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-1 beta: 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-1 beta: 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-1 beta-exposed islets but not in Ad-IL-1Ra-infected islets control: 0.82 +/- 0.2%; control+ IL-1 beta: 1.77 +/- 0.2; IRAP: 0.61 +/- 0.2%; IRAP+ IL-1 beta: 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-1 beta 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.