TGF-β1 suppresses IFN-γ-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation

Hiromi Takaki, Yasumasa Minoda, Keiko Koga, Giichi Takaesu, Akihiko Yoshimura, Takashi Kobayashi

Research output: Contribution to journalArticle

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Abstract

TGF-β1 is a well-known immunosuppressive cytokine; however, little is known of the effect of TGF-β1 on antigen-presenting cells (APCs). In this report, we investigated the molecular mechanisms of the suppressive effects of TGF-β1 on APCs including dendritic cells and macrophages. Although TGF-β1 did not greatly affect the activation of APCs, as assessed by the induction of IL-12 or the upregulation of CD40 in response to LPS, it strongly inhibited IFN-γ-induced nitric oxide (NO) production from macrophages and dendritic cells. Using murine macrophage-like cell line RAW 264.7, we demonstrated that TGF-β1 not only reduced the inducible NO synthase (iNOS) protein stability but also suppressed the iNOS gene transcription. We also found that TGF-β1 directly inhibited IFN-γ-induced STAT1 activation by reducing STAT1 tyrosine phosphorylation. The IFN-γ Type I receptor (IFNGR1) was found to be associated with the TGF-β1 Type I receptor (TGF-βRI) and was phosphorylated by the TGF-βRI. Reduced activation of STAT1 by TGF-β1 was abrogated by the mutation in the IFNGR1 in which the serine residues of potential sites of phosphorylation by TGF-βRI were replaced by alanine residues. Thus, multiple mechanisms are present for the TGF-β1-mediated reduction of iNOS production, and we propose a novel mechanism for regulating inflammatory cytokine by an anti-inflammatory cytokine, TGF-β1; i.e. suppression of IFN-γ-induced STAT1 activation by an association of the IFNGR1 with the TGF-βRI.

Original languageEnglish
Pages (from-to)871-882
Number of pages12
JournalGenes to Cells
Volume11
Issue number8
DOIs
Publication statusPublished - 2006 Aug
Externally publishedYes

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Antigen-Presenting Cells
Nitric Oxide Synthase
Proteolysis
Nitric Oxide
Macrophages
Cytokines
Dendritic Cells
Phosphorylation
Protein Stability
Nitric Oxide Synthase Type II
Interleukin-12
Immunosuppressive Agents
Alanine
Serine
Tyrosine
Anti-Inflammatory Agents
Up-Regulation
Mutation
Genes

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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TGF-β1 suppresses IFN-γ-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation. / Takaki, Hiromi; Minoda, Yasumasa; Koga, Keiko; Takaesu, Giichi; Yoshimura, Akihiko; Kobayashi, Takashi.

In: Genes to Cells, Vol. 11, No. 8, 08.2006, p. 871-882.

Research output: Contribution to journalArticle

Takaki, Hiromi ; Minoda, Yasumasa ; Koga, Keiko ; Takaesu, Giichi ; Yoshimura, Akihiko ; Kobayashi, Takashi. / TGF-β1 suppresses IFN-γ-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation. In: Genes to Cells. 2006 ; Vol. 11, No. 8. pp. 871-882.
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