Interleukin-17 stimulates inducible nitric oxide synthase-dependent toxicity in mouse beta cells.
The influence of the proinflammatory cytokine interleukin (IL)-17 on inducible nitric oxide (NO) synthase (iNOS)-mediated NO release was investigated in the mouse insulinoma cell line MIN6 and mouse pancreatic islets. IL-17 markedly augmented iNOS mRNA/protein expression and subsequent NO production induced in MIN6 cells or pancreatic islets by different combinations of interferon-gamma, tumor necrosis factor-alpha, and IL-1beta. The induction of iNOS by IL-17 was preceded by phosphorylation of p38 mitogen-activated protein kinase (MAPK), and inhibition of p38 MAPK activation completely abolished IL-17-stimulated NO release. IL-17 enhanced the NO-dependent toxicity of proinflammatory cytokines toward MIN6 cells, while IL-17-specific neutralizing antibody partially reduced the NO production and rescued insulinoma cells and pancreatic islets from NO-dependent damage induced by activated T cells. Finally, a significant increase in blood IL-17 levels was observed in a multiple low-dose streptozotocin model of diabetes, suggesting that T cell-derived IL-17 might be involved in NO-dependent damage of beta cells in this disease.
Miljkovic
D
D
Institute for Biological Research Sinisa Stankovic, Belgrade, Serbia and Montenegro.
Cvetkovic
I
I
Momcilovic
M
M
Maksimovic-Ivanic
D
D
Stosic-Grujicic
S
S
Trajkovic
V
V
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D020381:Interleukin-17 / Q000502:physiology*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000502:physiology / Q000633:toxicity*; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020381:Interleukin-17; D011994:Recombinant Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases