Gene Associated With Retinoid–Interferon–Induced Mortality 19 Attenuates Murine Autoimmune Arthritis by Regulation of Th17 and Treg Cells
Young-Mee Moon,1 Jennifer Lee,2 Seon-Yeong Lee,1 Yang-Mi Her,1 Jun-Geol Ryu,1
Eun-Kyung Kim,1 Hea-Jin Son,1 Seung-Ki Kwok,2 Ji Hyeon Ju,2 Chul-Woo Yang,2
Sung-Hwan Park,2 Ho-Youn Kim,2 and Mi-La Cho2
1Young-Mee Moon, MS, Seon-Yeong Lee, PhD, Yang-Mi Her, MS, Jun-Geol Ryu, MS, Eun-Kyung Kim, MS, Hea-Jin Son, MS:Catholic University of Korea, Seoul, South Korea; 2Jennifer Lee, MD, Seung-Ki Kwok, MD, PhD, Ji Hyeon Ju, MD, PhD, Chul-Woo Yang,MD, PhD, Sung-Hwan Park, MD, PhD, Ho-Youn Kim, MD, PhD,Mi-La Cho, PhD: Seoul St. Mary’s Hospital and Catholic University of Korea, Seoul, South Korea.
Ms. Y.-M. Moon and Dr. J. Lee contributed equally to this work.
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 CD4IL-17 cells and CD4pSTAT3 cells were decreased, while the numbers of CD4CD25Foxp3 cells and CD4pSTAT5 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-1, IL-6, tumor necrosis factor , 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.
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