Biochemical mechanisms of lipid-A-mediated enhancement of platelet secretory responses to aggregated immunoglobulins

Abstract

The mechanism by which endotoxins enhance the secretory response of washed preparations of human platelets to aggregated immunoglobulins (Agg-HGG) has been examined. Preparations of endotoxins from several rough mutants of bacteria enhance, by approximately 50-fold, the release of serotonin initiated by Agg-HGG. Endotoxins from smooth strains do not manifest this enhancement, and all endotoxin preparations are completely inactive in the absence of Agg-HGG. Preincubation and wash experiments have demonstrated that the critical initial interaction is the formation of complexes between the endotoxin and the Agg-HGG stimulus and is not dependent on an initial endotoxin-platelet interaction. Pretreatment of platelets with substimulatory concentrations of Agg-HGG, followed by the addition of endotoxin, causes a temporal decay in the degree of endotoxin-induced enhancement, which is inversely related to the concentration of Agg-HGG. This stimulus-specific desensitization suggests that the endotoxin-Agg-HGG complexes initiate release by a pathway similar to that initiated by Agg-HGG alone. We postulate that the endotoxin either enhances or stabilizes a localized platelet membrane perturbation or deformation, initiated by the Agg-HGG stimulus.