Interleukin (IL)-1beta toxicity to islet beta cells: Efaroxan exerts a complete protection.
Interleukin (IL)-1beta-treated rat islets of Langerhans were exposed in vitro either to the imidazoline compound, Efaroxan, or to the selective inducible nitric oxide synthase (iNOS) inhibitor, 1400W, in a medium containing a high concentration of glucose (16.7 mmol/L). Our data have evidenced the following: (i) addition of Efaroxan to islet cultures inhibited IL-1beta activation of ICE (cysteine protease IL-1beta converting enzyme) while addition of 1400W did not; (ii) Efaroxan completely inhibited IL-1beta-induced suppression of insulin secretion and induction of iNOS mRNA transcripts, and, in addition, counteracted islet beta-cell protein profile alterations, Bax-cytochrome c translocation, caspase activation, and apoptosis; (iii) 1400W inhibited IL-1beta induction of iNOS, but failed to completely counteract the other cytotoxic effects; (iv) the two compounds, moreover, exerted different effects on manganese superoxide dismutase (MnSOD), in fact, while Efaroxan inhibited the early stimulatory effect of IL-1beta on MnSOD, 1400W did not. Thus, Efaroxan completely protected islet beta cells from damage caused by IL-1beta-induced toxicity, while compound 1400W only inhibited NO radical production without altering the cytokine's cytotoxicity. Our observations have evidenced that suppression of ICE activation is required to counteract IL-1beta-mediated islet beta cell toxicity, and that IL-1beta-induced apoptosis is NO-independent and involves the cytochrome c-mitochondrial pathway.
Papaccio
Gianpaolo
G
Department of Experimental Medicine, Section of Histology and Embryology, School of Medicine, 2nd University of Naples, Naples, Italy. gianpaolo.papaccio@unina2.it
Graziano
Antonio
A
Valiante
Salvatore
S
D'Aquino
Riccardo
R
Travali
Salvatore
S
Nicoletti
Ferdinando
F
D000154:Aconitate Hydratase / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D000317:Adrenergic alpha-Antagonists; D000578:Amidines; C494828:Bax protein, rat; D001572:Benzofurans; D001596:Benzylamines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007328:Insulin; D007375:Interleukin-1; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009566:Nitrates; D009573:Nitrites; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase; D020169:Caspases; D000154:Aconitate Hydratase; C062597:efaroxan