Stimulating properties of 5-oxo-eicosanoids for human monocytes: synergism with monocyte chemotactic protein-1 and -3.
The newly described products of 5-hydroxyeicosanoid dehydrogenase, 5-oxo-6,8,11,14-eicosatetraenoic acid (ETE) and 5-oxo-15(OH)ETE, induced directional migration and actin polymerization of human monocytes in vitro. At peak concentrations, the two eicosanoids had a chemotactic activity of about 40% of that observed in the presence of an optimal concentration of FMLP and twice the activity elicited by the related eicosanoid 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE). 15-Oxo-ETE showed a very low but detectable chemotactic activity. All of these chemotactic responses were blocked by Bordetella pertussis toxin, but were resistant to LY255283, a leukotriene B4 (LTB4) receptor antagonist. 5-Oxo-ETEs and 5-HETE induced homologous desensitization of chemotactic response, but did not cross-desensitize to other chemotactic agonists (e.g., monocyte chemotactic protein (MCP)-1 and LTB4). 5-Oxo-ETEs increased in a synergistic fashion the monocyte migration to MCP-1 and MCP-3. In the same range of concentrations, 5-oxo-ETE increased MCP-1-induced release of arachidonic acid from labeled monocytes. No synergistic interaction was observed when FMLP was used as chemoattractant. Thus, this study identifies monocytes as cells responsive to 5-oxo-ETEs and shows that monocyte activation by 5-oxo-ETEs occurs through an LTB4 receptor-independent mechanism that associates with pertussis toxin-sensitive G proteins. The synergistic interaction between 5-oxo-ETEs and C-C chemokines, two families of mediators both synthesized by phagocytic cells, may be relevant in vivo for the regulation of monocyte accumulation at sites of allergic and inflammatory reactions.
Sozzani
S
S
Mario Negri Institute of Pharmacologic Research, Milan, Italy.
Zhou
D
D
Locati
M
M
Bernasconi
S
S
Luini
W
W
Mantovani
A
A
O'Flaherty
J T
JT
D000199:Actins / Q000096:biosynthesis; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000494:pharmacology*; D054410:Chemokine CCL7; D002630:Chemotactic Factors / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines; D004357:Drug Synergism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D018945:Monocyte Chemoattractant Proteins / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism
D000199:Actins; D001095:Arachidonic Acids; C515450:CCL7 protein, human; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D002630:Chemotactic Factors; D016207:Cytokines; D006893:Hydroxyeicosatetraenoic Acids; D018945:Monocyte Chemoattractant Proteins; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid