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

Atsushi Kitani, Ivan Fuss, Kazuhiko Nakamura, Fumiyuki Kumaki, Takashi Usui, Warren Strober

研究成果: ジャーナルへの寄稿記事

187 引用 (Scopus)

抄録

Interleukin (IL)-10 and transforming growth factor (TGF)-β1 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-β1 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-β1-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-β1 expression, we established that IL-10 production by Th1 cells occurs after exposure to TGF-β1 from either an endogenous or exogenous source. In addition, using a self-inactivating retrovirus luciferase reporter construct we showed that TGF-β1 induces Smad4, which then binds to and activates the IL-10 promoter. Furthermore, intranasal TGF-β1 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-β1-mediated fibrosis. Taken together, these findings suggest that the induction of IL-10 by TGF-β1 is not fortuitous, but instead fulfills important requirements of TGF-β1 function after its secretion by regulatory T cells.

元の言語英語
ページ(範囲)1179-1188
ページ数10
ジャーナルJournal of Experimental Medicine
198
発行部数8
DOI
出版物ステータス出版済み - 10 20 2003

Fingerprint

Transforming Growth Factors
Regulatory T-Lymphocytes
Interleukin-10
Fibrosis
Doxycycline
Th1 Cells
Plasmids
Trinitrobenzenes
Intranasal Administration
Sulfonic Acids
Bleomycin
Retroviridae
Colitis
Luciferases
Mucous Membrane
Spleen
Cytokines
Inflammation

All Science Journal Classification (ASJC) codes

  • Immunology

これを引用

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. / Kitani, Atsushi; Fuss, Ivan; Nakamura, Kazuhiko; Kumaki, Fumiyuki; Usui, Takashi; Strober, Warren.

:: Journal of Experimental Medicine, 巻 198, 番号 8, 20.10.2003, p. 1179-1188.

研究成果: ジャーナルへの寄稿記事

@article{ca48c627c74d42489291c84716429c4a,
title = "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",
abstract = "Interleukin (IL)-10 and transforming growth factor (TGF)-β1 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-β1 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-β1-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-β1 expression, we established that IL-10 production by Th1 cells occurs after exposure to TGF-β1 from either an endogenous or exogenous source. In addition, using a self-inactivating retrovirus luciferase reporter construct we showed that TGF-β1 induces Smad4, which then binds to and activates the IL-10 promoter. Furthermore, intranasal TGF-β1 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-β1-mediated fibrosis. Taken together, these findings suggest that the induction of IL-10 by TGF-β1 is not fortuitous, but instead fulfills important requirements of TGF-β1 function after its secretion by regulatory T cells.",
author = "Atsushi Kitani and Ivan Fuss and Kazuhiko Nakamura and Fumiyuki Kumaki and Takashi Usui and Warren Strober",
year = "2003",
month = "10",
day = "20",
doi = "10.1084/jem.20030917",
language = "English",
volume = "198",
pages = "1179--1188",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "8",

}

TY - JOUR

T1 - 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

AU - Kitani, Atsushi

AU - Fuss, Ivan

AU - Nakamura, Kazuhiko

AU - Kumaki, Fumiyuki

AU - Usui, Takashi

AU - Strober, Warren

PY - 2003/10/20

Y1 - 2003/10/20

N2 - Interleukin (IL)-10 and transforming growth factor (TGF)-β1 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-β1 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-β1-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-β1 expression, we established that IL-10 production by Th1 cells occurs after exposure to TGF-β1 from either an endogenous or exogenous source. In addition, using a self-inactivating retrovirus luciferase reporter construct we showed that TGF-β1 induces Smad4, which then binds to and activates the IL-10 promoter. Furthermore, intranasal TGF-β1 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-β1-mediated fibrosis. Taken together, these findings suggest that the induction of IL-10 by TGF-β1 is not fortuitous, but instead fulfills important requirements of TGF-β1 function after its secretion by regulatory T cells.

AB - Interleukin (IL)-10 and transforming growth factor (TGF)-β1 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-β1 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-β1-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-β1 expression, we established that IL-10 production by Th1 cells occurs after exposure to TGF-β1 from either an endogenous or exogenous source. In addition, using a self-inactivating retrovirus luciferase reporter construct we showed that TGF-β1 induces Smad4, which then binds to and activates the IL-10 promoter. Furthermore, intranasal TGF-β1 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-β1-mediated fibrosis. Taken together, these findings suggest that the induction of IL-10 by TGF-β1 is not fortuitous, but instead fulfills important requirements of TGF-β1 function after its secretion by regulatory T cells.

UR - http://www.scopus.com/inward/record.url?scp=0142219250&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0142219250&partnerID=8YFLogxK

U2 - 10.1084/jem.20030917

DO - 10.1084/jem.20030917

M3 - Article

VL - 198

SP - 1179

EP - 1188

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 8

ER -