INTERLEUKIN-1-BETA INHIBITS PHOSPHOLIPASE-C AND INSULIN-SECRETION AT SITES APART FROM K-ATP CHANNEL

Although interleukin-1 beta (IL-1 beta) reduces pancreatic islet conte nt of ATP and GTP, the distal events that mediate its inhibitory effec ts on insulin secretion remain poorly understood. Herein, the activati on of phospholipase C (PLC) was quantified during islet perifusions. A n 18-h exposure to IL-1 beta (100 pM) totally vitiated activation of P LC induced by glucose, an effect that requires ATP and GTP and closure of the ATF-dependent K+ (K-ATP) channel. Surprisingly, however, when islets were depolarized directly using either of two agonists, glyburi de (which does not act via generation of purine nucleotides) or 40 mM K+ (which acts distal to K-ATP channel), PLC and insulin secretion wer e again obliterated by IL-1 beta. IL-1 beta also reduced the labeling of phosphoinositide substrates; however, this effect was insufficient to explain the inhibition of PLC, since the effects on substrate label ing, but not on PLC, were prevented by coprovision of guanosine or ade nosine. Furthermore, when IL-1 beta-treated islets piers exposed to 10 0 mu M carbachol (which activates PLC partially independent of extrace llular Ca2+), the effects were still obliterated by IL-1 beta. These d ata (together with the finding that IL-1 beta inhibited Ca2+-induced i nsulin release) suggest that, in addition to its effects on ATP synthe sis and thereby on the K-ATP channel, IL-1 beta has at least two undes cribed. distal effects to block both PLC as well as Ca2+-induced exocy tosis. The latter correlated best with IL-1 beta's effect to impede ph osphainositide synthesis, since it also was reversed by guanosine or a denosine.