Cytokines affect PDX-1 expression, insulin and proinsulin secretion from iNOS deficient murine islets.
In rodent islets, exposure to interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) induces expression of inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) formation, which may inhibit islet function. However, cytokines may also induce NO-independent islet suppression. The present aim was to investigate the effect of cytokine exposure to iNOS deficient (iNOS-/-) mouse islets on various islet functions. Islets from iNOS-/- and wt mice exposed to IL-1beta or (IL-1beta + IFN-gamma) for 2-20 h showed different kinetics of glucose-stimulated insulin secretion. In iNOS-/- islets, IL-1beta at high glucose induced a delayed and prolonged stimulation of insulin secretion, and this was followed by an increase in phospholipase D mRNA expression. After 6 and 24 h, proinsulin convertase 1 and 2 (PC1 and PC2) mRNA expression was suppressed and proinsulin secretion increased from wt islets. In iNOS-/- islets, PC1 expression was recovered after 24 h, and there was no difference in proinsulin secretion. PDX-1 mRNA expression was suppressed independent of NO-formation. We conclude that cytokines induce both NO-dependent and NO-independent functional inhibition of murine beta-cells.
Andersson
Annika K
AK
Uppsala University, Department of Medical Cell Biology, Biomedicum, Sweden.
Börjesson
Andreas
A
Sandgren
Johanna
J
Sandler
Stellan
S
D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000235:genetics; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism; D011384:Proinsulin / Q000378:metabolism*; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
D016207:Cytokines; D018398:Homeodomain Proteins; D007328:Insulin; D007375:Interleukin-1; D012333:RNA, Messenger; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D009569:Nitric Oxide; D007371:Interferon-gamma; D011384:Proinsulin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D010739:Phospholipase D; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2; D005947:Glucose