Adenoviral overexpression of interleukin-1 receptor antagonist protein increases beta-cell replication in rat pancreatic islets.
The naturally occurring inhibitor of interleukin-1 (IL-1) action, interleukin-1 receptor antagonist protein (IRAP), binds to the type 1 IL-1 receptor but does not initiate IL-1 signal transduction. In this study, we have determined the effects of IL-1beta and IRAP overexpression on adult beta-cell replication and viability. IL-1beta reduced dramatically beta-cell replication in adult rat islets both at 5.5 mM (control: 0.29+/-0.04%; IL-1beta: 0.02+/-0.02%, P<0.05) and 22.2 mM glucose (control: 0.84+/-0.2%; IL-1beta: 0.05+/-0.05%, P<0.05). This effect was completely prevented in islets overexpressing IRAP after adenoviral gene transfer at 5.5 mM (Ad-IL-1Ra+IL-1beta: 0.84+/-0.1%, P<0.05) and 22.2 mM glucose (Ad-IL-1Ra+IL-1beta: 1.22+/-0.2%, P<0.05). Moreover, overexpression of IRAP increased glucose-stimulated beta-cell replication in the absence of IL-1beta exposure (Ad-IL-1Ra: 1.59+/-0.5%, P<0.05). beta-Cell death (TUNEL technique) was increased in IL-1beta-exposed islets but not in Ad-IL-1Ra-infected islets (control: 0.82+/-0.2%; control+IL-1beta: 1.77+/-0.2; IRAP: 0.61+/-0.2%; IRAP+IL-1beta: 0.86+/-0.1%, P<0.05). Comparable results were obtained by flow cytometry. To determine the effect of IRAP overexpression on beta-cell replication in vivo, Ad-IL-1Ra-transduced islets were transplanted into streptozotocin diabetic rats. beta-Cell replication was significantly increased in IRAP-overexpressing islet grafts (0.98+/-0.3%, P<0.05) compared to normal pancreas (0.35+/-0.02%), but not in control islet grafts (0.50+/-0.1%). This study shows that in addition to the effects of IL-1beta on beta-cell viability, this cytokine exerts a deleterious action on beta-cell replication, which can be prevented by IRAP overexpression, and provides support for the potential use of IRAP as a therapeutic tool.
Téllez
N
N
Laboratory of Diabetes and Experimental Endocrinology, Endocrine Unit, Hospital Universitari Bellvitge, University of Barcelona, Barcelona, Spain.
Montolio
M
M
Biarnés
M
M
Castaño
E
E
Soler
J
J
Montanya
E
E
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D011917:Rats, Inbred Lew; D012795:Sialoglycoproteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods
D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins