부산대학교 도서관

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-1ßand IRAP overexpression on adultß-cell replication and viability. IL-1ßreduced dramaticallyß-cell replication in adult rat islets both at 5.5?mM (control: 0.29±0.04%; IL-1ß: 0.02±0.02%, P<0.05) and 22.2?mM glucose (control: 0.84±0.2%; IL-1ß: 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-1ß: 0.84±0.1%, P<0.05) and 22.2?mM glucose (Ad-IL-1Ra+IL-1ß: 1.22±0.2%, P<0.05). Moreover, overexpression of IRAP increased glucose-stimulatedß-cell replication in the absence of IL-1ßexposure (Ad-IL-1Ra: 1.59±0.5%, P<0.05).ß-Cell death (TUNEL technique) was increased in IL-1ß-exposed islets but not in Ad-IL-1Ra-infected islets (control: 0.82±0.2%; control+IL-1ß: 1.77±0.2; IRAP: 0.61±0.2%; IRAP+IL-1ß: 0.86±0.1%, P<0.05). Comparable results were obtained by flow cytometry. To determine the effect of IRAP overexpression onß-cell replication in vivo, Ad-IL-1Ra-transduced islets were transplanted into streptozotocin diabetic rats.ß-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-1ßonß-cell viability, this cytokine exerts a deleterious action onß-cell replication, which can be prevented by IRAP overexpression, and provides support for the potential use of IRAP as a therapeutic tool.Gene Therapy (2005) 12, 120-128. doi:10.1038/sj.gt.3302351 Published online 2 December 2004 [ABSTRACT FROM AUTHOR]