Murine tumor necrosis factor α–induced adipose‐related protein (tumor necrosis factor α–induced protein 9) deficiency leads to arthritis via interleukin‐6 overproduction with enhanced NF‐κB,STAT‐3 signaling,and dysregulated apoptosis of macrophages |
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Authors: | Asuka Inoue Isao Matsumoto Yoko Tanaka Naoto Umeda Yuki Tanaka Masahiko Mihara Satoru Takahashi Takayuki Sumida |
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Abstract: | Objective To elucidate the role of tumor necrosis factor α–induced adipose‐related protein (TIARP; or tumor necrosis factor α–induced protein 9 [TNFAIP‐9]) in the development and pathogenesis of arthritis. Methods We generated TIARP‐deficient (TIARP−/−) mice and investigated several organs in aged mice. Peritoneal macrophages were collected and cultured with lipopolysaccharide (LPS) and TNFα, and then the production of cytokines and subsequent NF‐κB signal transduction were analyzed. We also examined the susceptibility of young TIARP−/− mice to collagen‐induced arthritis (CIA). Draining lymph nodes and splenocytes were isolated and cultured, and serum levels of anti–type II collagen (anti‐CII) antibodies, interleukin‐6 (IL‐6), and TNFα on day 60 were measured. We further investigated the effects of anti–IL‐6 receptor monoclonal antibody (mAb) on the development of arthritis in TIARP−/− mice. IL‐6/STAT‐3 signaling was also analyzed using TIARP−/− macrophages. Results TIARP−/− mice developed spontaneous enthesitis and synovitis, had high serum levels of IL‐6, had increased CD11b+ cell counts in the spleen, and showed enhanced LPS‐ and TNFα‐induced IL‐6 expression in macrophages. Sustained degradation of IκBα with dysregulated apoptosis was also noted in TIARP−/− macrophages. CIA was clearly exacerbated in TIARP−/− mice, accompanied by marked neutrophil and macrophage infiltration in joints. The levels of anti‐CII antibodies in serum were unchanged, whereas autoreactive Th1 cell and Th17 cell responses were higher in TIARP−/− mice. Treatment with anti–IL‐6 receptor mAb prevented the development of CIA in TIARP−/− mice, and TIARP−/− macrophages showed increased IL‐6–induced STAT‐3 phosphorylation. Conclusion These findings suggest that TIARP acts as a negative regulator of arthritis by suppressing IL‐6 production, its signaling and TNFα‐induced NF‐κB signaling, resulting in enhanced apoptosis in macrophages. |
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