title: A pro-inflammatory role for A20 and ABIN family proteins in human fibroblast-like synoviocytes in rheumatoid arthritis.
abstract: Circuit of chronic inflammation in the joints of rheumatoid arthritis (RA) starts from the production of inflammatory cytokines by fibroblast-like synoviocytes (FLS) stimulated by TNFα produced by inflammatory cells mainly composed of macrophages. In this context, TNFα/NF-κB pathway plays an essential role for the transcription of pro-inflammatory cytokines. Here we show that the kinetics of pro-inflammatory cytokine genes induced by TNFα in FLS from RA was synchronized with that of A20, ABIN1, and ABIN3 that have been thought as negative regulators for NF-κB activation. Furthermore, based on this finding, we could tentatively categorize the RA-FLS into two groups; TNFα low-responder and high-responder FLS. The high responders that have abundant mRNA levels of NF-κB inhibitory molecules were also accompanied with the marked induction of the pro-inflammatory cytokines by the stimulation with TNFα. The low responders RA-FLS did not show this property, nor did FLS from osteoarthritis. Phosphorylation dependent degradation of IκBα as well as NF-κB activation upon stimulation with TNFα was significantly enhanced in the high-responder FLS lines. Surprisingly, single transfection of each NF-κB inhibitor was enough to facilitate the transcription of pro-inflammatory cytokines, suggesting that there is an unknown pro-inflammatory function for A20 and ABIN family proteins in RA-FLS.
authors.affiliation: Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Igarashi
authors.forename: Ayano
authors.initials: A
authors.lastname: Yahagi
authors.forename: Taro
authors.initials: T
authors.lastname: Saika
authors.forename: Jun
authors.initials: J
authors.lastname: Hashimoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tomita
authors.forename: Hideki
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Ishihara
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013583:Synovial Membrane / Q000473:pathology; D015533:Transcriptional Activation / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; C117046:TNIP1 protein, human; C426747:TNIP3 protein, human; D014409:Tumor Necrosis Factor-alpha; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3