Lipoxin A(4) and B-4 are potent stimuli for human monocyte migration and adhesion: Selective inactivation by dehydrogenation and reduction

Monocyte recruitment and adherence are important events in inflammatory and vascular diseases. Here, we evaluated the actions of lipoxin A(4) (LXA(4)) and LXB(4), a series of lipoxygenase products from arachidonic acid generated by cell-cell interactions, on human monocytes. LXA(4) and LXB(4) (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 > LXA(4) approximate to LXB(4) approximate to MIP-1 alpha. Lipoxins also stimulated monocyte adherence to laminin. In addition, human monocytes rapidly transformed LXA(4) and LXB(4) to several metabolites. LXB(4) (>80%) was converted within 30 s to new products, in a trend similar to that of LXA(4). The novel monocyte-derived LXB(4) products were identified as 5-oxo-6,7-dihydro-LXB(4) and 6,7-dihydro-LXB(4), indicating a role for site-selective dehydrogenation and reduction. Unlike monocytes, intact polymorphonuclear leukocytes (PMN) did not metabolize LXA(4) in significant quantities, and only similar to 12% of exogenous LXB(4) was omega-oxidized to 20-OH-LXB(4) and 20-COOH-LXB(4) by PMN. To determine if lipoxin conversion altered bioactivity, we evaluated the actions of these metabolites on monocytes. Each of the novel products of LXA(4) and LXB(4) from monocytes, namely oxo- and dihydrolipoxins, were essentially inactive in stimulating monocyte adherence. In contrast, the omega-oxidation products of LXB(4) isolated from PMN were equipotent with LXB(4) for monocyte adherence. Dehydrogenation of LXA(4) 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 LXA(4) and LXB(4) 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.