Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis.
Interleukin (IL)-10 and transforming growth factor (TGF)-beta1 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 mice, 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.
Kitani
Atsushi
A
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N238, 10 Center Drive, Bethesda, MD 20892, USA.
Fuss
Ivan
I
Nakamura
Kazuhiko
K
Kumaki
Fumiyuki
F
Usui
Takashi
T
Strober
Warren
W
D000818:Animals; D001761:Bleomycin; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology*; D018274:Electroporation; D005355:Fibrosis / Q000139:chemically induced / Q000517:prevention & control*; D005786:Gene Expression Regulation; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000378:metabolism*; D008264:Macrophages; D008297:Male; D051379:Mice; D051785:Smad Proteins; D013601:T-Lymphocytes / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D004268:DNA-Binding Proteins; D051785:Smad Proteins; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D016753:Interleukin-10