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TGF- Suppresses IFN--STAT1-Dependent Gene Transcription by Enhancing STAT1-PIAS1 Interactions in Epithelia but Not Monocytes/Macrophages¹

Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada

IFN- and TGF- are important regulators of mucosal immunity, typically functioning in opposition to each other. In this study, we assessed whether TGF- could modulate IFN--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- (1 ng/ml; 5–60 min), followed by IFN- 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--SMAD signaling. Epithelia, but not macrophages, pretreated with TGF- were hyporesponsive to IFN- stimulation as indicated by reduced expression of four STAT1-regulated genes and reduced STAT1 DNA binding on EMSA. However, STAT1 Tyr⁷⁰¹-, Ser⁷²⁷ phosphorylation, and nuclear recruitment of STAT1 were not significantly different in IFN- with or without TGF--treated cells, indicating that the effects of TGF- are downstream of IFN-R-JAK-STAT1 interaction. The TGF- 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- blockade of IFN- activity in epithelia is via enhanced sequestering of STAT1 by pre-existing protein inhibitor of activated STAT1. These results demonstrate that TGF- rapidly suppresses IFN--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-.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Canadian Institutes for Health Research Grant MT-13421 (to D.M.M.). D.M.M. is supported by an Alberta Heritage Foundation for Medical Research Scientist Award and a Canada Research Chair (Tier 1). C.R. is a recipient of Natural Sciences and Engineering Research Council of Canada studentship and had former support from a Premiers Research Excellence Award (to D.M.M.), Canadian Institutes for Health Research, and Ontario Graduate studentships.

² Address correspondence and reprint requests to Dr. Derek M. McKay, Gastrointestinal Research Group, Department of Physiology and Biophysics, HS-1877, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Canada. E-mail address: dmckay{at}ucalgary.ca

³ Abbreviations used in this paper: PIAS1, protein inhibitor of activated STAT1; GBP-1, guanylate binding protein 1; hSIE, high-affinity sis-inducible element; iNOS, inducible NO synthase; IRF-1, IFN--regulated factor-1; RIPA, radioimmunoprecipitation assay; SAPK, stress-activated protein kinase; siRNA, small interfering RNA.

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