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J. Biol. Chem., Vol. 279, Issue 25, 26789-26796, June 18, 2004

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Interferon but Not Interleukin 12 Activates STAT4 Signaling in Human Vascular Endothelial Cells^*

Nicholas Torpey¶, Stephen E. Maher||, Alfred L. M. Bothwell||, and Jordan S. Pober||**

From the Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, the Department of Pathology, and the ^||Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510 and the ^¶Department of Medicine, Addenbrooke's Hospital, Cambridge CB22QQ, United Kingdom

STAT4 signaling, activated by either interleukin 12 (IL12) or interferon (IFN), promotes T_H1 responses in CD4⁺ T cells. Vascular endothelial cells (EC) may also become polarized in response to various cytokines, favoring recruitment and activation of T_H1 or T_H2 effector cells. Here we have investigated the role of the STAT4 pathway in EC. Cultured human umbilical vein EC (HUVEC) express low levels of STAT4, which may be tyrosine-phosphorylated by treatment with IFN but not IL12. This is because HUVEC lack both subunits of the IL12 receptor (IL12R1 and IL12R2), even following treatment with various cytokines. IL12 phosphorylation of STAT4 can be observed in HUVEC that have been transduced to express the IL12R. To identify STAT4-induced genes we pursued three approaches: analysis by DNA microarray and quantitative RT-PCR (Q-PCR) of the IL12 responses in IL12R-transduced EC; analysis by Q-PCR of IFN responses in STAT4-overexpressing EC; and analysis of IFN responses in U3A neuroblastoma cell lines that express either STAT1 or STAT4, but not both. In all three instances we observe STAT4-mediated induction of the chemokine monocyte chemoattractant protein 1 (MCP1) and suppressor of cytokine signaling 3 (SOCS3) mRNA, and we confirm the production of each protein in both IL12R-transduced EC and STAT4-transduced U3A cells. These observations reveal that there is a STAT4 response of EC, activated by IFN but not IL12, and that it may modulate the pro-inflammatory behavior of EC.

Received for publication, February 11, 2004 , and in revised form, April 13, 2004.

^* This work was supported by National Institutes of Health Grant P01 HL70295 and by a National Kidney Research Fund (United Kingdom) training fellowship (to N. T.). 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.

^** To whom correspondence should be addressed: Yale University School of Medicine, 295 Congress Ave., BCMM Room 454, New Haven, CT 06510. Tel.: 203-737-2292; Fax: 203-737-2293; E-mail: Jordan.pober{at}yale.edu.

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