title: IL-33 regulates TNF-α dependent effects in synovial fibroblasts.
abstract: The recently described IL-33 acts as a pro-inflammatory cytokine, inducing             the expression of multiple responses in the target cells. Although a nuclear localization             of IL-33 has been described, its exact functional relevance is presently unknown.             The present study was conducted to analyze the effects of IL-33 on the TNF-α induced             synthesis of the pro-inflammatory mediators IL-6, IL-8, and monocyte chemotactic             protein-1 (MCP-1) and the pro-destructive molecules matrix metalloproteinase-1             (MMP-1), MMP-3, and TIMP-1 of rheumatoid arthritis synovial fibroblast (RA-SFs)             using RNA overexpression and silencing. TNF-α significantly induced IL-33 mRNA             expression and protein synthesis in RA-SFs. TNF-α-induced IL-33 protein expression             was mediated via p38 signaling. Immunohistochemistry for IL-33 clearly showed             that nuclear translocation of IL-33 was induced in TNF-α stimulated RA-SFs. IL-33             overexpression enhanced TNF-α-induced pro-inflammatory and pro-destructive functions             in RA-SFs. IL-33 silencing significantly downregulated TNF-α-induced pro-inflammatory             functions, whereas TNF-α-induced pro-destructive functions were less influenced             by IL-33 silencing. This study identifies IL-33 as a critical regulator/enhancer             of TNF-α-induced functions in RA-SFs, pointing to a central role of this cytokine             in the perpetuation of pro-inflammatory and pro-destructive processes in rheumatoid             arthritis (RA) and other inflammatory and degenerative diseases.
authors.affiliation: Experimental Rheumatology Unit, Department of Orthopedics, University Hospital Jena, Kloster-lausnitzer Str. 81, D-07607 Eisenberg, Germany. elke.kunisch@med.uni-jena.de
authors.forename: Elke
authors.initials: E
authors.lastname: Kunisch
authors.forename: Saritha
authors.initials: S
authors.lastname: Chakilam
authors.forename: Muktheshwar
authors.initials: M
authors.lastname: Gandesiri
authors.forename: Raimund W
authors.initials: RW
authors.lastname: Kinne
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D000067596:Interleukin-33; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013583:Synovial Membrane / Q000166:cytology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; C506536:IL33 protein, human; C508600:IL6 protein, human; D000067596:Interleukin-33; D015850:Interleukin-6; D016209:Interleukin-8; D007378:Interleukins; D012333:RNA, Messenger; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1