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.

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.