Pituitary adenylate cyclase-activating polypeptide prevents cytokine-induced cytotoxicity via inhibition of inducible nitric oxide synthase expression in beta TC cells.
Type 1 diabetes mellitus is an autoimmune disease resulting from apoptotic destruction of pancreatic beta-cells. The activation of inducible nitric oxide synthase (iNOS) by inflammatory cytokines is considered a mediator of destruction in beta-cells. Recent findings showed that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), whose distribution was identified in pancreatic neurons, inhibited nitric oxide (NO) production in cytokine-activated macrophages. In the present study, we investigated the cytoprotective effect of PACAP in the cytokine-exposed mice beta-cell line, beta TC cells. 1 x 10(-8) M PACAP inhibited the reduction of cell viability, NO production, expression of iNOS mRNA, and iNOS promoter activity caused by the combination of three proinflammatory cytokines. Selective iNOS inhibitor also showed the cytoprotective effect in beta TC cells. These data suggested that PACAP has a cytoprotective effect in cytokine-treated beta-cells through inhibition of iNOS transcription.
Sekiya
K
K
First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya 466-8550, Japan. ksekiya@med.nagoya-u.ac.jp
Nagasaki
H
H
Ozaki
N
N
Suzuki
A
A
Miura
Y
Y
Oiso
Y
Y
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
C495401:ADCYAP1 protein, human; D016207:Cytokines; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D008156:Luciferases; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II