Immunoregulatory properties of novel specific inhibitors of 5-lipoxygenase.
The immunoregulatory properties of novel specific inhibitors of 5-lipoxygenase (5-LO) were investigated in vitro. These novel acetohydroxamic acids were found to inhibit the proliferation of lymphocytes in response to Interleukin-1 (IL-1) and Interleukin-2 (IL-2). Mitogen- and antigen-induced lymphoproliferation were likewise inhibited and so too was the spontaneous proliferation of transformed cells of myeloid and lymphoid origin. In this respect the compounds were one-tenth as potent as azathioprine on a molar basis. The production of IL-1 and IL-2 remained unaffected. Inhibition of lymphocyte proliferation was not related to inhibition of 5-LO. The latter occurred at 40-fold lower concentrations of 5-LO inhibitor. Moreover, inhibition of lymphoproliferation was not reversible in the presence of excess arachidonic acid. IL-1-induced collagenase production by chondrocytes was unaffected by 5-LO inhibitors. Contrary to a number of published reports, products of 5-LO do not appear to be obligatory mediators in IL-1 and IL-2 signal transduction. The immunosuppressive action of the 5-LO inhibitors described here seems to be a novel secondary property of the compounds.
Liu
D S
DS
Department of Experimental Immunobiology, Wellcome Research Laboratories, Kent, U.K.
Liew
F Y
FY
Rhodes
J
J
D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D044482:Benzeneacetamides; D002358:Cartilage, Articular / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007107:Immune System / Q000187:drug effects*; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D003012:Microbial Collagenase / Q000096:biosynthesis; D008934:Mitogens / Q000494:pharmacology; D011817:Rabbits; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000941:Antigens; D044482:Benzeneacetamides; D006877:Hydroxamic Acids; D007375:Interleukin-1; D007376:Interleukin-2; D016859:Lipoxygenase Inhibitors; D008934:Mitogens; C056616:N-(4-benzyloxybenzyl)acetohydroxamic acid; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; D001091:Arachidonate Lipoxygenases; D001094:Arachidonate 5-Lipoxygenase; D003012:Microbial Collagenase