title: CD45 modulation of CXCR1 and CXCR2 in human polymorphonuclear leukocytes.
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.
authors.affiliation: Department of Physiology, The University of Western Ontario, and John P. Robarts Research Institute, London, Canada.
authors.forename: G B
authors.initials: GB
authors.lastname: Mitchell
authors.forename: M H
authors.initials: MH
authors.lastname: Khandaker
authors.forename: R
authors.initials: R
authors.lastname: Rahimpour
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: A I
authors.initials: AI
authors.lastname: Lazarovits
authors.forename: J G
authors.initials: JG
authors.lastname: Pickering
authors.forename: H
authors.initials: H
authors.lastname: Suria
authors.forename: J
authors.initials: J
authors.lastname: Madrenas
authors.forename: D K
authors.initials: DK
authors.lastname: Pomerantz
authors.forename: R D
authors.initials: RD
authors.lastname: Feldman
authors.forename: D J
authors.initials: DJ
authors.lastname: Kelvin
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D016227:Benzoquinones; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054407:Chemokine CCL4; D015536:Down-Regulation; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism* / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism*; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D017828:Rifabutin / Q000031:analogs & derivatives; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016227:Benzoquinones; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D016209:Interleukin-8; D047029:Lactams, Macrocyclic; D019402:Macrophage Inflammatory Proteins; D011809:Quinones; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017493:Leukocyte Common Antigens