In this study, we compared the effects of
interleukin-1 beta (IL-1 beta) and tumour
necrosis factor (TNF) on in vitro rat gastric fundus motility.
IL-1 beta and TNF produced rapid, concentration-dependent relaxation of the rat gastric fundus strips with maximal effect at 300 pg ml-1 and 10 ng ml-1, and estimated EC50S
at 10 and 450 pg ml-1, respectively. The relaxant effects of
IL-1 beta and TNF were not influenced by the inhibition of
cyclo-oxygenase or
NO-synthase activities.
IL-1 beta- and TNF-induced gastric relaxations were inhibited by
BW 755c, which inhibits both
cyclo-oxygenase and
lipoxygenase (LO),
BW A4c, which selectively inhibits the 5-LO pathway, and
SC 41930, a selective
leukotriene B4 (
LTB4) receptor antagonist, providing pharmacological evidence that
LTB4 is involved in the relaxant effects of both
cytokines. The
IL-1 beta- and TNF-induced activation of 5-LO pathway did not appear to be triggered by
phospholipase A2. An alternative pathway could involve the activation of a
phospholipase C, specific for
phosphatidylcholine, from which, in sequence: the formation of
diacylglycerol (DAG), DAG-induced activation of
protein kinase C and the formation of free
arachidonic acid from DAG would ensue. This mechanism is suggested by the finding that
LTB4 is able to mimic
cytokine-induced strip relaxation only in the presence of
phorbol 12-myristate 13-acetate, which selectively activates
protein kinase C.