The effect of inhibition of leukotriene B4 release on lipopolysaccharide-induced production of neutrophil attractant/activation protein-1 (interleukin-8) by human alveolar macrophages.
Whereas we observed previously that concentrations of the lipoxygenase inhibitor nordihydroguaiaretic acid that inhibited leukotriene B4 release from lipopolysaccharide-stimulated human alveolar macrophages in vitro also inhibited subsequent interleukin-8 release, we hypothesized that leukotriene B4 release was required for the release of interleukin-8. Alveolar macrophages from normal nonsmoking volunteers were adhered to plastic and incubated with varying concentrations (25-250nM) of the 5-lipoxygenase activating protein inhibitor MK-886 prior to stimulation with lipopolysaccharide. MK-886 inhibited leukotriene B4 release in a concentration-dependent manner. The concentration of MK-886 that inhibited release by 50% was 53.3 +/- 23.1nM (mean +/- SD), n = 4. Interleukin-8 concentrations in 24hr supernatants were not inhibited by incubation of the cells with any concentration of MK-886, including those that inhibited leukotriene B4 release by > 95%. Thus, MK-886 is an effective inhibitor of human alveolar macrophage release of leukotriene B4, and the release of leukotriene B4 is not a prerequisite for alveolar macrophage release of interleukin-8.
Pulmonary and Critical Care Section, Yale University School of Medicine, West Haven, Ct.
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JA
Rankin
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Harris
D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D002722:Chlorobenzenes
D007211:Indoles; D016209:Interleukin-8; D007975:Leukotriene B4; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes