CHEMOATTRACTANT RECEPTOR CROSS-TALK AS A REGULATORY MECHANISM IN LEUKOCYTE ADHESION AND MIGRATION

Leukocytes express multiple chemoattractant receptors that can trigger adhesion and direct their migration. Regulation of such proadhesive a nd migratory responses must often occur in a complex cytokine milieu i n vivo, in which multiple receptors may be engaged simultaneously or s equentially, Here we have examined the interplay between interleukin-8 (IL-8) receptor and formyl peptide receptor (fPR) stimulation and its consequences for leukocyte adhesion and chemotactic responses. IL-8 h as no significant effect on fMLP-stimulated adhesion and migration of human neutrophils, indicating that leukocytes have the potential to re spond to sequential proadhesive and chemoattractant stimuli during hom ing and targeted migration. In contrast, fMLP at greater than or equal to 10 nM totally abrogated proadhesive and chemoattractant responses to IL-8, a trans effect to which the fPR itself is relatively resistan t. N-formyl peptides are released by invasive bacteria and lysed cells , and the dominance of the fPR may ensure that signals from these term inal phagocyte targets can override host-derived recruitment signaling through IL-8 and other chemokine receptors. Asymmetric inhibition of adhesion-triggering responses is also observed in lymphoid cells trans fected with IL-8 receptor A and fPR, but in this cellular context chem otactic responses are bidirectionally abrogated, suggesting the potent ial for downstream desensitization of motility programs as well. Cross talk between chemoattractant receptors and their signaling pathways m ay help target leukocyte migration in the context of complex chemoattr actant arrays in vivo.