INTERLEUKIN-1-BETA AND TUMOR-NECROSIS-FACTOR-ALPHA INHIBIT ACID-SECRETION IN CULTURED RABBIT PARIETAL-CELLS BY MULTIPLE PATHWAYS

Background-The cytokines interleukin 1 beta (IL-1 beta) and tumour nec rosis factor alpha (TNF-alpha) are inhibitors of gastric acid secretio n when administered systematically. Aims-To investigate the inhibitory effect of IL-1 beta and TNF-alpha on cultured, acid secreting parieta l cells in order to determine the mechanism of this inhibition. Method s-Rabbit parietal. cells were prepared by collagenase-EDTA digestion a nd counter flow elutriation. Acid secretory activity was assessed by a minopyrine accumulation, Results-IL-1 beta and TNF-alpha inhibited bas al and stimulated acid secretion in a dose dependent manner; near maxi mal effects were seen with both at 10 ng/ml. Inhibition was maximal wi th 15 minutes pretreatment but seen with up to 18 hours of preincubati on. Both cytokines inhibited histamine, carbachol, gastrin, forskolin, and A23187 stimulated acid secretion but had no effect on stimulation by dibutyryl-cAMP. inhibition of acid secretion was not accompanied b y a change in radioligand binding to histamine H-2 or gastrin/CCKB rec eptors. Pertussis toxin abolished the inhibitory effects on histamine and forskolin stimulation. The tyrosine kinase inhibitor herbimycin re duced the inhibitory effects of TNF-alpha against all stimuli but only reduced the effects of IL-1 beta against histamine and forskolin stim ulation. Conclusions-IL-1 beta and TNF-alpha seem to inhibit parietal cell acid secretion by multiple pathways; the inhibition occurs at pos treceptor level and involves pertussis toxin and tyrosine kinase depen dent and independent pathways. Mucosal production of cytokines may be important in the regulation of gastric acid secretion.