期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 418, 期 2, 页码 234-240出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2011.12.156
关键词
Mouse; Helper T cells; Cytokine signaling; EAE
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- National Institute of Biomedical Innovation (NIBIO)
- SENSHIN Research Foundation
- Kanae Foundation for the Promotion of Medical Science
- Mochida Memorial Foundation
- Uehara Memorial Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [09J10943, 23659435, 22390167] Funding Source: KAKEN
Th17 cells, which have been implicated in autoimmune diseases, require STAT3 signaling activated by IL-6 or IL-23 for their development. Other Th1 and Th2 cytokines such as IL-2, IFN-gamma and IL-4 strongly suppress Th17 development. Recently, CP-690,550 (tofacitinib), originally developed as a JAK3 inhibitor, has been shown to be effective in phase III clinical trials of rheumatoid arthritis and collagen-induced arthritis (CIA) models, but the precise mechanism of the effect, especially with respect to Th17 cells, is poorly understood. To our surprise, a low dose CP-690,550 was found to accelerate the onset of experimental autoimmune encephalomyelitis (EAE) at a concentration that suppressed CIA. At an early stage after immunization, more IL-17 production was observed in 15 mg/kg body weight CP-690,550-treated mice than in untreated mice. In vitro, CP-690,550 inhibited both Th1 and Th2 development, while promoting Th17 differentiation at 10-50 nM concentrations. Enhancement of Th17 by CP-690,550 is probably due to suppression of IL-2 signaling, because anti-IL-2 antibodies cancel the Th17-promoting effect of CP-690,550. CP-690,550 selectively inhibited IFN-induced STAT1, IL-4-induced STAT6 and IL-2-induced STAT5 at 3-30 nM, while suppression of IL-6-induced STAT3 phosphorylation required a concentration greater than 100 nM. In HEK293T cells, CP-690,550 less effectively suppressed JAK1-mediated STAT3 phosphorylation compared with JAK3. These results suggest that CP-690,550 has a different effects among JAKs and STATs, thereby affecting helper T cell differentiation, and murine autoimmune disease models. (C) 2012 Elsevier Inc. All rights reserved.
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