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.
Mario Negri Institute of Pharmacologic Research, Milan, Italy.
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Sozzani
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Zhou
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Locati
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Bernasconi
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Luini
A
A
Mantovani
J T
JT
O'Flaherty
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