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Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

TGF-ß1 is a well-known immunosuppressive cytokine; however, little is known of the effect of TGF-ß1 on antigen-presenting cells (APCs). In this report, we investigated the molecular mechanisms of the suppressive effects of TGF-ß1 on APCs including dendritic cells and macrophages. Although TGF-ß1 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--induced nitric oxide (NO) production from macrophages and dendritic cells. Using murine macrophage-like cell line RAW 264.7, we demonstrated that TGF-ß1 not only reduced the inducible NO synthase (iNOS) protein stability but also suppressed the iNOS gene transcription. We also found that TGF-ß1 directly inhibited IFN--induced STAT1 activation by reducing STAT1 tyrosine phosphorylation. The IFN- Type I receptor (IFNGR1) was found to be associated with the TGF-ß1 Type I receptor (TGF-ßRI) and was phosphorylated by the TGF-ßRI. Reduced activation of STAT1 by TGF-ß1 was abrogated by the mutation in the IFNGR1 in which the serine residues of potential sites of phosphorylation by TGF-ßRI were replaced by alanine residues. Thus, multiple mechanisms are present for the TGF-ß1-mediated reduction of iNOS production, and we propose a novel mechanism for regulating inflammatory cytokine by an anti-inflammatory cytokine, TGF-ß1; i.e. suppression of IFN--induced STAT1 activation by an association of the IFNGR1 with the TGF-ßRI.

^* Correspondence: E-mail: yakihiko{at}bioreg.kyushu-u.ac.jp

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