Two Distinct Gamma Interferon-Inducible Promoters of the Major Histocompatibility Complex Class II Transactivator Gene Are Differentially Regulated by STAT1, Interferon Regulatory Factor 1, and Transforming Growth Factor beta

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Molecular and Cellular Biology, January 1999, p. 431-440, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Two Distinct Gamma Interferon-Inducible Promoters of the Major Histocompatibility Complex Class II Transactivator Gene Are Differentially Regulated by STAT1, Interferon Regulatory Factor 1, and Transforming Growth Factor $beta$

Janet F. Piskurich, Michael W. Linhoff, Ying Wang, and Jenny P.-Y. Ting^*

Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Received 11 August 1998/Returned for modification 9 September 1998/Accepted 28 September 1998

The major histocompatibility complex (MHC) class II transactivator (CIITA) is the master regulatory factor required for appropriateexpression of class II MHC genes. Understanding the expressionof CIITA is key to understanding the regulation of class II MHCgenes. This report describes the independent regulation of twodistinct CIITA promoters by cytokines with opposing functions,gamma interferon (IFN- $gamma$ ) and transforming growth factor $beta$ (TGF- $beta$ ).A functional analysis of deletion mutations of the upstream promoter(promoter III) identified an IFN- $gamma$ -responsive region located approximately5 kb from the transcriptional start site. An in vivo DNase I hypersensitivityanalysis detected a hypersensitive site in this area which supportsthe relevance of this region. When the downstream promoter (promoterIV) was studied by in vivo genomic footprinting, IFN- $gamma$ -inducedchanges at putative binding sites for STAT1, interferon regulatoryfactor 1 (IRF-1), and E-box proteins were seen. Gel shift andsupershift analyses for IRF-1 confirmed the in vivo footprintresults. The role of the IFN- $gamma$ -inducible transcription factorSTAT1 was examined functionally. Although both promoters werecontrolled by STAT1, promoter-specific regulation was exhibited.The IFN- $gamma$ response of promoter III was completely dependent onSTAT1 and not IRF-1, while promoter IV was partially activatedby IRF-1 in the total absence of STAT1 expression. While bothpromoters were affected by TGF- $beta$ , activation of promoter III byIFN- $gamma$ was more severely diminished by TGF- $beta$ treatment. The differentialcontrol of CIITA promoters by TGF- $beta$ , IRF-1, and STAT1 may be importantin refining regulation of class II MHC genes in different celltypes and under different stimulatoryconditions.

^* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology,CB 7295, University of North Carolina at Chapel Hill, Chapel Hill,NC 27599. Phone: (919) 966-5538. Fax: (919) 966-3015. E-mail:panyun{at}med.unc.edu.

Molecular and Cellular Biology, January 1999, p. 431-440, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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