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J. Biol. Chem., Vol. 282, Issue 13, 9797-9804, March 30, 2007

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Essential Role of the JAK/STAT1 Signaling Pathway in the Expression of Inducible Nitric-oxide Synthase in Intestinal Epithelial Cells and Its Regulation by Butyrate^*

Mateja Stempelj¹, Michele Kedinger, Leonard Augenlicht, and Lidija Klampfer²

From the Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467 and INSERM U682, Université Louis Pasteur, 67200 Strasbourg, France

Nitric oxide (NO) is a highly reactive free radical that modulates tumorigenesis through its ability to regulate cell proliferation, cell death, migration and angiogenesis. Although the role of NO has been well studied in inflammatory cells, much less is known about the regulation of NO production in epithelial cells. We demonstrated that in intestinal epithelial cells the expression of inducible NO synthase (iNOS), the critical enzyme in the synthesis of NO, is synergistically stimulated by bacterial lipopolysaccharide (LPS) and interferon (IFN) or by the combination of tumor necrosis factor (TNF) and IFN at the transcriptional level. Expression of iNOS and the production of NO in response to LPS/IFN were significantly increased upon induction of oncogenic K-Ras, underlying frequently elevated expression of iNOS in colon cancer. Silencing of STAT1, a major transcription factor involved in signaling by IFN, or pharmacological inhibition of JAKs, kinases that phosphorylate STATs, prevented the induction of iNOS and the production of NO in response to stimulation of cells with LPS/IFN or TNF/IFN, underscoring the importance of the intact JAK/STAT signaling in the regulation of iNOS expression in intestinal epithelial cells. Butyrate, a histone deacetylase (HDAC) inhibitor and a dietary chemopreventive agent, decreased NO production in macrophages and in intestinal myofibroblasts, consistent with its anti-inflammatory activity. In contrast, in intestinal epithelial cells, butyrate significantly enhanced the expression of iNOS and the production of NO in response to treatment with LPS/IFN. Despite the fact that, like butyrate, three structurally unrelated inhibitors of HDAC activity, trichostatin A, suberoylanilide hydroxamic acid, and apicidin, induced acetylation of H3 and H4 in epithelial cells, they failed to increase the production of NO, demonstrating that butyrate regulates NO production in epithelial cells in an HDAC-independent manner. The ability of butyrate to regulate the production of NO in a variety of cell types is likely to underlie its potent chemopreventive and anti-inflammatory activity.

Received for publication, October 5, 2006 , and in revised form, January 17, 2007.

^* This work was supported by NCI, National Institutes of Health Grants RO1 CA111361 (to L. K.), U54 CA100926 (to L. A.), and P30-13330. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Current address: Dept. of Pharmacology, Medical School of Ljubljana, 1000 Ljubljana, Slovenia.

² To whom correspondence should be addressed: Albert Einstein Cancer Center, Montefiore Medical Center, 111 E. 210th St., Bronx, NY 10467. Tel.: 718-920-6579; Fax: 718-882-4464; E-mail: lklampf{at}aecom.yu.edu.

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