Bioactions of 5-Hydroxyicosatetraenoate and its Interaction with Platelet-Activating Factor

Abstract

In a variety of stimulated cells, platelet-activating fa~ tor (PAF} and numerous arachidonate derivatives are coproducts that form as a consequence of recepto~mediated phospholipid mobilization. These lipid co-products produce a plethora of biological effects in a wide variety of cell systems. Furthermore, they often have a fascinating, although less widely appreciated, interaction. 5-HETE, at submicromolar concentrations, exerts relatively few direct bioactions. It does, however, potently (16-160 nM) raise cytosolic free calcium [Ca2+]i and augment PAFinduced responses in human polymorphonuclear neutrophils {PMN) by as much as 10~ to 100~fold. 5-HETE acts on PMN by a structurally specific, stereospecific and pertussis toxin-inhibitable mechanism. In addition, PMN exposed to 5-HETE eYhlbit homologous but not heterologous desensitization. These findings suggest that 5-HETE, like PAF, may bind to its own specific plasmalemmal receptors to exert its unique set of bioactions. However, further investigation is required to demonstrate any putative 5-HETE receptors. Other potential mechanisms of 5-HETE-induced bioactions together with the possible effects of 5-HETE on PAF transduction mechanisms are also discussed.

Mechanisms of platelet-activating factor-induced lipid body formation: requisite roles for 5-lipoxygenase and de novo protein synthesis in the compartmentalization of neutrophil lipids.

“…Moreover, the specific LTB 4 receptor antagonist CP-105,696 (15) had no inhibitory effect on PAF-induced lipid body formation, excluding a role for both exogenous and endogenous LTB 4 as a mediator of PAF-induced lipid body formation. Another PMN activator derived from the 5-LO pathway is 5(S)-HETE (26,27). Lipid body formation in human PMN was dose dependently induced by both R and S isomers of 5-HETE ( Fig.…”

Phospholipases and activation of the NADPH oxidase

“…These second messengers bind to and activate cellular protein kinases, including protein kinase C (PKC). Arachidonic acid, the product of phospholipase A,, can directly activate PKC (4), or it can be metabolized via the lipoxygenase or cyclooxygenase pathways (5). Phospholipase C activity results in two products, 1,2-diacylglycerol and inositol trisphosphate (Ins 1,4,5P3).…”