title: TWEAK promotes the production of Interleukin-17 in rheumatoid arthritis.
abstract: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is an inflammatory cytokine that modulates several biological responses by inducing chemokines and proinflammatory cytokines. We hypothesized that TWEAK could promote secretion of IL-17, an amplifier of inflammatory arthritis. To test this, we investigated the capacity of TWEAK to induce IL-17 production in T cells via the fibroblast growth factor-inducible gene 14 (Fn14, also known as TWEAK receptor) signal pathway in rheumatoid arthritis (RA). Fn14 and IL-17 were highly expressed in arthritic tissues of collagen-induced arthritis (CIA) mice. TWEAK induced production of IL-17 alone and synergistically with lipopolysaccharide. In naïve murine T cells, TWEAK promoted Th17 differentiation. The expression of Fn14 was predominant in Th17 cells. TWEAK and IL-17 concentrations were significantly higher in synovial fluid and serum in RA patients than OA patients. In addition, we identified CD4(+)IL-17(+)Fn14(+) cells in synovium from RA patients. TWEAK promoted IL-17 production synergistically with IL-23 or IL-21 and blockade of Fn14 with Fn14-Fc suppressed Th17 differentiation. Conversely, this treatment enhanced Treg differentiation. These results suggest that TWEAK induces IL-17 production and may be a therapeutic target in the treatment of RA.
authors: The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea. wlstlf81@catholic.ac.kr
authors: Jin-Sil
authors: JS
authors: Park
authors: Mi-Kyung
authors: MK
authors: Park
authors: Seon-Yeong
authors: SY
authors: Lee
authors: Hye-Jwa
authors: HJ
authors: Oh
authors: Mi-Ae
authors: MA
authors: Lim
authors: Woo-Tae
authors: WT
authors: Cho
authors: Eun-Kyung
authors: EK
authors: Kim
authors: Ji-Hyeon
authors: JH
authors: Ju
authors: Young-Woo
authors: YW
authors: Park
authors: Sung-Hwan
authors: SH
authors: Park
authors: Mi-La
authors: ML
authors: Cho
authors: Ho-Youn
authors: HY
authors: Kim
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D020381:Interleukin-17 / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D053759:Interleukin-23 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010003:Osteoarthritis / Q000097:blood / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000097:blood* / Q000235:genetics / Q000494:pharmacology; D000098546:Interleukin-21
chemical_list: D000074049:Cytokine TWEAK; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors; D000098546:Interleukin-21