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 EC50 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 B4 receptor antagonist, providing pharmacological evidence that leukotriene B4 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 A2. 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 B4 is able to mimic cytokine-induced strip relaxation only in the presence of phorbol 12-myristate 13-acetate, which selectively activates protein kinase C.
Montuschi
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P
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.
Tringali
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G
Currò
D
D
Ciabattoni
G
G
Parente
L
L
Preziosi
P
P
Navarra
P
P
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D005260:Female; D005748:Gastric Fundus / Q000187:drug effects* / Q000502:physiology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D016859:Lipoxygenase Inhibitors; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D013755:Tetradecanoylphorbol Acetate