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J. Biol. Chem., Vol. 282, Issue 46, 33515-33529, November 16, 2007

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A Novel Role of the Interferon-inducible Protein IFI16 as Inducer of Proinflammatory Molecules in Endothelial Cells^*

Patrizia Caposio, Francesca Gugliesi, Claudia Zannetti, Simone Sponza, Michele Mondini, Enzo Medico^¶, John Hiscott^||, Howard A. Young^**, Giorgio Gribaudo, Marisa Gariglio, and Santo Landolfo¹

From the Department of Public Health and Microbiology and the ^¶Institute for Cancer Research and Treatment, University of Turin, Turin 10126, Italy, the ^||Lady Davis Institute, McGill University, Montreal H3T 1E2, Canada, the ^**Laboratory of Experimental Immunology, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, and the Department of Clinical and Experimental Medicine, University of Piemonte Orientale, 28100 Novara, Italy

The human IFI16 gene is an interferon-inducible gene implicated in the regulation of endothelial cell proliferation and tube morphogenesis. Immunohistochemical analysis has demonstrated that this gene is highly expressed in endothelial cells in addition to hematopoietic tissues. In this study, gene array analysis of human umbilical vein endothelial cells overexpressing IFI16 revealed an increased expression of genes involved in immunomodulation, cell growth, and apoptosis. Consistent with these observations, IFI16 triggered expression of adhesion molecules such as ICAM-1 and E-selectin or chemokines such as interleukin-8 or MCP-1. Treatment of cells with short hairpin RNA targeting IFI16 significantly inhibited ICAM-1 induction by interferon (IFN)- demonstrating that IFI16 is required for proinflammatory gene stimulation. Moreover, functional analysis of the ICAM-1 promoter by deletion- or site-specific mutation demonstrated that NF-B is the main mediator of IFI16-driven gene induction. NF-B activation appears to be triggered by IFI16 through a novel mechanism involving suppression of IB mRNA and protein expression. Support for this finding comes from the observation that IFI16 targeting with specific short hairpin RNA down-regulates NF-B binding activity to its cognate DNA and inhibits ICAM-1 expression induced by IFN-. Using transient transfection and luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we demonstrate indeed that activation of the NF-B response is mediated by IFI16-induced block of Sp1-like factor recruitment to the promoter of the IB gene, encoding the main NF-B inhibitor. Activation of NF-B accompanied by induction of proinflammatory molecules was also observed when IB expression was down-regulated by specific small interfering RNA, resulting in an outcome similar to that observed with IFI16 overexpression. Taken together, these data implicate IFI16 as a novel regulator of endothelial proinflammatory activity and provide new insights into the physiological functions of the IFN-inducible gene IFI16.

Received for publication, March 2, 2007 , and in revised form, July 25, 2007.

^* This work was supported by grants from MIUR (PRIN and 60%), Regione Piemonte and Fondazione Internazionale di Ricerca in Medicina Sperimentale, and Fondazione San Paolo, Turin. 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 To whom correspondence should be addressed: Laboratory of Viral Pathogenesis, Dept. of Public Health and Microbiology, Medical School of Turin, Via Santena 9, 10126 Torino, Italy. Tel.: 39-011-6705636; Fax: 39-011-6705646; E-mail: santo.landolfo{at}unito.it.

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