Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction

Abstract

Monocyte recruitment and adherence are important events in inflammatory and vascular diseases. Here, we evaluated the actions of lipoxin A4 (LXA4) and LXB4, a series of lipoxygenase products from arachidonic acid generated by cell-cell interactions, on human monocytes. LXA4 and LXB4 (10(-7) M) each increased monocyte migration in chamber chemotaxis assays and, in migration under agarose, exhibited chemotactic indices similar to those of the chemotactic peptide formyl-methionyl-leucyl-phenylalanine at 10(-10)-10(-8) M and to the chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha) at 10(-8)-10(-7) M with a rank order of potency: Monocyte chemotactic protein-1 alpha > LXA4 approximately LXB4 approximately MIP-1 alpha. Lipoxins also stimulated monocyte adherence to laminin. In addition, human monocytes rapidly transformed LXA4 and LXB4 to several metabolites. LXB4 (> 80%) was converted within 30 s to new products, in a trend similar to that of LXA4. The novel monocyte-derived LXB4 products were identified as 5-oxo-6,7-dihydro-LXB4 and 6,7-dihydro-LXB4, indicating a role for site-selective dehydrogenation and reduction. Unlike monocytes, intact polymorphonuclear leukocytes (PMN) did not metabolize LXA4 in significant quantities, and only approximately 12% of exogenous LXB4 was omega-oxidized to 20-OH-LXB4 and 20-COOH-LXB4 by PMN. To determine if lipoxin conversion altered bioactivity, we evaluated the actions of these metabolites on monocytes. Each of the novel products of LXA4 and LXB4 from monocytes, namely oxo- and dihydrolipoxins, were essentially inactive in stimulating monocyte adherence. In contrast, the omega-oxidation products of LXB4 isolated from PMN were equipotent with LXB4 for monocyte adherence. Dehydrogenation of LXA4 in monocytes appears to be carried out by a 15-hydroxyprostaglandin dehydrogenase, which is present in human monocytes as determined by reverse transcription PCR and Western blots. Together, these results provide the first evidence that LXA4 and LXB4 are both potent stimulants for migration and adherence of human monocytes. Moreover, they underscore the importance of the major route of lipoxin metabolism in leukocytes, namely, the rapid dehydrogenation and inactivation carried out by monocytes.