Ms. Y.-M. Moon and Dr. J. Lee contributed equally to this work.
Gene Associated With Retinoid-Interferon-Induced Mortality 19 Attenuates Murine Autoimmune Arthritis by Regulation of Th17 and Treg Cells
Article first published online: 25 FEB 2014
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 3, pages 569–578, March 2014
How to Cite
Moon, Y.-M., Lee, J., Lee, S.-Y., Her, Y.-M., Ryu, J.-G., Kim, E.-K., Son, H.-J., Kwok, S.-K., Ju, J. H., Yang, C.-W., Park, S.-H., Kim, H.-Y. and Cho, M.-L. (2014), Gene Associated With Retinoid-Interferon-Induced Mortality 19 Attenuates Murine Autoimmune Arthritis by Regulation of Th17 and Treg Cells. Arthritis & Rheumatology, 66: 569–578. doi: 10.1002/art.38267
- Issue published online: 25 FEB 2014
- Article first published online: 25 FEB 2014
- Accepted manuscript online: 18 NOV 2013 11:18AM EST
- Manuscript Accepted: 31 OCT 2013
- Manuscript Received: 30 APR 2013
- Ministry for Health and Welfare, Republic of Korea. Grant Number: Korean Health Technology R&D Project grant A092258
- Ministry of Education, Science, and Technology, Republic of Korea
- National Research Foundation of Korea. Grant Number: Basic Science Research Program grant 2012-0006135
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.