CD45 modulation of CXCR1 and CXCR2 in human polymorphonuclear leukocytes

All leukocytes express the cell surface glycoprotein CD45, which has intrin sic intracellular protein tyrosine phosphatase activity. CD45 is known to p lay a regulatory role in activation-induced signaling in lymphocytes; howev er, little is known of its role in non-lymphoid leukocytes. Therefore, we e xamined the potential effect of CD45 on chemokine-induced signaling in huma n neutrophils (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti-CD45RB antibody (Bra11) down-modulated expression of the chem okine receptors CXCR1 and CXCR2 to 44 +/- 10% and 47 +/- 9% of their respec tive controls. The tyrosine kinase inhibitors genistein and herbimycin A si gnificantly inhibited the Bra11-induced downmodulation of CXCR1 and CXCR2. Furthermore, Bra11-treated PMN were functionally inhibited in their capacit y to exhibit IL-8-induced transient intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by the fact that N-formyl-Met-Leu-P he (fMLP) receptor expression and function were not lost following Bra11 tr eatment. The effect of Bra11 on IL-8-mediated function and receptor express ion was paralleled by decreased tyrosine phosphorylation of a 54- to 60-kDa protein. These findings indicate that CD45 can act to modulate PMN respons es to chemokines; thus agents regulating CD45 can potentially modulate leuk ocyte traffic and may represent a novel therapeutic approach towards the tr eatment of inflammatory diseases.