The influence of lipoxygenase inhibitors on the in vitro production of human leukocytic pyrogen and lymphocyte activating factor (interleukin-1)

Leukocytic pyrogen (LP), the endogenous mediator of fever, is synthesized and released from mononuclear phagocytes following activation by several microbial and immunologically-derived substances. Purified fractions of LP also stimulate thymocyte proliferation and LP seems to be indistinguishable from lymphocyte activating factor (LAF) otherwise known as interleukin-1 (IL-1). In the present investigation, we have examined the effect on IL-1 production of drugs inhibiting both cyclooxygenase- and lipoxygenase-mediated transformations of arachidonic acid (ETYA, 5,8,11,14-eicosatetraynoic acid and compound BW755C, 3-amino-1-3-trifluoromethylphenyl-2-pyrazoline). Ibuprofen inhibited the production of PGE2 from stimulated human monocytes but had no effect on LP and LAF release. ETYA prevented LP production from human monocytes when added to the incubation fluid prior to activation by Staphylococcus albus. When added after cell activation, ETYA was ineffective. Similar results were obtained using BW755C. Prostaglandin E2 (PGE2) levels in cell supernates were markedly decreased in the presence of either drug when compared to supernates from untreated, stimulated cells. Low PGE2 levels were also demonstrated in supernates of cells in which either ETYA or BW755C were added 1 hour after stimulation. Pretreatment with BW755C also resulted in decreased LAF activity in the supernates of mononuclear cells stimulated with staphylococci, endotoxin, or muramyl dipeptide. Other experiments demonstrated that crude or purified human LP retains its activity following treatment with soybean lipoxidase. These findings indicate that a product of arachidonate lipoxygenase is important in the sequence of events underlying cell activation for the production of human LP/LAF/IL-1. The possibility that LP might be an eicosanoid-peptide conjugate structurally resembling the leukotrienes was ruled out.