HUMAN INTERLEUKIN-1 INDUCES A RAPID RELAXATION OF THE RABBIT ISOLATED MESENTERIC-ARTERY

1 Strips of rabbit superior mesenteric artery, precontracted with phenylephrine, relaxed when exposed to human recombinant interleukin-1 (IL-1) of the alpha or beta-types. The effect was observed within 10 min, was optimal 32 min after the application of the cytokines and concentration-dependent (12-290 pM). 2 IL-1-alpha and IL-1-beta were equipotent in relaxing the rabbit mesenteric artery. A synthetic fragment corresponding to IL-1-beta 163-171 was approximately one million fold less active than IL-1-beta. The tripeptide Lys-D-Pro-Thr, an analogue of IL-1-beta 193-195, was inactive as an antagonist of IL-1-beta on the preparation. 3 Indomethacin (2.8-mu-M) prevented or acutely reversed IL-1-induced relaxations in the rabbit mesenteric artery. Purified haemoglobin (10-mu-M) or the removal of endothelium had no effect on relaxations elicited by IL-1-beta. 4 The preparation exhibited some selectivity for IL-1 as recombinant human tumour necrosis factor-alpha (TNF-alpha), IL-2 or IL-6 failed to influence it. TNF-alpha was not synergistic with a subthreshold concentration of IL-1-beta. 5 Immunoreactive 6-keto-prostaglandin F1-alpha and prostaglandin E2 were increased in the bathing fluid of isolated mesenteric arteries exposed to IL-1-beta as compared to controls. 6 A supernatant of lipopolysaccharide-stimulated human monocytes produced a relaxation of the preparation with a profile similar to that produced with IL-1s and there was a good quantitative agreement between the extent of the relaxation and the enzyme immunoassay measurements of IL-1-alpha and IL-1-beta in the supernatant. Furthermore the relaxation of crude monocyte IL-1 was prevented by preincubating with antibodies to IL-1-alpha and IL-1-beta. This experiment illustrates the possible use of the preparation for bioassay of IL-1. 7 It is concluded that either form of IL-1 relaxes the precontracted rabbit mesenteric artery by a prostaglandin-dependent, nitric oxide-independent mechanism. The model is also useful for distinguishing the mechanism of IL-1-induced hypotension in vivo in rabbits.