Reciprocal Regulation of TH17 and Regulatory T Cells by Methotrexate and Its Therapeutic Effects in Collagen-induced Arthritis (CIA).
- Author:
Eun Mi PARK
1
;
Mi Kyung PARK
;
Dong Gun LEE
;
Seung Ye BAEK
;
Jung Won WOO
;
Seung Ki KWOK
;
Mi La CHO
;
Sung Hwan PARK
Author Information
- Publication Type:In Vitro ; Original Article
- Keywords: Methotrexate; Collagen-induced arthritis; Cytokines; TH17 cells; Regulatory T cells
- MeSH: Animals; Antibodies; Antirheumatic Agents; Arthritis; Arthritis, Experimental; Arthritis, Rheumatoid; Cartilage; Collagen Type II; Cytokines; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Homeostasis; Immune System; Immunoglobulins; Immunohistochemistry; Inflammation; Interleukin-17; Interleukin-6; Joints; Methotrexate; Mice; Microscopy, Fluorescence; Phosphorylation; Spleen; T-Lymphocytes, Regulatory; Th17 Cells; Tumor Necrosis Factor-alpha
- From:Journal of Rheumatic Diseases 2013;20(2):94-102
- CountryRepublic of Korea
- Language:Korean
- Abstract: OBJECTIVE: Methotrexate is the first-line drug in treatment of rheumatoid arthritis (RA) exhibiting higher efficacy and better tolerability than most other DMARDs. To have a better understanding of the anti-arthritic mechanism of methotrexate, we investigated the effect of methotrexate on suppressing the autoimmune inflammatory and destructive arthritis in collagen-induced arthritis (CIA) mice. METHODS: The effects of methotrexate on joint inflammation were assessed by clinical scoring and histologic analysis. Levels of cytokines and autoreactive antibodies were analyzed by immunohistochemistry and ELISA. The population of TH17 and Foxp3+ regulatory T (Treg) cells and phosphorylation of their critical transcription activators, STAT3 and STAT5, were examined by fluorescence microscopy and flow cytometry, respectively. RESULTS: Treatment with methotrexate significantly alleviated joint inflammation and cartilage destruction in CIA. Serum levels of total immunoglobulins G, G1, G2a specific to type II collagen were also reduced considerably in methotrexate-treated mice. The drug inhibited the expression of proinflammatory cytokines such as IL-1beta, TNF-alpha, IL-6 and IL-17 in arthritic joints ex vivo as well as by splenocytes in vitro. Moreover, methotrexate treatment resulted in reciprocal modulation of TH17 cells and Foxp3+ regulatory T (Treg) cells in spleen tissues, in which TH17 cells were decreased and Treg cells in number were increased. Subsequent analysis of CD4+T cells showed that phosphorylation of STAT3 was decreased whereas phosphorylation of STAT5 was increased in methotrexate-treated mice. CONCLUSION: Methotrexate treatment effectively suppressed autoimmune arthritis and restored homeostasis of the immune system by reciprocal regulation of TH17 and Treg cells in a mouse model of collagen-induced arthritis.
