Treatment of experimental (trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-β1 plasmid:TGF-β1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor β2 chain downregulation

Atsushi Kitani, Ivan J. Fuss, Kazuhiko Nakamura, Owen M. Schwartz, Takashi Usui, Warren Strober

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Abstract

In this study, we show that a single intranasal dose of a plasmid encoding active transforming growth factor β1 (pCMV-TGF-β1) prevents the development of T helper cell type 1 (Th1)mediated experimental colitis induced by the haptenating reagent, 2,4,6-trinitrobenzene sulfonic acid (TNBS). In addition, such plasmid administration abrogates TNBS colitis after it has been established, whereas, in contrast, intraperitoneal administration of rTGF-β1 protein does not have this effect. Intranasal pCMV-TGF-β1 administration leads to the expression of TGFβ1 mRNA in the intestinal lamina propria and spleen for 2 wk, as well as the appearance of TGF-β1- producing T cells and macrophages in these tissues, and is not associated with the appearances of fibrosis. These cells cause marked suppression of interleukin (IL)-12 and interferon (IFN)-γ production and enhancement of IL- 10 production; in addition, they inhibit IL-12 receptor β2 (IL-12Rβ2) chain expression. Coadministration of anti-IL-10 at the time of pCMVTGF-β1 administration prevents the enhancement of IL-10 production and reverses the suppression of IL-12 but not IFN-γ secretion. However, anti-IL-10 leads to increased tumor necrosis factor α production, especially in established colitis. Taken together, these studies show that TGF-β1 inhibition of a Th1- mediated colitis is due to: (a) suppression of IL-12 secretion by IL-10 induction and (b) inhibition of IL-12 signaling via downregulation of IL- 12Rβ2 chain expression. In addition, TGF-β1 may also have an inhibitory effect on IFN-γ transcription.

Original languageEnglish
Pages (from-to)41-52
Number of pages12
JournalJournal of Experimental Medicine
Volume192
Issue number1
DOIs
Publication statusPublished - Jul 3 2000

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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