An Imidazoline Compound Completely Counteracts Interleukin-1β toxic Effects to Rat Pancreatic Islet β Cells

Gianpaolo Papaccio,Francesco A Pisanti,Michela Galdieri,Klaus Bendtzen,Ferdinando Nicoletti

doi:10.1007/bf03402163

Abstract

In vitro studies have demonstrated that interleukin (IL)-1beta decreases insulin and DNA contents in pancreatic islet beta cells, causing structural damage, that it is toxic to cultured human islet beta cells and that it is able to induce apoptosis in these cells. Isolated rat islets of Langerhans were exposed in vitro to interleukin (IL)-1beta and either the imidazoline compound RX871024 (RX) or/and M40403, an Mn-containing superoxide dismutase mimetic (MnSODm). Insulin secretion, on days 1, 2 and 3 after challenge with 3 ng/ml of IL-1beta, was almost abolished and this was accompanied by an early increase in MnSOD activity. By days 2 and 3, SOD activities were lower than those of untreated controls and NO significantly increased by day 2. Moreover, IL-1beta induced a significant increase in MnSOD transcripts, while iNOS mRNA appeared by days 2 and 3 when MnSOD mRNA was absent. RX blocked all toxic effects of IL-1beta by maintaining insulin secretion and islet beta cell phenotype, including the inhibition of nonspecific proteins and of iNOS induction. In contrast, the MnSODm, failed to counteract iNOS induction as well as the reduced insulin secretion. In summary, our findings stress that IL-1beta-induced suppression of insulin secretion may be related to iNOS induction in beta cells and that RX can reverse this effect, by maintaining insulin secretion. Oppositely, the MnSODm is not able to restore IL-1beta-suppressed insulin secretion. Hence, imidazoline compounds may protect beta cells against damage caused by IL-1beta-induced free oxygen and nitrogen radicals.

Highlights

In vitro studies have demonstrated that interleukin (IL)-1␤ decreases insulin and DNA contents in pancreatic islet ␤ cells, causing structural damage [1,2,3]
Since it is still uncertain to what extent free radicals may contribute to the toxic effect of IL-1␤ on ␤ cells, we studied the effects of an imidazoline compound and an Mn-containing superoxide dismutase mimetic (MnSODm) on the in vitro responses of isolated rat islets to IL-1␤ with emphasis on the effects on the transcriptional levels and activities of MnSOD, CuZnSOD and total SOD, and expression of inducible form of nitric oxide synthase (iNOS) and nitric oxide production
When both the imidazoline compound and the SODm were added to IL-1␤ cultured islets, the total islet insulin secretion was slightly lower with respect to the levels found after the use of RX by alone, but higher than those observed using the SODm

Summary

Introduction

In vitro studies have demonstrated that interleukin (IL)-1␤ decreases insulin and DNA contents in pancreatic islet ␤ cells, causing structural damage [1,2,3]. Administration of superoxide dismutase (SOD), the first cellular defense against toxic free radicals, protects ␤ cells from damage induced by alloxan and/or streptozotocin [9,10,11,12,13]. In vitro studies have demonstrated that interleukin (IL)-1␤ decreases insulin and DNA contents in pancreatic islet ␤ cells, causing structural damage, that it is toxic to cultured human islet ␤ cells and that it is able to induce apoptosis in these cells. RX blocked all toxic effects of IL-1␤ by maintaining insulin secretion and islet ␤ cell phenotype, including the inhibition of nonspecific proteins and of iNOS induction.

Methods

Results

Conclusion