| First Author | Inoue A | Year | 2012 |
| Journal | Arthritis Rheum | Volume | 64 |
| Issue | 12 | Pages | 3877-85 |
| PubMed ID | 22886597 | Mgi Jnum | J:269840 |
| Mgi Id | MGI:6275754 | Doi | 10.1002/art.34666 |
| Citation | Inoue A, et al. (2012) 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-kappaB, STAT-3 signaling, and dysregulated apoptosis of macrophages. Arthritis Rheum 64(12):3877-85 |
| abstractText | 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. METHODS: We generated TIARP-deficient (TIARP(-/-) ) mice and investigated several organs in aged mice. Peritoneal macrophages were collected and cultured with lipopolysaccharide (LPS) and TNFalpha, and then the production of cytokines and subsequent NF-kappaB 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 TNFalpha 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 TNFalpha-induced IL-6 expression in macrophages. Sustained degradation of IkappaBalpha 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 TNFalpha-induced NF-kappaB signaling, resulting in enhanced apoptosis in macrophages. |
