Suppressive effects of glucagon-like peptide-1 on interferon-gamma-induced nitric oxide production in insulin-producing cells is mediated by inhibition of tumor necrosis factor-alpha production.
During the development of Type 1 diabetes, inflammatory cytokines are known to induce the expression of inducible nitric oxide synthase (iNOS) in pancreatic islets, and subsequent production of nitric oxide (NO) contributes to beta cell destruction. Glucagon-like peptide-1 (GLP-1) has been shown to reduce cytokine-induced apoptosis of beta cells. In this study, we investigated whether GLP-1 affects cytokine-induced NO production, resulting in the inhibition of beta-cell apoptosis. We treated MIN6N8a mouse beta cells with interferon (IFN)-gamma in the presence or absence of GLP-1 and found that IFN-gamma treatment induced iNOS mRNA expression and NO production, which was significantly inhibited by treatment with GLP-1. Blocking of GLP-1 receptor signaling via the cyclic AMP and phosphatidylinositol 3-kinase pathway did not directly affect the suppressive effect of GLP-1 on IFN- gamma-induced iNOS mRNA expression. Further studies revealed that IFN-gamma induced the expression of TNF-alpha mRNA and protein, which synergistically induced NO production, and GLP-1 treatment inhibited this induction of TNF-alpha. To examine whether the reduction of TNF-alpha by GLP-1 treatment plays a role in suppressing NO production, we treated MIN6N8a cells with IFN-gamma in the presence of anti-TNF-alpha neutralizing antibody and found that NO production was reduced. In addition, treatment of mouse islets with GLP-1 inhibited the expression of iNOS and TNFmRNA. These results suggest that GLP-1 inhibits IFN-gamma-induced NO production by suppression of TNF-alpha production.
Hahm
E
E
Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, North Chicago, Illinois, USA.
Lee
Y-S
YS
Jun
H-S
HS
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D007328:Insulin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D052216:Glucagon-Like Peptide 1