TGF-β suppresses IFN-γ-STAT1-dependent gene transcription by enhancing STAT1-PIAS1 interactions in epithelia but not monocytes/macrophages

Colin Reardon, Derek M. McKay

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

IFN-γ and TGF-β are important regulators of mucosal immunity, typically functioning in opposition to each other. In this study, we assessed whether TGF-β could modulate IFN-γ-induced STAT1 signaling. Model epithelial cell lines (HEp-2, HT-29, and T84) or monocytes/macrophages (THP-1 cell line, human blood mononuclear cells) were pretreated with TGF-β (1 ng/ml; 5-60 min), followed by IFN-γ exposure (20 ng/ml; 30 min), and then STAT1 transcriptional activity, DNA-binding activity, phosphorylation, and methylation were assessed. Some epithelia were transfected with an expression plasmid encoding SMAD7 to block TGF-β-SMAD signaling. Epithelia, but not macrophages, pretreated with TGF-β were hyporesponsive to IFN-γ stimulation as indicated by reduced expression of four STAT1-regulated genes and reduced STAT1 DNA binding on EMSA. However, STAT1 Tyr701-, Ser 727 phosphorylation, and nuclear recruitment of STAT1 were not significantly different in IFN-γ with or without TGF-β-treated cells, indicating that the effects of TGF-β are downstream of IFN-γR-JAK-STAT1 interaction. The TGF-β effect was not dependent on ERK1/2, p38, or JNK activation but was prevented by overexpression of the inhibitory SMAD7 protein. Additional studies suggest that TGF-β blockade of IFN-γ activity in epithelia is via enhanced sequestering of STAT1 by pre-existing protein inhibitor of activated STAT1. These results demonstrate that TGF-β rapidly suppresses IFN-γ-driven STAT1 signaling by reducing DNA binding via promotion of STAT1-protein inhibitor of activated STAT1 interactions and not inhibition of STAT1 activation; an event that may be specific to epithelia and represent a novel mode of action of TGF-β.

Original languageEnglish (US)
Pages (from-to)4284-4295
Number of pages12
JournalJournal of Immunology
Volume178
Issue number7
StatePublished - Apr 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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