Short Exposure of Rat Pancreatic Islets to Interleukin-1β Induces a Sustained but Reversible Impairment in β-Cell Function: Influence of Protease Activation, Gene Transcription, and Protein Synthesis*

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Abstract
In an attempt to gain further knowledge about the mechanism of action of recombinant interleukin-1β (rIL-β) on rat pancreatic β-cells, we studied the effects of short term rIL-lβ exposure (50 U/ml for 1 h) on islet function over the next 72 h. There was an initial increase in glucose-induced insulin release, followed by a decrease in islet function, reaching a nadir (values of insulin release about 20% of those observed in control islets) 10–12 h after treatment with the cytokine. Thereafter, the islets recovered their function, reaching levels of insulin secretion similar to the control values after 72 h. Short term exposure to rIL-1β did not induce a decrease in either islet DNA or islet insulin content. Using this experimental approach, we tested whether 1-h incubation of islets in the presence of various agents plus rlL- 1β could counteract the inhibitory effects of the cytokine 10–12 h later. Both actinomycin-D (5μ/ml), an inhibitor of DNA transcription, and Nαp-tosyl-L-lysine chloromethyl ketone (0.1 mM), a protease inhibitor, could protect the islets. There was also a weak protection by dimethyl urea (61 mM), a free radical scavenger, but no protection by cycloheximide (10 μg/ml), an inhibitor of protein synthesis, or amiloride (12.5 μM), a blocker of Na,+/H+ exchange. In a subsequent series of experiments, the islets were exposed for 6 h to different test agents after the initial 1-h exposure to rIL-1β. In this context, there was a clear protection by cycloheximide and actinomycin-D and a lesser protection by Nα-p-tosyl-L-lysine chloromethyl ketone. These data suggest that early steps of the actions of rIL-1β on rat pancreatic islets are mediated by protease activation and gene transcription, followed by protein synthesis. The identity of the protein(s) remains to be clarified. (Endocrinology128: 1611–1616,1991)

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