Rebamipide suppresses collagen-induced arthritis through reciprocal regulation of th17/treg cell differentiation and heme oxygenase 1 induction.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Catholic University of Korea, Seoul, South Korea.
Su-Jin
SJ
Moon
Jin-Sil
JS
Park
Yun-Ju
YJ
Woo
Mi-Ae
MA
Lim
Sung-Min
SM
Kim
Seon-Yeong
SY
Lee
Eun-Kyung
EK
Kim
Hee Jin
HJ
Lee
Weon Sun
WS
Lee
Sang-Hi
SH
Park
Jeong-Hee
JH
Jeong
Sung-Hwan
SH
Park
Ho-Youn
HY
Kim
Mi-La
ML
Cho
Jun-Ki
JK
Min
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D002454:Cell Differentiation / Q000187:drug effects*; D016207:Cytokines / Q000097:blood; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D018501:Antirheumatic Agents; D001323:Autoantibodies; D016207:Cytokines; D015363:Quinolones; D051547:Heme Oxygenase-1; C052785:rebamipide; D000409:Alanine