GH inhibits interferon-gamma-induced signal transducer and activator of transcription-1 activation and expression of the inducible isoform of nitric oxide synthase in INS-1 cells.
Interferon-gamma and TNFalpha synergistically induce the inducible isoform of nitric oxide synthase and elicit severe cytotoxicity in pancreatic beta-cells. We demonstrate here that GH, the well known beta-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-kappa B. GH inhibited tyrosine phosphorylation and DNA binding of signal transducer and activator of transcription-1 promoted by interferon-gamma, whereas nuclear factor-kappa B activation by TNFalpha 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-gamma 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-gamma 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-gamma 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-gamma and TNFalpha, thereby preventing the cytotoxicity to beta-cells.
Sekine
N
N
nobuosek-tky@umin.ac.jpDepartment of Internal Medicine, University of Tokyo School of Medicine, Tokyo 113-0033, Japan.
Fukumoto
S
S
Ishikawa
T
T
Okazaki
T
T
Fujita
T
T
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D005947:Glucose / Q000494:pharmacology; D013006:Growth Hormone / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D016328:NF-kappa B; D012333:RNA, Messenger; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C491589:Socs1 protein, rat; C494081:Stat1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D014443:Tyrosine; D007371:Interferon-gamma; D013006:Growth Hormone; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005947:Glucose