Lipoxin A4 (LXA4) and its stable analogs downregulate chemokine secretion in polarized epithelia. This anti-inflammatory effect has been suggested to be mediated by the LXA4receptor (LXA4R), a G protein-coupled receptor. To determine whether LXA4R is expressed on the apical, basolateral, or both poles of intestinal epithelia, an NH2-terminal c-myc epitope tag was added to the human LXA4R cDNA and recombinant retroviruses were used to transduce polarized epithelial cells. In polarized T84 intestinal epithelial cells, c-myc-LXA4R was preferentially expressed on the basolateral surface as indicated by cell surface-selective biotinylation and confocal microscopy. Furthermore, expression of c-myc-LXA4R and a truncation mutant lacking the cytoplasmic terminus was primarily confined to the lateral subdomain. We also observed that the expression of myc-LXA4 conferred enhanced downregulation of IL-8 expression in response to LXA4analog and that blockade of the CysLT1 receptor by montelukast did not prevent this response to LXA4 analog. Thus LXA4generated in or near the paracellular space via neutrophil-epithelial interactions can rapidly act on epithelial LXA4R to downregulate epithelial promotion of intestinal inflammation.