1. ¹Laboratory of Diabetes and Experimental Endocrinology, Endocrine Unit, Hospital Universitari Bellvitge, University of Barcelona, Barcelona, Spain
2. ²Biology Unit, Serveis Científico-Tècnics, Campus Bellvitge, University of Barcelona, Barcelona, Spain

Correspondence: Dr E Montanya, Endocrine Unit (13-2), Hospital Universitari Bellvitge, Feixa Llarga, s/n 08907 L'Hospitalet de Llobregat, Barcelona, Spain

Received 29 January 2004; Accepted 12 June 2004; Published online 2 December 2004.

Abstract

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-1 and IRAP overexpression on adult -cell replication and viability. IL-1 reduced dramatically -cell replication in adult rat islets both at 5.5 mM (control: 0.290.04%; IL-1: 0.020.02%, P<0.05) and 22.2 mM glucose (control: 0.840.2%; IL-1: 0.050.05%, P<0.05). This effect was completely prevented in islets overexpressing IRAP after adenoviral gene transfer at 5.5 mM (Ad-IL-1Ra+IL-1: 0.840.1%, P<0.05) and 22.2 mM glucose (Ad-IL-1Ra+IL-1: 1.220.2%, P<0.05). Moreover, overexpression of IRAP increased glucose-stimulated -cell replication in the absence of IL-1 exposure (Ad-IL-1Ra: 1.590.5%, P<0.05). -Cell death (TUNEL technique) was increased in IL-1-exposed islets but not in Ad-IL-1Ra-infected islets (control: 0.820.2%; control+IL-1: 1.770.2; IRAP: 0.610.2%; IRAP+IL-1: 0.860.1%, P<0.05). Comparable results were obtained by flow cytometry. To determine the effect of IRAP overexpression on -cell replication in vivo, Ad-IL-1Ra-transduced islets were transplanted into streptozotocin diabetic rats. -Cell replication was significantly increased in IRAP-overexpressing islet grafts (0.980.3%, P<0.05) compared to normal pancreas (0.350.02%), but not in control islet grafts (0.500.1%). This study shows that in addition to the effects of IL-1 on -cell viability, this cytokine exerts a deleterious action on -cell replication, which can be prevented by IRAP overexpression, and provides support for the potential use of IRAP as a therapeutic tool.