CD45 modulation of CXCR1 and CXCR2 in human polymorphonuclear leukocytes. |
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| Authors: | G B Mitchell M H Khandaker R Rahimpour L Xu A I Lazarovits J G Pickering H Suria J Madrenas D K Pomerantz R D Feldman D J Kelvin |
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| Affiliation: | Department of Physiology, The University of Western Ontario, and John P. Robarts Research Institute, London, Canada. |
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| Abstract: | All leukocytes express the cell surface glycoprotein CD45, which has intrinsic intracellular protein tyrosine phosphatase activity. CD45 is known to play a regulatory role in activation-induced signaling in lymphocytes; however, little is known of its role in non-lymphoid leukocytes. Therefore, we examined the potential effect of CD45 on chemokine-induced signaling in human neutrophils (polymorphonuclear cells, PMN). Treating isolated PMN for 2 h with an anti-CD45RB antibody (Bra11) down-modulated expression of the chemokine receptors CXCR1 and CXCR2 to 44 +/- 10% and 47 +/- 9% of their respective controls. The tyrosine kinase inhibitors genistein and herbimycin A significantly inhibited the Bra11-induced down-modulation of CXCR1 and CXCR2. Furthermore, Bra11-treated PMN were functionally inhibited in their capacity to exhibit IL-8-induced transient intracellular Ca2+ increases. Selected targeting of CXC receptors is indicated by the fact that N-formyl-Met-Leu-Phe (fMLP) receptor expression and function were not lost following Bra11 treatment. The effect of Bra11 on IL-8-mediated function and receptor expression was paralleled by decreased tyrosine phosphorylation of a 54- to 60-kDa protein. These findings indicate that CD45 can act to modulate PMN responses to chemokines; thus agents regulating CD45 can potentially modulate leukocyte traffic and may represent a novel therapeutic approach towards the treatment of inflammatory diseases. |
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