5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes.
5-Oxo-eicosatetraenoate (5-oxoETE) is gaining recognition as a chemotactic factor for eosinophilic (Eo) as well as neutrophilic (Neu) polymorphonuclear leukocytes. We found that the eicosanoid was far stronger than C5a, platelet-activating factor (PAF), leukotriene B4 (LTB4), or FMLP in stimulating Eo chemotaxis. Moreover, it had weak intrinsic degranulating effects on otherwise unstimulated Eo, produced prominent degranulation responses in Eo primed by granulocyte-macrophage CSF, and enhanced the Eo-degranulating potencies of PAF, C5a, LTB4, and FMLP by up to 10,000-fold. Low picomolar levels of 5-oxoETE also induced Eo to activate mitogen-activated protein kinases (MAPKs), as defined by shifts in the electrophoretic mobility and tyrosine phosphorylation of two immunodetectable proteins, p44 and p42. 5-OxoETE was > or = 100-fold weaker or unable to stimulate any of these responses in Neu. Finally, 5-oxo-15-hydroxy-ETE and 5-hydroxy-ETE activated both cell types, but were weaker than 5-oxoETE and had Eo/Neu potency ratios approaching unity. 5-OxoETE, thus, is uniquely potent and selective in promoting Eo not only to migrate, but also to release granule enzymes and activate MAPKs. By triggering MAPK activation, the eicosanoid may also influence the production of anaphylactoid lipids (e.g., PAF), arachidonic acid metabolites, and cytokines. 5-OxoETE therefore possesses a biologic profile well suited for mediating Eo-dominated allergic reactions in vivo.
O'Flaherty
J T
JT
Department of Medicine, Wake Forest University Medical Center, Winston-Salem, NC 27157, USA.
Kuroki
M
M
Nixon
A B
AB
Wijkander
J
J
Yee
E
E
Lee
S L
SL
Smitherman
P K
PK
Wykle
R L
RL
Daniel
L W
LW
D001095:Arachidonic Acids / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002631:Chemotactic Factors, Eosinophil / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009504:Neutrophils / Q000187:drug effects*
D001095:Arachidonic Acids; D002631:Chemotactic Factors, Eosinophil; D006893:Hydroxyeicosatetraenoic Acids; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; C075441:5-oxo-15-hydroxy-6,8,11,13-eicosatetraenoic acid; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases