Promoting M Phi Transepithelial Migration By Stimulating The Epithelial Cell P2y(2) Receptor

In intestine, neutrophils are recruited in response to bacterial infiltration and their anticellular activities contribute to inflammatory bowel diseases. In contrast, little is known regarding the recruitment of M Phi to the intestinal epithelium. Extracellular adenosine and uridine 5'-triphosphate (ATP and UTP) can function as leukocyte chemoattractants. We investigated the effects of these nucleotides on the ability of intestinal epithelial cells (IEC) to promote M Phi transepithelial migration and adhesion. ATP and UTP promoted the migration of neutrophil-like PLB-985 cells and M Phi across a Caco-2 monolayer. The M Phi-like U-937 cells adhered to nucleotide-stimulated IEC monolayers. In mice with intestinal inflammation, there were infiltrating CD68(+) M Phi in the colonic epithelium and CD68(+) M Phi present at the apical surface of colonocytes. We determined that ATP and UTP activated the P2Y(2) receptor P (P2Y(2)R) to increase ICAM-1 expression, which mediated the adhesion of M Phi to the apical surface of IEC. Intriguingly, stimulation of IEC with nucleotides did not increase the adhesion of neutrophils. However, in the presence of adherent M Phi, there was adhesion of neutrophils, suggesting that M Phi may serve as anchors for neutrophil adhesion. These studies provide insight into the inflammatory mechanisms that contribute to inflammatory bowel diseases and identify potential therapeutic targets for the treatment of gastrointestinal disorders.