title: RX871024 reduces NO production but does not protect against pancreatic beta-cell death induced by proinflammatory cytokines.
abstract: The imidazoline compound RX871024 reduces IL-1beta-induced NO production thereby protecting against IL-1beta-induced beta-cell apoptosis. The aim of this study was to evaluate whether imidazolines RX871024 and efaroxan protect beta-cells against death in the presence of a combination of the cytokines IL-1beta, IFNgamma, and TNFalpha. To address this issue, experiments involving different methods for detection of cell death, different concentrations of the cytokines, and a variety of conditions of preparation and culturing of ob/ob mouse islets and beta-cells have been carried out. Thoroughly performed experiments have not been able to demonstrate a protective effect of RX871024 and efaroxan on beta-cell death induced by the combination of cytokines. However, the inhibitory effect of RX871024 on NO production in ob/ob mouse islets and beta-cells was still observed in the presence of all three cytokines and correlated with the decrease in p38 MAPK phosphorylation. Conversely, efaroxan did not affect cytokine-induced NO production. Our data indicate that a combination of pro-inflammatory cytokines IL-1beta, IFNgamma, and TNFalpha, conditions modelling those that take place in type 1 diabetes, induces pancreatic beta-cell death that does not directly correlate with NO production and cannot be counteracted with imidazoline compounds.
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Irina I
authors.initials: II
authors.lastname: Zaitseva
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sharoyko
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.forename: Suad
authors.initials: S
authors.lastname: Efendic
authors.forename: Christopher
authors.initials: C
authors.lastname: Guerin
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Nicotera
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Zaitsev
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D001572:Benzofurans; D016207:Cytokines; D007093:Imidazoles; D007211:Indoles; D007328:Insulin; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; C062597:efaroxan