STIMULATING PROPERTIES OF 5-OXO-EICOSANOIDS FOR HUMAN MONOCYTES - SYNERGISM WITH MONOCYTE CHEMOTACTIC PROTEIN-1 AND PROTEIN-3

The newly described products of 5-hydroxyeicosanoid dehydrogenase, 5-o xo-6,8,11,14-eicosatetraenoic acid (ETE) and 5-oxo-15(OH)ETE, induced directional migration and actin polymerization of human monocytes in v itro. At peak concentrations, the two eicosanoids had a chemotactic ac tivity of about 40% of that observed in the presence of an optimal con centration of FMLP and twice the activity elicited by the related eico sanoid 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE). 15-Oxo-ETE showed a very low but detectable chemotactic activity, All of these ch emotactic responses were blocked by Bordetella pertussis toxin, but we re resistant to LY255283, a leukotriene B-4 (LTB(4)) receptor antagoni st. 5-Oxo-ETEs and 5-HETE induced homologous desensitization of chemot actic response, but did not cross-desensitize to other chemotactic ago nists (e.g., monocyte chemotactic protein (MCP)-1 and LTB(4)). 5-Oxo-E TEs increased in a synergistic fashion the monocyte migration to MCP-1 and MCP-3, In the same range of concentrations, 5-oxo-ETE increased M CP-1-induced release of arachidonic acid from labeled monocytes. No sy nergistic interaction was observed when FMLP was used as chemoattracta nt. Thus, this study identifies monocytes as cells responsive to 5-oxo -ETEs and shows that monocyte activation by 5-oxo-ETEs occurs through an LTB(4) receptor-independent mechanism that associates with pertussi s toxin-sensitive G proteins. The synergistic interaction between 5-ox o-ETEs and C-C chemokines, two families of mediators both synthesized by phagocytic cells, may be relevant in vivo for the regulation of mon ocyte accumulation at sites of allergic and inflammatory reactions.