Interleukin-1beta-induced alteration in a beta-cell phenotype can reduce cellular sensitivity to conditions that cause necrosis but not to cytokine-induced apoptosis.
Previous work has shown that interleukin-1beta (IL-1beta) alters protein expression in beta-cells. This alteration is associated with cell death in isolated rat islets but not in isolated rat beta-cells. We examined whether IL-1beta pretreatment of isolated beta-cells influences their sensitivity to toxic agents. After a 24-h culture with IL-1beta (30 U/ml), beta-cells exhibited a lower expression of the beta-cell-specific protein transcription factor pancreatic and duodenal homeobox gene (PDX)-1, glucose transporter GLUT2, and proinsulin convertase PC2, with a marked reduction (60-70%) in glucose-induced insulin production and selective sensitivity to the toxins alloxan (ALX) and streptozotocin (STZ). On the other hand, the cells presented an increased expression of Mn-superoxide dismutase, heat shock protein 70, inducible heme oxygenase, and inducible nitrite oxide synthase. This IL-1beta-induced alteration in beta-cell phenotype resulted in a reduced cellular sensitivity to the beta-cell-specific toxins ALX and STZ; the production of nontoxic conditions of nitric oxide (NO) also rendered the cells less susceptible to radical-induced damage. Exposure to IL-1beta can thus protect beta-cells against conditions that cause necrosis; however, it did not protect against apoptosis induced by the additional presence of interferon-gamma or tumor necrosis factor-alpha. Release of IL-1beta in the endocrine pancreas is thus not necessarily the cause of massive NO-dependent beta-cell destruction. On the contrary, IL-1beta may protect these cells against necrosis, though with a loss of their characteristic phenotype and homeostatic functions.
Ling
Z
Z
Faculty of Medicine, Diabetes Research Center, Vrije Universiteit Brussel, Belgium.
Van de Casteele
M
M
Eizirik
D L
DL
Pipeleers
D G
DG
D000496:Alloxan / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D008297:Male; D009336:Necrosis; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009994:Osmolar Concentration; D010641:Phenotype; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D016207:Cytokines; D007375:Interleukin-1; D020030:Nitric Oxide Donors; D011506:Proteins; D014230:Triazoles; D013311:Streptozocin; D000496:Alloxan; C082874:GEA 3162