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