Drs. Moon and J.-S. Park contributed equally to this work. Drs. Cho and Min contributed equally to this work.
Rebamipide Suppresses Collagen-Induced Arthritis Through Reciprocal Regulation of Th17/Treg Cell Differentiation and Heme Oxygenase 1 Induction
Article first published online: 28 MAR 2014
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 4, pages 874–885, April 2014
How to Cite
Moon, S.-J., Park, J.-S., Woo, Y.-J., Lim, M.-A., Kim, S.-M., Lee, S.-Y., Kim, E.-K., Lee, H. J., Lee, W. S., Park, S.-H., Jeong, J.-H., Park, S.-H., Kim, H.-Y., Cho, M.-L. and Min, J.-K. (2014), Rebamipide Suppresses Collagen-Induced Arthritis Through Reciprocal Regulation of Th17/Treg Cell Differentiation and Heme Oxygenase 1 Induction. Arthritis & Rheumatology, 66: 874–885. doi: 10.1002/art.38310
- Issue published online: 28 MAR 2014
- Article first published online: 28 MAR 2014
- Accepted manuscript online: 10 DEC 2013 02:31PM EST
- Manuscript Accepted: 3 DEC 2013
- Manuscript Received: 4 JUN 2013
- Ministry of Health and Welfare, Republic of Korea (Korean Health Technology R&D Project). Grant Number: A092258
- Institute of Clinical Medicine Research, Bucheon St. Mary's Hospital Research Fund. Grant Number: BCMC13YA07
Rebamipide, a gastroprotective agent, has the ability to scavenge reactive oxygen radicals. Increased oxidative stress is implicated in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to investigate the impact of rebamipide on the development of arthritis and the pathophysiologic mechanisms by which rebamipide attenuates arthritis severity in a murine model of RA.
Collagen-induced arthritis (CIA) was induced in DBA/1J mice. Anti–type II collagen antibody titers and interleukin-17 (IL-17) levels were determined using enzyme-linked immunosorbent assay. The expression of transcription factors was analyzed by immunostaining and Western blotting. Frequencies of IL-17–producing CD4+ T cells (Th17 cells) and CD4+CD25+FoxP3+ Treg cells were analyzed by flow cytometry.
Rebamipide reduced the clinical arthritis score and severity of histologic inflammation and cartilage destruction in a dose-dependent manner. The joints isolated from rebamipide-treated mice with CIA showed decreased expression of nitrotyrosine, an oxidative stress marker. Rebamipide-treated mice showed lower circulating levels of type II collagen–specific IgG, IgG1, and IgG2a. Whereas the number of Th17 cells in spleens was decreased in rebamipide-treated mice with CIA, a significant increase in the number of Treg cells in spleens was observed. In vitro, rebamipide inhibited Th17 cell differentiation through STAT-3/retinoic acid receptor–related orphan nuclear receptor γt and reciprocally induced Treg cell differentiation through FoxP3. Rebamipide increased Nrf2 nuclear activities in murine CD4+ T cells and LBRM-33 murine T lymphoma cells. Heme oxygenase 1 (HO-1) expression in the spleens was markedly increased in rebamipide-treated mice.
The inhibitory effects of rebamipide on joint inflammation are associated with recovery from an imbalance between Th17 cells and Treg cells and with activation of an Nrf2/HO-1 antioxidant pathway.