Evidence that interleukin-1 and lipoxygenase metabolites mediate the lethal effect of complete Freund's adjuvant in adrenalectomized rats.
Injection of complete Freund's adjuvant (CFA) into the right hind paw of adrenalectomized (ADX) rats caused a lethal effect, maximal after 3 days. Treatment of animals with polyclonal sera raised against either murine recombinant (mr) IL-1 alpha or mrIL-1 beta gave significant protection, suggesting the involvement of this cytokine in the observed lethality. Death was also caused by the intravenous injection of human recombinant (hr) IL-1 beta in ADX rats. No lethality was induced by either CFA or hrIL-1 beta in sham-operated (SHO) rats. The administration of dexamethasone or the dural cyclooxygenase/lipoxygenase inhibitor BW 755c significantly protected against the lethality induced by both CFA and hrIL-1 beta. The cyclooxygenase inhibitors, indomethacin and acetylsalicyclic acid, were ineffective. WEB 2086, a PAF-acether receptor antagonist, gave partial but not significant protection. These results suggest that activation of arachidonic acid metabolism is involved in the observed lethality, with lipoxygenase metabolites as possible final effectors. These experimental models of lethalities may be useful for the in vivo evaluation of drugs interfering with the synthesis and/or biological effects of IL-1.
Sclavo Research Centre, Laboratory of Pharmacology, Siena, Italy.
M
M
Perretti
K G
KG
Mugridge
C
C
Becherucci
L
L
Parente
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000633:toxicity*; D000315:Adrenalectomy; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology / Q000633:toxicity*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D009637:Masoprocol / Q000494:pharmacology; D010529:Peritoneal Cavity / Q000166:cytology; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000633:toxicity
D000276:Adjuvants, Immunologic; D007375:Interleukin-1; D016859:Lipoxygenase Inhibitors; D011994:Recombinant Proteins; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D009637:Masoprocol; D003907:Dexamethasone; D001241:Aspirin; D007213:Indomethacin