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* Department of Microbiology and
Department of Medicine, Columbia University, New York, NY 10032
MHC type II (MHC II) expression is tightly regulated in macrophages and potently induced by IFN-
(type II IFN). In contrast, type I IFNs (IFN-Is), which are far more widely expressed, fail to induce MHC II expression, even though both classes of IFNs direct target gene expression through Stat1. The unexpected finding that IFN-Is effectively induce MHC II expression in Stat2–/– macrophages provided an opportunity to explore this conundrum. The ensuing studies revealed that deletion of Stat2, which uniquely transduces signals for IFN-Is, leads to a loss in the IFN-I-dependent induction of suppressor of cytokine signaling-1. Impairment in the expression of this important negative regulator led to a striking prolongation in IFN-I-dependent Stat1 activation, as well as enhanced expression of the target gene, IFN-regulatory factor-1. The prolonged activity of these two transcription factors synergized to drive the transcription of CIITA, the master regulator of MHC II expression, analogous to the pattern observed in IFN--treated macrophages. Thus, IFN-I-dependent suppressor of cytokine signaling-1 expression plays an important role in distinguishing the biological response between type I and II IFNs in macrophages.
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 National Institutes of Health Grants AI 058211, HL 55413, 5T32 GM 07367, and 5T32 AI 07525, and the Burroughs Wellcome Fund (APP 2010).
2 W.Z. and E.N.C. contributed equally to this study.
3 Current address: Department of Pathology, Stanford University, Stanford CA 94304.
4 Address correspondence and reprint requests to Dr. Christian Schindler, Columbia University, Hammer Health Science Center 1212, 701 West 168th Street, New York, NY 10032. E-mail address: cws4{at}columbia.edu
5 Abbreviations used in this paper: MHC I, MHC type I; MHC II, MHC class II; IRF, IFN-regulatory factor; IFNAR, IFN-
receptor; ISRE, IFN-stimulated response element; IFN-I, type I IFN; GAS, -activation site; BM, bone marrow; BMM, BM macrophage; WT, wild type; DC, dendritic cell; Socs, suppressor of cytokine signaling; ChIP, chromatin immunoprecipitation; Q-PCR, quantitative PCR; RPA, RNase protection assay; ISGF-3, IFN-stimulated gene factor 3; USF-1, upstream stimulatory factor 1.
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