SIGNAL-TRANSDUCTION MECHANISMS FOR LEUKOTRIENE-B(4) INDUCED HYPERADHESIVENESS OF ENDOTHELIAL-CELLS FOR NEUTROPHILS

We have previously demonstrated that leukotriene B4 (LTB4) induces in vitro a transient state of hyperadhesiveness in cultured human umbilic al vein endothelial cells (HUVEC) for neutrophils (PMN). The magnitude of this response is intermediate of that conferred by thrombin and by platelet-activating factor (PAF). This report shows that the LTB4 res ponse was neither related to HUVEC expression of PAF (because it could not be blocked by the PAF receptor antagonist WEB-2086), nor to acces s to LTB4 receptors on neutrophils (as shown by LTB4 receptor desensit ization experiments). However, it could be partly blocked by treating HUVEC with an LTB4 receptor antagonist (SC-41930). LTB4 evoked a rise of intracellular calcium concentrations, [Ca2+]i, in the HUVEC, and th e hyperadhesive HUVEC response to LTB4 was abrogated by buffering of [ Ca2+]i by Quin-2. The response was not inhibited by treating HUVEC wit h pertussis toxin before LTB4. Neutrophils showed no signs of activati on when adhering to LTB4-treated HUVEC because they did not i) release lactoferrin, or ii) react with an increase of [Ca2+]i, and iii) they bound equally well to the stimulated endothelial cells after having be en treated with pertussis toxin so that up-regulation of PMN adhesion to LTB4 was abolished. LTB4-treated HUVEC did not shed factors that mo dulated neutrophil adherence or chemotaxis. Thus, LTB4 promotes HUVEC hyperadhesiveness for PMN, and the transduction mechanism involves cal cium ions, may depend on a surface receptor for LTB4, but does not inv olve pertussis toxin-sensitive G proteins or PMN activation.