Gene Associated With Retinoid‐Interferon‐Induced Mortality 19 Attenuates Murine Autoimmune Arthritis by Regulation of Th17 and Treg Cells

Objective STAT‐3 is a key transcriptional factor in the interleukin‐6 (IL‐6)–mediated differentiation of Th17 cells. Because Th17 is believed to be a central player in rheumatoid arthritis (RA), we sought to evaluate whether an endogenous inhibitor of the STAT3 gene, GRIM‐19 (gene associated with retinoid–interferon–induced mortality 19), could attenuate the progression and severity of murine collagen‐induced arthritis (CIA) through suppression of Th17 cells and, reciprocally, could increase expression of Treg cells. Methods Overexpression of GRIM‐19 was produced either by intravenous/intramuscular administration of a GRIM‐19 overexpression vector in DBA1/J mice or by development of GRIM‐19–transgenic (Tg) mice on a C57BL/6 background. Clinical signs were scored for arthritis severity, and mouse splenocytes, serum, and joint tissue were obtained for immunostaining and histologic analyses. Results The numbers of CD4+IL‐17+ cells and CD4+pSTAT3+ cells were decreased, while the numbers of CD4+CD25+Foxp3+ cells and CD4+pSTAT5+ cells were increased, in both GRIM‐19 vector–transfected and GRIM‐19–Tg mice. Administration of the GRIM‐19 overexpression vector into mice with CIA markedly suppressed the clinical and histologic signs of arthritis in the affected joints. Similarly, when CIA was induced in GRIM‐19–Tg mice, the arthritis phenotype was markedly attenuated and the expression of inflammatory cytokines (IL‐1β, IL‐6, tumor necrosis factor α, and IL‐17) in the arthritic joints was also significantly reduced. Moreover, bone marrow–derived monocyte/macrophages obtained from GRIM‐19–Tg mice showed attenuated RANKL–induced osteoclastogenesis in vitro. Conclusion GRIM‐19 improved the clinical and histologic features of CIA and also inhibited osteoclast formation. These findings suggest that GRIM‐19 may be a novel treatment agent for RA.