Alteration of Macrophage Responsiveness to Platelet-Activating Factor by Interferon-γ and Lipopolysaccharide

Platelet-activating factor (PAF) can modulate several macrophage responses associated with tumoricidal and inflammatory activity. To determine how macrophage responsiveness to PAF may be altered by interferon-γ (IFN-γ) or lipopolysaccharide (LPS), we studied PAF receptor-associated activities. Pretreatment of murine peritoneal macrophages with either LPS or IFN-γ suppressed macrophage responsiveness to both PAF-induced calcium mobilization and superoxide anion (O−2) production. This suppression of macrophage responsiveness to PAF was maximal when 25 U/ml IFN-γ or 100 ng/ml LPS was initially added for 6 hr. Macrophages pretreated with LPS or IFN-γ remained refractory to PAF-induced rise in intracellular calcium for 4 to 24 hr. Macrophages preincubated with 25 U/ml IFN-γ remained refractory to PAF-induced calcium mobilization for up to 4 hr. LPS and IFN-γ treatment also decreased PAF-induced, calcium-dependent O−2production. When added together, IFN-γ increased the suppression of PAF-induced intracellular calcium mobilization and inhibited O−2production mediated by LPS. To assess whether suppression was mediated through altered PAF receptors, binding affinities were determined; two binding affinities were demonstrated. Initial incubation of macrophages with LPS or IFN-γ added alone or together decreased the number of cell surface PAF receptors and their binding affinity. These studies demonstrated that pretreatment with IFN-γ and LPS can suppress select PAF-induced macrophage functions. Downregulation of PAF receptor activity may represent a means by which macrophages regulate the capacity and magnitude of some PAF-induced responses.