INTERLEUKIN-1-BETA-INDUCED AND TUMOR-NECROSIS-FACTOR-INDUCED INHIBITION OF RAT GASTRIC FUNDUS MOTILITY IN-VITRO

In this study, we compared the effects of interleukin-1 beta (IL-1 bet a) and tumour necrosis factor (TNF) on in vitro rat gastric fundus mot ility. IL-1 beta and TNF produced rapid, concentration-dependent relax ation of the rat gastric fundus strips with maximal effect at 300 pg m l(-1) and 10 ng ml(-1), and estimated EC(50)s at 10 and 450 pg ml(-1), respectively. The relaxant effects of IL-1 beta and TNF were not infl uenced by the inhibition of cyclo-oxygenase or NO-synthase activities. IL-1 beta- and TNF-induced gastric relaxations were inhibited by BW 7 55c, which inhibits both cyclo-oxygenase and lipoxygenase (LO), BW A4c , which selectively inhibits the 5-LO pathway, and SC 41930, a selecti ve leukotriene B4 (LTB4) receptor antagonist, providing pharmacologica l evidence that LTB4 is involved in the relaxant effects of both cytok ines. The IL-1 beta- and TNF-induced activation of 5-LO pathway did no t appear to be triggered by phospholipase A2. An alternative pathway c ould involve the activation of a phospholipase C, specific for phospha tidylcholine, from which, in sequence: the formation of diacylglycerol (DAG), DAG-induced activation of protein kinase C and the formation o f free arachidonic acid from DAG would ensue. This mechanism is sugges ted by the finding that LTB4 is able to mimic cytokine-induced strip r elaxation only in the presence of phorbol 12-myristate 13-acetate, whi ch selectively activates protein kinase C.