressed in type 2 AECs following IL-4 exposure. EBV bound to type 2 AECs membrane increases significantly following pre-treatment with IL-4 (p<0.001) and decreasing antagonizing CD21 receptor (p<0.01). 200mug/ml G418-mediated selection of EBV-Neomycin resistant infected cells selected IL-4 pre-exposed type 2 AECs. Our study of a viral cell line model provides evidence to suggest that CD21-dependent viral entry plays a crucial role in type 2 AECs, indicative of an IL-4 response EBV infection in IPF.