title: Suppression of the development of tumoricidal function in gamma interferon-treated human peripheral blood monocytes by lipopolysaccharide: the role of cyclooxygenase metabolites.
abstract: Bacterial lipopolysaccharide (LPS) is generally regarded as one of the most potent macrophage activators. Thus, LPS has been used as an obligatory second signal to stimulate macrophage cytotoxic function against a wide array of bacterial and neoplastic targets. In this study, however, we define conditions under which LPS can suppress the development of cytotoxic function in normal human peripheral blood monocytes. When monocytes were treated with a priming dose of gamma interferon (gamma-INF), followed 18-24 hr later by a triggering dose of LPS, significant cytotoxic function developed. However, when monocytes were treated with even minimal amounts of LPS during priming with interferon, the development of cytotoxic function following stimulation with a second, triggering dose of LPS was virtually abolished. This effect could be produced from 0 to 14 hr following the addition of gamma-INF. The inhibition of monocyte cytotoxicity which was produced by LPS treatment during priming was dose dependent and could not be overcome by modifying either the priming dose of gamma-IFN or the triggering dose of LPS. The suppression was largely overcome, however, by treatment with the cyclooxygenase inhibitor, indomethacin. The possibility that LPS-induced suppression of monocyte cytotoxicity was mediated by products of the cyclooxygenase pathway was supported further in this study by demonstrating that LPS stimulated the production of significant amounts of prostaglandin E2 (PGE2) from monocytes and that this was facilitated by gamma-IFN. In kinetics studies, it appeared that LPS suppression of monocyte activation was correlated temporally with a heightened sensitivity to suppression by exogenously added PGE2, a condition which was reduced greatly by the end of the priming phase.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, Rush Medical College, Chicago, Illinois 60612.
authors.forename: E
authors.initials: E
authors.lastname: Chu
authors.forename: L C
authors.initials: LC
authors.lastname: Casey
authors.forename: J E
authors.initials: JE
authors.lastname: Harris
authors.forename: D P
authors.initials: DP
authors.lastname: Braun
mesh_terms: D016923:Cell Death / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013997:Time Factors
chemical_list: D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D007371:Interferon-gamma; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin