Transforming growth factor (TGF)-β1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-β1-mediated fibrosis

被引:209
作者
Kitani, A
Fuss, I
Nakamura, K
Kumaki, F
Usui, T
Strober, W
机构
[1] Natl Inst Allergy & Infect Dis, Lab Clin Invest, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA
[2] Natl Lung Heart & Blood Inst, Pathol Lab, NIH, Bethesda, MD 20892 USA
关键词
Th1; cells; trinitrobenzene sulfonic acid; fibrosis; doxycycline; transcription;
D O I
10.1084/jem.20030917
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Interleukin (IL)-10 and transforming growth factor (TGF)-betal 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-beta1 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-beta1-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-beta1 expression, we established that IL-10 production by Th1 cells occurs after exposure to TGF-beta1 from either an endogenous or exogenous source. In addition, using a self-inactivating retrovirus luciferase reporter construct we showed that TGF-beta1 induces Smad4, which then binds to and activates the IL-10 promoter. Furthermore, intranasal TGF-beta1 plasmid administration ameliorates bleomycin-induced fibrosis in wild-type but not IL-10-deficient juice, strongly suggesting that the amelioration is IL-10 dependent and that IL-10 protects mice from TGF-beta1-mediated fibrosis. Taken together, these findings suggest that the induction of IL-10 by TGF-beta1 is not fortuitous, but instead fulfills important requirements of TGF-beta1 function after its secretion by regulatory T cells.
引用
收藏
页码:1179 / 1188
页数:10
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