Protection of islet cells from inflammatory cell death in vitro.
Islet cells cocultured with activated macrophages are lysed within 15 h in vitro. We showed previously that nitric oxide generated by macrophages is a major mediator of islet cell death. We have now probed several pathways to interfere with the chain of events leading to islet cell death. Scavenging of extracellular oxygen radicals by superoxide dismutase and catalase did not improve islet cell survival. Scavenging of extra- and intracellular oxygen radicals by two potent substances, citiolone and dimethyl-thiourea, also did not reduce islet cell lysis, while a lipid-soluble scavenger, probucol, provided partial protection. These findings argue against a synergistic action of nitric oxide and oxygen radicals in islet cell toxicity. The inhibition of poly(ADP-ribose)polymerase by 3-aminobenzamide significantly improved islet cell survival. Selective inhibitors of cyclooxygenase, such as indomethacin or acetylsalicylic acid, did not improve islet cell survival. Full protection was seen in the presence of NDGA, an inhibitor of lipoxygenase, and partial suppression was caused by BW755c, an inhibitor of both lipoxygenase and cyclooxygenase. We conclude that inflammatory islet cell death caused by activated macrophages involves the activation of arachidonic acid metabolism and of poly(ADP-ribose)polymerase, but that scavenging of oxygen free radicals provides little protection from lysis.
Burkart
V
V
Diabetes Research Institute, Heinrich-Heine University, Düsseldorf, Germany.
Kolb
H
H
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D016923:Cell Death; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004260:DNA Repair; D007515:Islets of Langerhans / Q000473:pathology*; D008264:Macrophages / Q000276:immunology*; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D019323:omega-N-Methylarginine
D001549:Benzamides; D017382:Reactive Oxygen Species; D019323:omega-N-Methylarginine; D016718:Arachidonic Acid; C025160:3-aminobenzamide; D001120:Arginine; D011065:Poly(ADP-ribose) Polymerases