Anti-Inflammatory Actions of Lipoxin A4 Stable Analogs Are Demonstrable in Human Whole Blood: Modulation of Leukocyte Adhesion Molecules and Inhibition of Neutrophil-Endothelial Interactions

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Abstract
We have examined in whole blood the actions of 2 lipoxin A4 (LXA4) stable analogs, 15-R/S-methyl-LXA4 and 16-phenoxy-LXA4, for their impact on the expression of adhesion molecules on human leukocytes and coronary artery endothelial cells (HCAEC) and on neutrophil adhesion to HCAEC in vitro. Both LXA4 analogs in nanomolar to micromolar concentrations prevented shedding of L-selectin and downregulated CD11/CD18 expression on resting neutrophils, monocytes, and lymphocytes. Changes in CD11/CD18 expression were blocked by the mitogen-activated protein kinase kinase inhibitor PD98059. The LXA4 analogs also attenuated changes in L-selectin and CD11/CD18 expression evoked by platelet-activating factor (PAF), interleukin-8, or C-reactive protein-derived peptide 201-206 with IC50 values of 0.2 to 1.9 μmol/L, whereas they did not affect lipopolysaccharide (LPS)– or tumor necrosis factor-–stimulated expression of E-selectin and intercellular adhesion molecule-1 on HCAEC. These LXA4analogs markedly diminished adhesion of neutrophils to LPS-activated HCAEC. Inhibition of adhesion was additive with function blocking anti–E-selectin and anti–L-selectin antibodies, but was not additive with anti-CD18 antibody. Combining LXA4 analogs with dexamethasone (100 nmol/L) almost completely inhibited PAF-induced changes in adhesion molecule expression on leukocytes and gave additive inhibition of neutrophil adhesion to HCAEC. Culture of HCAEC with dexamethasone, but not with LXA4 analogs, also decreased neutrophil attachment. Together, these results indicate that LXA4 stable analogs modulate expression of both L-selectin and CD11/CD18 on resting and immunostimulated leukocytes and inhibit neutrophil adhesion to HCAEC by attenuating CD11/CD18 expression. These actions are additive with those of glucocorticoids and may represent a novel and potent regulatory mechanism by which LXA4 and aspirin-triggered 15-epi-LXA4 modulate leukocyte trafficking.

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