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GH Inhibits Interferon--Induced Signal Transducer and Activator of Transcription-1 Activation and Expression of the Inducible Isoform of Nitric Oxide Synthase in INS-1 Cells

Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo 113-0033, Japan

Address all correspondence and requests for reprints to: Dr. Nobuo Sekine, Department of Internal Medicine, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: nobuosek-tky{at}umin.ac.jp

Interferon- and TNF synergistically induce the inducible isoform of nitric oxide synthase and elicit severe cytotoxicity in pancreatic ß-cells. We demonstrate here that GH, the well known ß-cell mitogen, inhibits nitric oxide production by reducing inducible nitric oxide synthase gene induction by the two cytokines and counteracts their cytotoxic effect in insulin-secreting INS-1 cells. To elucidate the underlying mechanism, we examined activation of the transcription factors implicated in the induction of inducible nitric oxide synthase, signal transducer and activator of transcription-1, and nuclear factor-B. GH inhibited tyrosine phosphorylation and DNA binding of signal transducer and activator of transcription-1 promoted by interferon-, whereas nuclear factor-B activation by TNF was not affected by GH. GH was found to induce suppressor of cytokine signaling-1 and -3, both of which are able to inhibit interferon- activation of signal transducer and activator of transcription-1, suggesting that they are likely to mediate the inhibitory action of GH. Finally, exposure of INS-1 cells to interferon- resulted in the impairment of insulin secretion in response to glucose, which was restored by the addition of GH. These results indicate that GH counteracts the effect of interferon- through the inhibition of signal transducer and activator of transcription-1. This action of GH may be sufficient to suppress the synergistic induction of inducible nitric oxide synthase by interferon- and TNF, thereby preventing the cytotoxicity to ß-cells.

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