title: TGF-beta1 suppresses IFN-gamma-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation.
abstract: TGF-beta1 is a well-known immunosuppressive cytokine; however, little is known of the effect of TGF-beta1 on antigen-presenting cells (APCs). In this report, we investigated the molecular mechanisms of the suppressive effects of TGF-beta1 on APCs including dendritic cells and macrophages. Although TGF-beta1 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-gamma-induced nitric oxide (NO) production from macrophages and dendritic cells. Using murine macrophage-like cell line RAW 264.7, we demonstrated that TGF-beta1 not only reduced the inducible NO synthase (iNOS) protein stability but also suppressed the iNOS gene transcription. We also found that TGF-beta1 directly inhibited IFN-gamma-induced STAT1 activation by reducing STAT1 tyrosine phosphorylation. The IFN-gamma Type I receptor (IFNGR1) was found to be associated with the TGF-beta1 Type I receptor (TGF-betaRI) and was phosphorylated by the TGF-betaRI. Reduced activation of STAT1 by TGF-beta1 was abrogated by the mutation in the IFNGR1 in which the serine residues of potential sites of phosphorylation by TGF-betaRI were replaced by alanine residues. Thus, multiple mechanisms are present for the TGF-beta1-mediated reduction of iNOS production, and we propose a novel mechanism for regulating inflammatory cytokine by an anti-inflammatory cytokine, TGF-beta1; i.e. suppression of IFN-gamma-induced STAT1 activation by an association of the IFNGR1 with the TGF-betaRI.
authors.affiliation: Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Takaki
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Minoda
authors.forename: Keiko
authors.initials: K
authors.lastname: Koga
authors.forename: Giichi
authors.initials: G
authors.lastname: Takaesu
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects; D000954:Antigens, Surface / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011489:Protein Denaturation / Q000187:drug effects; D017471:Receptors, Interferon / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology; D053773:Transforming Growth Factor beta1; D000096743:Interferon gamma Receptor
chemical_list: D000954:Antigens, Surface; D016207:Cytokines; D007371:Interferon-gamma; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D018125:Receptors, Transforming Growth Factor beta; D050794:STAT1 Transcription Factor; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000096743:Interferon gamma Receptor; C508961:Tgfb1 protein, mouse