EVIDENCE THAT INTERLEUKIN-1-BETA AND TUMOR-NECROSIS-FACTOR INHIBIT GASTRIC FUNDUS MOTILITY VIA THE 5-LIPOXYGENASE PATHWAY

In this study, we compared the effects of interleukin-1 beta and tumor necrosis factor (TNF) on in vitro rat gastric fundus motility. Interleukin-1 beta produced rapid, concentration-dependent relaxation of rat gastric fundus strips, similar to that seen with TNF, with a maximal effect at 30 U/ml and an estimated EC(50) at 0.9 U/ml The relaxant effects of interleukin-1 beta and TNF were not influenced by the inhibition of cyclooxygenase or nitric oxide-synthase activities. Interleukin-1 beta- and TNF-induced gastric relaxations were concentration dependently inhibited by BW 755c, which inhibits both cyclooxygenase and lipoxygenase, BW A4, which selectively inhibits the 5-lipoxygenase pathway, and SC 41930, a selective leukotriene B-4 receptor antagonist, providing pharmacological evidence that leukotriene B-4 is involved in the relaxant effects of both cytokines. The interleukin-1 beta and TNF-induced activation of 5-lipoxygenase pathway did not appear to be triggered by phospholipase A(2). An alternative pathway could involve the following steps: (i) activation of phospholipase C and the formation of diacylglycerol; (ii) diacylglycerol-induced activation of protein kinase C; (iii) formation of free arachidonic acid from diacylglycerol by diacylglycerol-lipase. This mechanism is suggested by the finding that leukotriene B-4 is able to mimick cytokine-induced strip relaxation only in the presence of phorbol 12-myristate 13-acetate, which selectively activates protein kinase C.