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J. Biol. Chem., Vol. 279, Issue 37, 38577-38589, September 10, 2004

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Class II Major Histocompatibility Complex Transactivator (CIITA) Inhibits Matrix Metalloproteinase-9 Gene Expression^*

Susan Nozell, Zhendong Ma, Cynthia Wilson, Reesha Shah, and Etty N. Benveniste

From the Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0005

Matrix metalloproteinases (MMPs) are a family of structurally related proteins with the collective capability to degrade all components of the extracellular matrix. Although MMP-mediated degradation of the extracellular matrix occurs physiologically, numerous pathological conditions exhibit increased MMP levels and excessive matrix degradation. Previous work from our laboratory has shown that interferon- inhibits MMP-9 expression in a manner dependent upon STAT-1. Here we extend our previous observations and show that the class II major histocompatibility complex transactivator (CIITA), a transcriptional target of STAT-1, is also capable of inhibiting MMP-9 expression. By using stable cell lines that inducibly express CIITA or various mutant forms of CIITA, we show that CIITA requires the ability to bind the CREB-binding protein (CBP) to effectively inhibit MMP-9 expression. Furthermore, we show that CIITA-mediated inhibition of the MMP-9 gene does not rely on the transcriptional capability of CIITA. These findings support a model wherein CIITA inhibits MMP-9 expression by binding to and sequestering CBP, which reduces the levels of CBP at the MMP-9 promoter, inhibits levels of acetylated histone 3 at the MMP-9 promoter, and subsequently inhibits MMP-9 expression.

Received for publication, April 5, 2004 , and in revised form, July 6, 2004.

^* This work was supported in part by United States Public Service NCI Grant CA-97247 and NINDS Grant NS-36765 from the National Institutes of Health (to E. N. B.). 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.

Supported by National Institutes of Health Postdoctoral Fellowship T32 AI-07493.

To whom correspondence should be addressed: Office of the Chair, Dept. of Cell Biology, University of Alabama at Birmingham, 1530 3rd Ave. S., MCLM 395, Birmingham, AL 35294-0005. Tel.: 205-934-7667; Fax: 205-975-6748; E-mail: tika{at}uab.edu.

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