| Abstrakt | | 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 is 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)is synergistically stimulated by bacterial lipopolysaccharide (LPS) and IFN gamma or by the combination of TNF and IFN gamma at the transcriptional level. Expression of iNOS and the production of NO in response to LPS/IFN gamma 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 IFNgamma, 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/IFNgammaor TNF/IFN gamma underscoring the importance of the intact JAK/STAT signaling in the regulation of iNOS expression in intestinal epithelial cells. Butyrate, an HDAC inhibitor and a dietary chemopreventive agent, decreased NO production in macrophages and in intestinal myofibroblats, 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/IFNgamma Despite the fact that, like butyrate, three structurally unrelated inhibitors of HDAC activity, TSA, SAHA 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. (Abs. trunc. at 2000 ch.)
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