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IL-4 Receptor (il-4 + receptor)
Selected AbstractsFunctional epitope of common , chain for interleukin-4 bindingFEBS JOURNAL, Issue 5 2002Jin-Li Zhang Interleukin 4 (IL-4) can act on target cells through an IL-4 receptor complex consisting of the IL-4 receptor , chain and the common , chain (,c). An IL-4 epitope for ,c binding has previously been identified. In this study, the ,c residues involved in IL-4 binding were defined by alanine-scanning mutational analysis. The epitope comprises ,c residues I100, L102, and Y103 on loop EF1 together with L208 on loop FG2 as the major binding determinants. These predominantly hydrophobic determinants interact with the hydrophobic IL-4 epitope composed of residues I11, N15, and Y124. Double-mutant cycle analysis revealed co-operative interaction between ,c and IL-4 side chains. Several ,c residues involved in IL-4 binding have been previously shown to be mutated in X-linked severe combined immunodeficiency. The importance of these binding residues for ,c function is discussed. These results provide a basis for elucidating the molecular recognition mechanism in the IL-4 receptor system and a paradigm for other ,c -dependent cytokine receptor systems. [source] Cytokine-mediated control of lipopolysaccharide-induced activation of small intestinal epithelial cellsIMMUNOLOGY, Issue 3 2007Michael Lotz Summary Cytokines with anti-inflammatory properties have been implicated in the prevention of inappropriate immune activation by commensal bacteria in the intestinal tract. Here, we analysed receptor expression, cellular signalling, and the inhibitory activity of interleukin (IL)-4, -10, -11, and -13 as well as of transforming growth factor-, on lipopolysaccharide-mediated small intestinal epithelial cell activation. Only IL-4 and IL-13 had a significant inhibitory effect on chemokine secretion and nitric oxide (NO) production in differentiated and polarized cells. Reverse transcription,polymerase chain reaction of primary intestinal epithelial cells obtained by laser-microdissection confirmed expression of the type II IL-4 receptor consisting of the IL-4 receptor , and the IL-13 receptor ,1. Also, IL-4 or IL-13 led to rapid signal transducer and activator of transcription 6 phosphorylation, diminished inducible NO synthase expression, and enhanced the antagonistic arginase 1 activity. In conclusion, cytokines such as IL-4 and IL-13 affect intestinal epithelial cells and exhibit a modulating activity on Toll-like receptor-4-mediated epithelial cell activation. [source] PIBF: The Double Edged Sword.AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2010Pregnancy, Tumor Citation Szekeres-Bartho J, Polgar B. PIBF: The Double Edged Sword. Pregnancy and Tumor. Am J Reprod Immunol 2010; 64: 77,86 Problem, The role of progesterone-dependent immunomodulation in the maintenance of normal pregnancy. Methods,In vitro and in vivo data on the effect that progesterone and its mediator progesterone-induced blocking factor (PIBF) exert on the immune functions of pregnant women are reviewed, together with clinical findings. Results, Activated pregnancy lymphocytes express progesterone receptors, which enable progesterone to induce a protein called PIBF. PIBF increases Th2 type cytokine production by signaling via a novel type of IL-4 receptor and activating the Jak/STAT pathway. PIBF inhibits phosholipase A2, thus reduces prostaglandin synthesis. PIBF inhibits perforin release in human decidual lymphocytes and reduces the deleterious effect of high NK activity on murine pregnancy. PIBF production is a characteristic feature of normal human pregnancy, and its concentration is reduced in threatened pregnancies. PIBF mRNA and protein are expressed in a variety of malignant tumors. Inhibition of PIBF synthesis increases survival rates of leukemic mice. Conclusion, Progesterone-induced blocking factor is produced by pregnancy lymphocytes and also by malignant tumors. The PIBF-induced Th2-dominant immune response is favorable during pregnancy but might facilitate tumor growth by suppressing local antitumor immune responses. [source] Role of Interleukins and Transforming Growth Factor-, in Chronic Rhinosinusitis and Nasal PolyposisTHE LARYNGOSCOPE, Issue 4 2005Dewayne T. Bradley MD Abstract Objectives: To determine the role of interleukin (IL)-4, IL-4 receptor (R), IL-6, IL-8, IL-11, and transforming growth factor (TGF)-, in chronic rhinosinusitis (CRS) and chronic rhinosinusitis with nasal polyposis (CRS/NP). Methods: Sinus tissue from patients undergoing endoscopic sinus surgery for CRS and CRS/NP was collected. Sinus tissue was then analyzed using reverse-transcription polymerase chain reaction (RT-PCR) to detect transcription of IL-4R, IL-6, IL-8, and IL-11. Sinus tissue samples were also cultured in vitro, treated with IL-4 for 24 hours, and real-time PCR was used to quantify the transcription of TGF-,. Results: Twenty patients were evaluated, 9 with CRS/NP and 11 with CRS alone. The mean age was 43 (20,74) years, with 13 females and 7 males. IL-4R, IL-6, IL-8, and IL-11 were identified by RT-PCR in all 20 patients. The transcription of TGF-, was found to be 3.2 times greater in patients with CRS/NP than in patients with CRS alone (P = .047). Conclusion: IL-6, IL-8, and IL-11 are nonspecific markers of sinus inflammation being transcribed in patients with CRS and patients with CRS/NP. However, patients with CRS/NP demonstrate increased transcription of TGF-, in response to IL-4 treatment, suggesting an IL-4 mediated mechanism for stromal proliferation in the formation of nasal polyposis. [source] Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin-4 from T cellsARTHRITIS & RHEUMATISM, Issue 1 2006Jörg H. W. Distler Objective Monocyte chemoattractant protein 1 (MCP-1; CCL2) has been implicated in the pathogenesis of fibrotic diseases and is up-regulated in patients with systemic sclerosis (SSc). The aim of the present study was to examine the mechanisms by which MCP-1 mediates its profibrotic effects in the setting of SSc. Methods The expression of receptors for MCP-1 on dermal fibroblasts was analyzed by real-time polymerase chain reaction and fluorescence-activated cell sorting. The ability of extracellular matrix proteins to bind and release MCP-1 was quantified by enzyme-linked immunosorbent assay. Th0 cells were isolated using a magnetic-activated cell sorting system and were stimulated twice in the presence of MCP-1. The synthesis of collagen was measured using the Sircol collagen assay kit. Results The glycosaminoglycan chondroitin sulfate, but not fibronectin or collagens, bound and released MCP-1 in a time-dependent manner. MCP-1 that was released from chondroitin sulfate induced the differentiation of interleukin-4 (IL-4),producing T cells in a dose-dependent manner. In turn, dermal fibroblasts from patients with SSc expressed IL-4 receptor, and stimulation with IL-4 significantly increased the production of collagen in dermal fibroblasts. In contrast, CCR2a and CCR2b, as well as D6 and US28 (other potential receptors of MCP-1), were not detectable in SSc and normal fibroblasts, and their expression was not induced by platelet-derived growth factor, IL-1,, or IL-4. In addition, MCP-1 had no direct effects on collagen production by fibroblasts. Conclusion MCP-1 has no direct effects on dermal fibroblasts but contributes to fibrosis in patients with SSc by inducing the differentiation of IL-4,producing T cells. Because MCP-1 has both proinflammatory and profibrotic effects, pharmacologic targeting of MCP-1 could be a promising therapeutic approach in SSc. [source] Haplotypes of the interleukin-4 receptor , chain gene associate with susceptibility to and severity of atopic asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 10 2004A.-M. Hytönen Summary Background Development of asthma is likely to depend on a complex interaction between environmental and genetic factors. Several groups have suggested the gene of the IL-4 receptor , chain (IL4R) as a candidate gene for the development of asthma, although association with single polymorphisms has shown contradicting results. Objective We chose to analyse IL4R gene haplotypes and assess their possible relevance in susceptibility to asthma and to certain clinical phenotypes. Methods IL4R gene haplotypes were analysed, based on the three markers C-3223T, Q551R and I50V, using the expectation,maximization algorithm, in 170 atopic asthma patients and 350 controls, all adult Swedish Caucasians. Results Our data showed significantly higher levels of soluble IL-4R (sIL-4R) in asthma patients compared with controls (P<0.0001). Furthermore, we showed a significant association between the IL4R haplotype containing the alleles T-3223, V50 and R551 (TVR) of the IL4R gene, and susceptibility to atopic asthma, with a frequency of 6.5% in the patients compared with 1% in the controls (P<0.0005). A subgroup of patients with heterozygous or homozygous state for the T-3223, V50 and R551 alleles, also had lower levels of sIL-4R in their circulation compared with patients with homozygous state in the C-3223, I50 and Q551 alleles (P<0.05) and showed less severe asthma according to lung function test (P<0.05). Analysis of single markers showed the T-3223 IL4R allele to associate with lower serum levels of sIL-4 receptor (P<0.0001) and patients carrying the T allele also had more symptoms of active asthma (wheezing, P<0.01; coughing, P<0.05 and breathing difficulties, P<0.01). Conclusion Our data suggest that asthmatic patients with low levels of sIL-4 receptor may represent a genetically distinct subgroup of atopic asthma. TVR haplotype analyses confirm the importance of IL4R as a candidate gene for susceptibility to asthma. This finding may have implications for the understanding of the pathogenesis of asthma and possibly for the development of more specific therapies. [source] Interleukin-4 increases murine airway response to kinins, via up-regulation of bradykinin B1 -receptors and altered signalling along mitogen-activated protein kinase pathwaysCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2004M. Bryborn Summary Background IL-4 is believed to play a role in asthma and chronic obstructive pulmonary disease through promotion of eosinophilic inflammation and mucus hypersecretion. Whether IL-4 can induce a direct effect on airway smooth muscle remains unknown. Objective To investigate the effect of IL-4 on airway smooth muscle, focusing on the contractile response to des-Arg9 -bradykinin and bradykinin. Methods Tracheal segments from murine airways were cultured for 1,8 days in the absence and presence of IL-4. The smooth muscle response induced by des-Arg9 -bradykinin and bradykinin was investigated in myographs. Expression levels for the IL-4-, bradykinin B1 - and B2 -receptors were characterized using RT-PCR. Specific inhibitors were used to study signal changes along the IL-4 receptor- (IL-4R-) coupled mitogen-activated protein (MAP) kinase (MAPK) pathways. Results IL-4 treatment increased the contractile response to des-Arg9 -bradykinin and bradykinin in a concentration- and time-dependent manner. Dexamethasone and the transcriptional inhibitor actinomycin D blocked this effect. c-Jun N-terminal kinase inhibitor SP600125 also blocked the effect of both des-Arg9 -bradykinin and bradykinin, whereas p38 inhibitor SB203580 blocked only the former and the MAPKK inhibitor PD098059, only the latter agonist responses. IL-4 treatment increased the mRNA levels representing bradykinin B1 - but not B2 -receptors. Levels of IL-4R were not altered during culture. Conclusion Long-term exposure to IL-4 increases the contractile response induced by des-Arg9 -bradykinin and bradykinin in cultured murine airways. This effect appears to be mediated via an up-regulation of B1 -receptors and altered signalling along the MAPK pathways. [source] Interleukin-13 and tumour necrosis factor-, synergistically induce eotaxin production in human nasal fibroblastsCLINICAL & EXPERIMENTAL ALLERGY, Issue 3 2000Terada Background There is increasing evidence that eotaxin is a key mediator in the development of tissue eosinophilia. However, the mechanism involved in the production of eotaxin has yet to be clarified. Most recently, it has been shown that interleukin (IL) -4 induces eotaxin in dermal fibroblasts. A novel cytokine termed IL-13, which binds to the ,-chain of the IL-4 receptor, shares many biological activities with IL-4. It is known that fibroblasts express the IL-4 receptor and produce collagen type I upon stimulation with IL-4. Objective We investigated whether IL-13, as well as IL-4, are able to induce eotaxin production in human nasal mucosal fibroblasts (HNMFs). Furthermore, we investigated the effect of costimulation of IL-13 and TNF, on eotaxin production. Methods HNMFs, isolated from inferior nasal mucosa samples, were stimulated by various kind of cytokines for 1,36 h at 37 °C in 5% CO2. The change in the expression of eotaxin mRNA was then evaluated by reverse transcriptase-polymerase chain reaction and the Southern blot analysis. The amount of eotaxin in the culture media was measured by ELISA. Results IL-13 as well as IL-4 dose-dependently induced eotaxin expression in HNMFs. Furthermore, IL-13 and TNF, synergistically induced eotaxin expression in HNMFs, while they hardly induced eotaxin expression in endothelial cells, epithelial cells or eosinophils. The synergy was observed when pre-incubation of HNMFs with IL-13 was followed by a stimulation with TNF,, or HNMFs were simultaneously stimulated with IL-13 and TNF,. Conclusion These results strongly indicate that IL-13, as well as IL-4, may be important in eotaxin-mediated eosinophilic inflammation in nasal mucosa. In addition, in nasal mucosa, fibroblasts are the major cell source for eotaxin. [source] Interleukin-4 and interleukin-13 enhance CCL26 production in a human keratinocyte cell line, HaCaT cellsCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2005S. Kagami Summary Eotaxin-2/CCL24 and eotaxin-3/CCL26 are CC chemokines and their receptor, CC chemokine receptor 3 is preferentially expressed on eosinophils. It was reported that vascular endothelial cells and dermal fibroblasts produced CCL26. However, the regulation of CCL24 and CCL26 production in keratinocytes has not been well documented. We investigated the expression and production of CCL24 and CCL26 in the human keratinocyte cell line, HaCaT cells. Reverse transcription and polymerase chain reaction was performed using these cells and Enzyme-linked immunosorbent assay was carried out using supernatant of these cells. The production of CCL24 in HaCaT cells was slightly enhanced by IL-4 and that of CCL26 was strongly enhanced by IL-4 and IL-13. Furthermore, TNF-, generated a synergistic effect on IL-4 enhanced CCL26 production. Dexamethasone, IFN-, and the p38 mitogen-activated protein kinase inhibitor SB202190 inhibited IL-4 enhanced CCL26 production. IL-4 enhanced production of CCL26 was inhibited by leflunomide and JAK inhibitor 1, but not by JAK3 inhibitor, which indicates that it is mediated by JAK1-STAT6-dependent pathway. This result also strongly suggests the involvement of the type 2 IL-4 receptor in IL-4 enhanced production of CCL26. These results suggest that keratinocytes are involved in the migration of CC chemokine receptor 3 positive cells such as eosinophils in a Th2-dominant situation like atopic dermatitis. [source] Expression and structure of interleukin 4 receptors in primary meningeal tumorsCANCER, Issue 10 2005Sachin Puri M.Sc. Abstract BACKGROUND It was reported previously that malignant human tumors, like glioma and medulloblastoma, express high-density interleukin (IL-4) receptor mRNA and protein. Because IL-4 receptors (R) are sensitive targets for targeted therapeutics, knowledge of the expression of these receptors in other central nervous system tumors is of great interest. In this study, the authors examined the expression and subunit composition of IL-4R complex in primary human meningiomas. METHODS Reverse transcription-polymerase chain reaction (RT-PCR) analysis for IL-13R,1, IL-4R, and IL-2R,c was performed on total RNA extracted from 35 meningiomas and a normal human brain tissue sample. Results were confirmed in nine randomly selected tumors by quantitative real-time PCR and in situ immunofluorescence assay. RESULTS Transcripts for the IL-4R, and IL-13R,1 chains were overexpressed in meningiomas compared with normal brain tissue. The levels of IL-4R, mRNA appeared to be higher compared with the levels of IL-13R,1 mRNA. The results also showed that tumors with higher disease grade tended to have increased mRNA expression for the IL-4R, chain. This IL-4R, mRNA overexpression appeared to be more frequent in younger patients (age < 37 years). The transcripts for IL-2R,c chain were not detected in any of the tumor samples or in normal brain tissue. Quantitative real-time PCR confirmed the results of the RT-PCR analysis. Meningiomas also demonstrated a bright immunofluorescent staining for the IL-4R, and IL-13R,1 chains but no staining for IL-2R,c. CONCLUSIONS Expression of the IL-4R, and IL-13R,1 chains and absence of IL-2,c expression established that meningiomas expressed type II IL-4Rs. These receptors may serve as a target for cytotoxin/immunotoxin therapy in patients with meningioma who are not amenable to surgical resection or for recurrent tumors. Cancer 2005. © 2005 American Cancer Society. 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