title: TL1A increased IL-6 production on fibroblast-like synoviocytes by preferentially activating TNF receptor 2 in rheumatoid arthritis.
abstract: TNF-like protein 1A (TL1A), a member of tumor necrosis factor family, recognized as a ligand of death receptor 3 (DR3) and decoy receptor 3 (DcR3). The interaction of TL1A and DR3 may participate in the pathogenesis of some autoimmune diseases including rheumatoid arthritis (RA). Our previous results showed that high concentrations of TL1A could be found in synovial and serum in RA patients, and it was correlated with disease severity. In addition, TL1A could promote Th17 differentiation induced by TGF-β and IL-6 and increased the production of IL-17A. In the present study, we found that TL1A could promote the expression of IL-6 on fibroblast-like synoviocytes (FLS) of RA patients via NF-κB and JNK signaling pathway. TL1A-stimulated FLS increased the percentage of Th17 of peripheral blood mononuclear cells (PBMC) in RA via the production of IL-6, a critical cytokine involved in the differentiation of Th17. Moreover, the blocking of tumor necrosis factor receptor 2 (TNFR2) decreased TL1A-stimulated IL-6 production by RA FLS. Our results suggest that TL1A was capable of acting on RA FLS to elevate IL-6 expression, which promoted the production of Th17. More importantly, we showed that TL1A could influence RA FLS through binding to TNFR2 rather than DR3 on FLS, which indicated that the treatment of TNF inhibitors not only blocked the TNF but also suppressed the TL1A in RA patients.
authors.affiliation: Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun south Road, Dalian 116044, Liaoning, China.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun south Road, Dalian 116044, Liaoning, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun south Road, Dalian 116044, Liaoning, China; Department of Rheumatology and Immunology, Hebei Medical University Third Affiliated Hospital, 139 Ziqiang Road, Shijiazhuang 050051, Hebei, China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun south Road, Dalian 116044, Liaoning, China.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun south Road, Dalian 116044, Liaoning, China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun south Road, Dalian 116044, Liaoning, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun south Road, Dalian 116044, Liaoning, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun south Road, Dalian 116044, Liaoning, China. Electronic address: Lixia416@163.com.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D000070918:Synoviocytes / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism*
chemical_list: C508717:IL17A protein, human; C508600:IL6 protein, human; D020381:Interleukin-17; D015850:Interleukin-6; D047889:Receptors, Tumor Necrosis Factor, Type II; C117026:TNFSF15 protein, human; D016212:Transforming Growth Factor beta; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15
keywords: Fibroblast-like synoviocytes (FLS); Interleukin-6 (IL-6); Rheumatoid arthritis; TNF-like cytokine 1A (TL1A); Tumor necrosis factor receptor (TNFR)