Remodeling of neutrophil phospholipids with 15(S)-hydroxyeicosatetraenoic acid inhibits leukotriene B4-induced neutrophil migration across endothelium.
5-Lipoxygenase products, such as leukotrienes, are important stimuli for leukocyte-mediated tissue injury in acute inflammation. 15-Hydroxyeicosatetraenoic acid (15-HETE) is an eicosanoid generated by a variety of cell types via the actions of 15-lipoxygenases and, in addition, cyclooxygenases and epoxygenases. 15-HETE levels are frequently elevated at sites of inflammation, and extracellular 15(S)-HETE is esterified rapidly into neutrophil (PMN) phospholipids in vitro to levels that are comparable with arachidonic acid. We present evidence that remodeling of PMN phospholipids with 15(S)-HETE stereoselectively inhibits PMN migration across endothelium in response to leukotriene B4 (LTB4) and other chemoattractants. Esterified 15(S)-HETE causes a striking reduction in the affinity of LTB4 cell-surface receptors for their ligand and inhibition of LTB4-triggered stimulus-response coupling. As a result of these actions, esterified 15(S)-HETE attenuates the cytoskeletal rearrangements and CD11/CD18-mediated adhesive events that subserve directed locomotion of PMN across endothelium. These observations indicate that products of the 5-lipoxygenase and 15-lipoxygenase pathways can exert counterbalancing influences on PMN trafficking across endothelium. They suggest that 15(S)-HETE may be a potent endogenous inhibitor of PMN-endothelial interactions in vivo and serve to limit or reverse acute inflammation.
Takata
S
S
Renal Division, Brigham and Women's Hospital, Boston, Massachusetts.
Matsubara
M
M
Allen
P G
PG
Janmey
P A
PA
Serhan
C N
CN
Brady
H R
HR
D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis; D018845:CD11 Antigens; D018821:CD18 Antigens; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D007975:Leukotriene B4 / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010743:Phospholipids / Q000097:blood*; D016028:Receptors, Leukocyte-Adhesion / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014471:Umbilical Veins
D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D006893:Hydroxyeicosatetraenoic Acids; D010743:Phospholipids; D016028:Receptors, Leukocyte-Adhesion; D007975:Leukotriene B4; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D013755:Tetradecanoylphorbol Acetate