Retinoic acid attenuates rheumatoid inflammation in mice.
Retinoic acid is the active vitamin A derivative and is well-known to have diverse immunomodulatory actions. In this study, we investigated the impact of all-trans retinoic acid (ATRA), a biologic key metabolite of vitamin A, on the development of arthritis and the pathophysiologic mechanisms by which ATRA might have antiarthritic effects in animal model of rheumatoid arthritis (RA; collagen-induced arthritis [CIA] in DBA/1J mice). We showed that treatment with ATRA markedly suppressed the clinical and histologic signs of arthritis in the CIA mice. It reduced the expression of IL-17 in the arthritic joints. Interestingly, Foxp3(+) regulatory T cells were markedly increased and IL-17-producing CD4(+) T cells (Th17 cells) were decreased in the spleens of ATRA-treated mice. In vitro treatment with ATRA induced the expression of Foxp3 and repressed the IL-17 expression in the CD4(+) T cells in mice. ATRA suppressed the production of total IgG and IgG2a in splenocytes that were stimulated by LPS. It also reduced serum levels of total IgG and IgG2 anti-collagen Abs and germinal center formation in CIA mice. In addition, the ATRA-treated mice showed decreased osteoclast formation in arthritic joints. Moreover, ATRA downregulated the expression of receptor activator of NF-κB ligand, the leading player of osteoclastogenesis, in the CD4(+) T cells and fibroblast-like synoviocytes from patients with RA. Furthermore, ATRA prevented both human monocytes and mice bone marrow-derived monocytes/macrophage cells from differentiating into osteoclasts. These data suggest ATRA might be an effective treatment modality for RA patients.
Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
Seung-Ki
SK
Kwok
Mi-Kyung
MK
Park
Mi-La
ML
Cho
Hye-Jwa
HJ
Oh
Eun-Mi
EM
Park
Dong-Gun
DG
Lee
Jennifer
J
Lee
Ho-Youn
HY
Kim
Sung-Hwan
SH
Park
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D002417:Cattle; D024043:Collagen Type II / Q000633:toxicity; D004195:Disease Models, Animal; D056724:Immunity, Humoral / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014212:Tretinoin / Q000008:administration & dosage / Q000627:therapeutic use*
D024043:Collagen Type II; D018836:Inflammation Mediators; D014212:Tretinoin