15-Hydroxyeicosatetraenoic acid inhibits neutrophil migration across cytokine-activated endothelium.
15-hydroxyeicosatetraenoic acid (15-HETE) is an eicosanoid, formed by the actions of 15-lipoxygenase, epoxygenases, and cyclooxygenases on arachidonic acid, whose tissue levels are often elevated during inflammation. The present study demonstrates that 15(S)-HETE is a potent inhibitor of polymorphonuclear neutrophil (PMN) migration across cytokine-activated endothelium in vitro. 15(S)-HETE is rapidly esterified into PMN phospholipids, and we report that 15-(S)-HETE-remodeled PMN displayed blunted adhesion to, and migration across, human endothelial cells that had been activated with either interleukin-1 beta or tumor necrosis factor-alpha Several lines of evidence suggested that 15(S)-HETE inhibited PMN transmigration by attenuating PMN responsiveness to endothelial cell-derived platelet-activating factor (PAF). The inhibitory action of 15(S)-HETE on transmigration was not restricted by the profile of adhesion molecules expressed by cytokine-activated endothelium. Interleukin-1 beta and tumor necrosis factor-alpha induce PAF production by endothelium, and PMN migration across cytokine-activated endothelium was inhibited by a PAF receptor antagonist. PMN migration across endothelium in response to exogenous PAF was dramatically inhibited following exposure of PMN to 15(S)-HETE. Furthermore, 15(S)-HETE-remodeled PMN displayed impaired cytoskeletal and adhesion responses when stimulated by exogenous PAF, two pivotal events in PMN migration across activated endothelium. 15(S)-HETE seemed to attenuate PMN responsiveness to PAF by inhibiting membrane-associated signal transduction events. In keeping with this interpretation, remodeling of PMN phospholipids with 15(S)-HETE was associated with a sixfold reduction in the affinity of specific high-affinity PAF receptors for their ligand and impaired PAF-triggered IP3 generation. In contrast, PMN adhesion responses stimulated by calcium ionophore or activators of protein kinase C remained intact. These results provide further evidence that 15(S)-HETE may be an important endogenous inhibitor of PMN-endothelial cell interaction that serves to limit or reverse neutrophil-mediated inflammation in vivo.
Takata
S
S
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Papayianni
A
A
Matsubara
M
M
Jimenez
W
W
Pronovost
P H
PH
Brady
H R
HR
D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010743:Phospholipids / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D006893:Hydroxyeicosatetraenoic Acids; D007375:Interleukin-1; D010743:Phospholipids; D014409:Tumor Necrosis Factor-alpha; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid