Inhibition of carbachol stimulated acid secretion by interleukin 1β in rabbit parietal cells requires protein kinase C

Background-Interleukin 1 beta (IL-1 beta) is a potent inhibitor of gastric acid secretion. Regulatory actions at several levels have previously been demonstrated, including direct inhibition of parietal cell acid secretion. Although IL-1 beta may activate several intracellular signalling pathways, the mechanisms responsible for inhibition of carbachol stimulated acid secretion have not been determined. Aims-To investigate the roles of protein kinase C (PKC) and the sphingomyelinase signalling pathways in the regulation of acid secretion by IL-1 beta. Methods-Rabbit parietal cells were obtained by collagenase-EDTA digestion and centrifugal elutriation. Acid secretion stimulated by carbachol and A23187 (to mimic elevations in intracellular calcium) was assessed by C-14 aminopyrine uptake in response to IL-1 beta, PKC, and sphingomyelinase manipulation. Results-IL-1 beta inhibited carbachol and A23187 stimulated acid secretion in a dose dependent manner. The inhibitory actions were completely reversed by each of three different PKC inhibitors, staurosporine, H-7, and chelerythrine, as well as by PKC depletion with high dose phorbol ester pretreatment. IL-1 beta did not downregulate parietal cell muscarinic receptor, IL-1 beta significantly increased membrane PKC activity. Activation of the sphingomyelinase/ceramide pathway had no effect on basal or stimulated acid secretion. The inhibitory action of IL-1 beta was independent of protein kinase A and protein kinase G activity. Conclusions-IL-1 beta directly inhibits parietal cell carbachol stimulated acid secretion. This action occurs distal to muscarinic receptor activation and elevations in intracellular calcium and requires PKC.