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. Interl eukin-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 eff ects of interleukin-1 beta and TNF were not influenced by the inhibiti on of cyclooxygenase or nitric oxide-synthase activities. Interleukin- 1 beta- and TNF-induced gastric relaxations were concentration depende ntly inhibited by BW 755c, which inhibits both cyclooxygenase and lipo xygenase, BW A4, which selectively inhibits the 5-lipoxygenase pathway , and SC 41930, a selective leukotriene B-4 receptor antagonist, provi ding pharmacological evidence that leukotriene B-4 is involved in the relaxant effects of both cytokines. The interleukin-1 beta and TNF-ind uced activation of 5-lipoxygenase pathway did not appear to be trigger ed by phospholipase A(2). An alternative pathway could involve the fol lowing steps: (i) activation of phospholipase C and the formation of d iacylglycerol; (ii) diacylglycerol-induced activation of protein kinas e C; (iii) formation of free arachidonic acid from diacylglycerol by d iacylglycerol-lipase. This mechanism is suggested by the finding that leukotriene B-4 is able to mimick cytokine-induced strip relaxation on ly in the presence of phorbol 12-myristate 13-acetate, which selective ly activates protein kinase C.