Potential roles of interleukin-17A in the development of skin fibrosis in mice
Version of Record online: 27 OCT 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 11, pages 3726–3735, November 2012
How to Cite
Okamoto, Y., Hasegawa, M., Matsushita, T., Hamaguchi, Y., Huu, D. L., Iwakura, Y., Fujimoto, M. and Takehara, K. (2012), Potential roles of interleukin-17A in the development of skin fibrosis in mice. Arthritis & Rheumatism, 64: 3726–3735. doi: 10.1002/art.34643
- Issue online: 27 OCT 2012
- Version of Record online: 27 OCT 2012
- Accepted manuscript online: 25 JUL 2012 09:54AM EST
- Manuscript Accepted: 17 JUL 2012
- Manuscript Received: 5 FEB 2012
- Ministry of Education, Science, and Culture of Japan
- Ministry of Health, Labor, and Welfare of Japan
- Core Research for Evolutional Science and Technology program grants from the Japan Science and Technology Agency
- Bio-oriented Technology Research Advancement Institution
Although transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF) have been considered to play central roles in the pathogenesis of systemic sclerosis (SSc), other cytokines may also be crucial for the development of SSc. The aim of this study was to examine the roles of T helper cytokines in the development of skin fibrosis.
To compare the roles of Th1, Th2, and Th17 cytokines, we examined bleomycin-induced SSc in mice deficient for interferon-γ (IFNγ), interleukin-4 (IL-4), and IL-17A. The mechanism by which IL-17A contributes to bleomycin-induced fibrosis was investigated in vivo and in vitro. The outcome of mice lacking IL-17A was also investigated in TSK-1 mice.
The loss of IL-17A significantly attenuated bleomycin-induced skin fibrosis, whereas a deficiency of IFNγ or IL-4 did not. Leukocyte infiltration and the expression of TGFβ and CTGF messenger RNA in bleomycin-injected skin were significantly reduced in IL-17A–deficient mice compared with wild-type (WT) mice. Daily bleomycin injections induced the expression of IL-17A in the skin and potent IL-17A producers in splenic CD4+ T cells from WT mice. Furthermore, a skin fibroblast cell line expressed increased TGFβ, CTGF, and collagen after the addition of recombinant IL-17A. IL-17A deficiency also attenuated skin thickness in TSK-1 mice.
This study demonstrates that IL-17A contributes to skin fibrosis in 2 mouse models of SSc. These findings suggest that inhibition of IL-17A represents a therapeutic target for antagonizing fibrotic skin disorders such as SSc.