Murine Tumor Necrosis Factor alpha-Induced Adipose-Related Protein (Tumor Necrosis Factor alpha-Induced Protein 9) Deficiency Leads to Arthritis via Interleukin-6 Overproduction With Enhanced NF-kappa B, STAT-3 Signaling, and Dysregulated Apoptosis of Macrophages

作者：Inoue Asuka; Matsumoto Isao^*; Tanaka Yoko; Umeda Naoto; Tanaka Yuki; Mihara Masahiko; Takahashi Satoru; Sumida Takayuki

来源：Arthritis and Rheumatism, 2012, 64(12): 3877-3885.

DOI：10.1002/art.34666

Objective. To elucidate the role of tumor necrosis factor alpha-induced adipose-related protein (TIARP; or tumor necrosis factor alpha-induced protein 9 [TNFAIP-9]) in the development and pathogenesis of arthritis. %26lt;br%26gt;Methods. We generated TIARP-deficient (TIARP(-/-)) mice and investigated several organs in aged mice. Peritoneal macrophages were collected and cultured with lipopolysaccharide (LPS) and TNF alpha, and then the production of cytokines and subsequent NF-kappa B 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 TNF alpha 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. %26lt;br%26gt;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 TNF alpha-induced IL-6 expression in macrophages. Sustained degradation of I kappa B alpha 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. %26lt;br%26gt;Conclusion. These findings suggest that TIARP acts as a negative regulator of arthritis by suppressing IL-6 production, its signaling and TNF alpha-induced NF-kappa B signaling, resulting in enhanced apoptosis in macrophages.

• 出版日期2012-12