The Journal of Experimental Medicine
Aegean Conferences: 2009 Conferences
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Published online 13 October 2003 doi:10.1084/jem.20030917
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© Rockefeller University Press, 0022-1007/2003/10/1179 $5.00
The Journal of Experimental Medicine, Volume 198, Number 8, 1179-1188

Transforming Growth Factor (TGF)-ß1–producing Regulatory T Cells Induce Smad-mediated Interleukin 10 Secretion That Facilitates Coordinated Immunoregulatory Activity and Amelioration of TGF-ß1–mediated Fibrosis

Atsushi Kitani1, Ivan Fuss1, Kazuhiko Nakamura1, Fumiyuki Kumaki2, Takashi Usui1 and Warren Strober1

1 Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases
2 Laboratory of Pathology, National Lung, Heart, and Blood Institute, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Warren Strober, Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N238, 10 Center Drive, Bethesda, MD 20892. Phone: (301) 496-6810; Fax: (301) 402-2240; email: wstrober{at}niaid.nih.gov

Interleukin (IL)-10 and transforming growth factor (TGF)-ß1 are suppressor cytokines that frequently occur together during a regulatory T cell response. Here we used a one gene doxycycline (Dox)-inducible plasmid encoding TGF-ß1 to analyze this association and test its utility. In initial studies, we showed that intranasal administration of this plasmid (along with Dox) led to the appearance of TGF-ß1–producing cells (in spleen and lamina propria) and the almost concomitant appearance of IL-10–producing cells. Moreover, we showed that these cells exert Dox-regulated suppression of the T helper cell (Th)1-mediated inflammation in trinitrobenzene sulfonic acid colitis. In subsequent in vitro studies using retroviral TGF-ß1 expression, we established that IL-10 production by Th1 cells occurs after exposure to TGF-ß1 from either an endogenous or exogenous source. In addition, using a self-inactivating retrovirus luciferase reporter construct we showed that TGF-ß1 induces Smad4, which then binds to and activates the IL-10 promoter. Furthermore, intranasal TGF-ß1 plasmid administration ameliorates bleomycin-induced fibrosis in wild-type but not IL-10–deficient mice, strongly suggesting that the amelioration is IL-10 dependent and that IL-10 protects mice from TGF-ß1–mediated fibrosis. Taken together, these findings suggest that the induction of IL-10 by TGF-ß1 is not fortuitous, but instead fulfills important requirements of TGF-ß1 function after its secretion by regulatory T cells.

Key Words: Th1 cells • trinitrobenzene sulfonic acid • fibrosis • doxycycline • transcription


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