Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis.
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ABSTRACT:
SUBMITTER: Iwaszko M
PROVIDER: S-EPMC8616130 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We have found that binding sites for interleukin-13 (IL-13) are overexpressed in a vast majority of high-grade astrocytomas (HGAs). These binding sites for IL-13 are distinct from the physiological receptor in that it does not bind IL-4. We also demonstrated that IL-13 receptor alpha 2 protein chain (IL-13Ralpha2), an IL-4-independent receptor for IL-13, is abundant among HGAs, but not in normal organs. To examine if IL-13Ralpha2 is the tumor-associated site for IL-13, we stably transfected normal Chinese hamster ovary (CHO) cells and glioma G-26 cells to express either human (h) or murine (m) IL-13Ralpha2. CHO-hIL-13Ralpha2(+) cells and G-26-h/mIL-13Ralpha2(+) cells, and not CHO and G-26 parental or mock-transfected cells, specifically bound IL-13 in an IL-4-independent manner. The IL-13Ralpha2(+) cells also became highly susceptible to the killing by an IL-13-based cytotoxic fusion protein. In loss of function studies, a HGA cell line, SNB-19, was transfected with antisense (as) hIL-13Ralpha2. as-SNB-19-hIL-13Ralpha2(+) cells lost their natural affinity towards IL-13 and became resistant to IL-13-based cytotoxins. The fact, that IL-13Ralpha2-positive cells bind IL-13 independent of IL-4, become susceptible to IL-13 cytotoxins, and cells deprived of IL-13Ralpha2 receptor lose these features, demonstrates that IL-13Ralpha2 is the brain tumor-associated receptor for IL-13.
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Project description:Interleukin (IL)-13 is a signature cytokine of type 2 inflammation important for the pathogenesis of various diseases, including allergic diseases. Signal transducer and activator of transcription (STAT) 6 is a critical transcriptional factor for the IL-13 signals; however, it remains unknown how expression of the IL-13-induced genes is differentiated by the transcriptional machineries. In this study, we identified IL-13-induced transcriptional factors in lung fibroblasts using DNA microarrays in which SOX11 was included. Knockdown of SOX11 down-regulated expression of periostin and CCL26, both of which are known to be downstream molecules of IL-13, whereas enforced expression of SOX11 together with IL-13 stimulation enhanced expression of periostin. Moreover, we found that in DNA microarrays combining IL-13 induction and SOX11 knockdown there exist both SOX11-dependent and -independent molecules in IL-13-inducible molecules. In the former, many inflammation-related and fibrosis-related molecules, including periostin and CCL26, are involved. These results suggest that SOX11 acts as a trans-acting transcriptional factor downstream of STAT6 and that in lung fibroblasts the IL-13 signals are hierarchically controlled by STAT6 and SOX11.
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Project description:Both interleukin-4 (IL-4) and IL-13 can bind to the shared receptor composed of the IL-4 receptor alpha chain and the IL-13 receptor alpha1 chain (IL-13Ralpha1); however, the mechanisms by which these ligands bind to the receptor chains are different, enabling the principal functions of these ligands to be different. We have previously shown that the N-terminal Ig-like domain in IL-13Ralpha1, called the D1 domain, is the specific and critical binding unit for IL-13. However, it has still remained obscure which amino acid has specific binding capacity to IL-13 and why the D1 domain acts as the binding site for IL-13, but not IL-4. To address these questions, in this study we performed mutational analyses for the D1 domain, combining the structural data to identify the amino acids critical for binding to IL-13. Mutations of Lys-76, Lys-77, or Ile-78 in c' strand in which the crystal structure showed interaction with IL-13, and those of Trp-65 and Ala-79 adjacent to the interacting site, resulted in significant impairment of IL-13 binding, demonstrating that these amino acids generate the binding site. Furthermore, mutations of Val-35, Leu-38, or Val-42 at the N-terminal beta-strand also resulted in loss of IL-13 binding, probably from decreased structural stability. None of the mutations employed here affected IL-4 binding. These results demonstrate that the D1 domain of IL-13Ralpha1 acts as an affinity converter, through direct cytokine interactions, that allows the shared receptor to respond differentially to IL-4 and IL-13.
| S-EPMC2782022 | biostudies-literature
Project description:ObjectiveThe adamalysin metalloproteinase 15 (ADAM15) has been shown to protect against development of osteoarthritis in mice. Here, we have investigated factors that control ADAM15 levels in cartilage.DesignSecretomes from wild-type and Adam15 -/- chondrocytes were compared by label-free quantitative mass spectrometry. mRNA was isolated from murine knee joints, either with or without surgical induction of osteoarthritis on male C57BL/6 mice, and the expression of Adam15 and other related genes quantified by RT-qPCR. ADAM15 in human normal and osteoarthritic cartilage was investigated similarly and by fluorescent immunohistochemistry. Cultured HTB94 chondrosarcoma cells were treated with various anabolic and catabolic stimuli, and ADAM15 mRNA and protein levels evaluated.ResultsThere were no significant differences in the secretomes of chondrocytes from WT and Adam15 -/- cartilage. Expression of ADAM15 was not altered in either human or murine osteoarthritic cartilage relative to disease-free controls. However, expression of ADAM15 was markedly reduced upon aging in both species, to the extent that expression in joints of 18-month-old mice was 45-fold lower than in that 4.5-month-old animals. IL-13 increased expression of ADAM15 in HTB94 ?cells by 2.5-fold, while modulators of senescence and autophagy pathways had no effect. Expression of Il13 in the joint was reduced with aging, suggesting this cytokine may control ADAM15 levels in the joint.ConclusionExpression of the chondroprotective metalloproteinase ADAM15 is reduced in aging human and murine joints, possibly due to a concomitant reduction in IL-13 expression. We thus propose IL-13 as a novel factor contributing to increased osteoarthritis risk upon aging.
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Project description:Expression of the adhesion molecule, CD146/MCAM/MelCAM, on T cells has been associated with recent activation, memory subsets and T helper type 17 (Th17) effector function, and is elevated in inflammatory arthritis. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA) and spondyloarthritides (SpA). Here, we compared the expression of CD146 on CD4(+) T cells between healthy donors (HD) and patients with RA and SpA [ankylosing spondylitis (AS) or psoriatic arthritis (PsA)] and examined correlations with surface markers and cytokine secretion. Peripheral blood mononuclear cells (PBMC) were obtained from patients and controls, and synovial fluid mononuclear cells (SFMC) from patients. Cytokine production [elicited by phorbol myristate acetate (PMA)/ionomycin] and surface phenotypes were evaluated by flow cytometry. CD146(+) CD4(+) and interleukin (IL)-17(+) CD4(+) T cell frequencies were increased in PBMC of PsA patients, compared with HD, and in SFMC compared with PBMC. CD146(+) CD4(+) T cells were enriched for secretion of IL-17 [alone or with IL-22 or interferon (IFN)-?] and for some putative Th17-associated surface markers (CD161 and CCR6), but not others (CD26 and IL-23 receptor). CD4(+) T cells producing IL-22 or IFN-? without IL-17 were also present in the CD146(+) subset, although their enrichment was less marked. Moreover, a majority of cells secreting these cytokines lacked CD146. Thus, CD146 is not a sensitive or specific marker of Th17 cells, but rather correlates with heterogeneous cytokine secretion by subsets of CD4(+) helper T cells.
| S-EPMC4337671 | biostudies-literature
Project description:BackgroundThere is increasing evidence supporting the impact of neoosteogenesis in the pathophysiology of chronic rhinosinusitis (CRS), especially in the recalcitrant group of patients. Runt-related transcription factor 2 (RUNX2), a member of the RUNX family, controls osteoblast differentiation and bone formation. However, the role and regulation of RUNX2 in CRS patients with neoosteogenesis remain unclear. The aim of the study is to determine the role of RUNX2 in neoosteogenesis of CRS patients.MethodsSinonasal bone and overlying mucosa samples were obtained from CRS patients with or without neoosteogenesis (n = 67) and healthy controls (n = 11). Double immunofluorescence, immunohistochemistry, and immunoblotting were used to evaluate RUNX2 expression in CRS patients with and without neoosteogenesis. In addition, the osteogenic activity of pro-inflammatory cytokines was examined by measuring alkaline phosphatase (ALP) activity and bone mineralisation in vitro.FindingsRUNX2 was highly expressed in osteoblasts of CRS patients with neoosteogenesis compared with tissues from control subjects and those with CRS without neoosteogenesis. Mucosal extracts from CRS patients with neoosteogenesis showed increased RUNX2 expression and ALP activity in C2C12 cells, whereas those from patients without neoosteogenesis did not. Expression of interleukin (IL)-13 and IL-17A was upregulated in CRS patients with neoosteogenesis. ALP activity and Alizarin Red staining showed IL-13 and IL-17A dose-dependent osteoblast differentiation and mineralisation in vitro.InterpretationThese findings suggested that IL-13- or IL-17A-induced RUNX2 contributed to new bone formation in CRS patients through its effect on the activity of osteoblasts. RUNX2 may be a novel target for preventing neoosteogenesis in CRS patients.
| S-EPMC6710985 | biostudies-literature
Project description:IntroductionA feature of rheumatoid arthritis (RA) is an imbalance between proinflammatory and anti-inflammatory cytokines. Several recent studies have implicated polymorphism in the IL-4 signalling pathway in the development of erosive RA. The aim of the present study was to investigate the role of polymorphism in the IL-4, IL-4Ralpha and IL-13 genes in RA, including an examination of epistasis.MethodsA total of 965 Caucasian patients with RA (cases) and 988 healthy control individuals (controls) were genotyped for five variants in the IL-4/IL-13 gene cluster (5q31.1) and two functional variants IL-4Ralpha (16p12.1). Individual genotype and haplotype frequencies were compared between cases and controls. The odd ratios were calculated with asymptotic 95% confidence intervals, and P values less than 0.05 were considered statistically significant. The potential association with radiological joint damage was also examined. Potential gene interactions were assessed using both stratified analysis and the linkage disequilibrium-based statistic.ResultsGenotype, allele and haplotype frequencies were equally distributed between RA cases and controls. Similarly, no association was detected between these variants and modified Larsen scores. Furthermore, no evidence of epistasis was detected between IL-4 or IL-13 genotypes and IL-4Ralpha.ConclusionThese results indicate that common variants of the IL-4/IL-13 pathway do not significantly contribute to RA susceptibility and radiological severity.
| S-EPMC2575626 | biostudies-literature