INFLUENCE OF PROTEASE ON INHIBITORY AND STIMULATORY EFFECTS OF INTERLEUKIN 1-BETA ON BETA-CELL FUNCTION

To elucidate the putative role of proteases in the action of interleukin 1-beta (IL-1-beta) on pancreatic beta-cells, we studied the effects on islet function of different protease inhibitors when added together with recombinant IL-1-beta to isolated rat pancreatic islets. It was found that the trypsin inhibitor N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) counteracted the acute stimulatory effects of IL-1-beta on islet glucose oxidation, insulin release, and biosynthesis. TLCK also partially or completely counteracted the long-term inhibitory effects of IL-1-beta on islet glucose oxidation, insulin biosynthesis, content, and release. This protease inhibitor also counteracted IL-1-beta-induced beta-cell cytotoxicity as assessed by DNA content measurements. Of the other group-specific protease inhibitors investigated, only N-tosyl-L-phenylalanine chloromethyl ketone, N-alpha-p-tosyl-L-arginine methyl ester, and chloromercuriphenylsulfonic acid were found to partially protect against IL-1-beta action. We concluded that protease activation, putatively a serine protease, may be an early and perhaps primary event in the action of IL-1-beta on beta-cells.