title: Regulation of stimulated integrin surface expression in human neutrophils by tyrosine phosphorylation.
abstract: The control of the adhesive properties of human neutrophils is an essential element of their defense function. One level at which this control is exerted involves the upregulation of the surface expression of beta 2-integrins. In this study, we have examined the potential involvement of tyrosine phosphorylation in the latter process. Two inhibitors of tyrosine kinases with differing modes of action, erbstatin and herbimycin A, were found to inhibit the expression of CD11b and CD18 stimulated by chemotactic factors (fMet-Leu-Phe or leukotriene B4) or growth factors (tumor necrosis factor alpha). This inhibition was not shared by an inactive analog of erbstatin or by the protein kinase C inhibitor Ro 31-8330. Erbstatin also inhibited the unveiling of activation-specific neoepitopes detected by antibody CBRM1/5. Pretreatment of neutrophils (but not of endothelial cells) with erbstatin inhibited the stimulation of neutrophils' adherence to endothelial cells induced by fMet-Leu-Phe. Augmentation of tyrosine phosphorylation by inhibiting tyrosine phosphatases using hydroperoxyvanadate led to an increased surface expression of CD11b and CD18 and enhanced the adhesion of neutrophils to endothelial cells. Finally, the leumedin NPC 15669, which had previously been shown to inhibit stimulated CD11b expression and neutrophil adherence to endothelial cells and to exhibit anti-inflammatory properties in various in vivo models of inflammation, inhibited the stimulation of tyrosine, phosphorylation induced by fMet-Leu-Phe. Taken together, these data establish a strong correlation between tyrosine phosphorylation and integrin upregulation in stimulated human neutrophils.
authors.affiliation: Centre de Recherche en Inflammation, Immunologie et Rhumatologie, CHUL, Ste-Foy, Québec, Canada.
authors.forename: P H
authors.initials: PH
authors.lastname: Naccache
authors.forename: N
authors.initials: N
authors.lastname: Jean
authors.forename: N W
authors.initials: NW
authors.lastname: Liao
authors.forename: J M
authors.initials: JM
authors.lastname: Bator
authors.forename: S R
authors.initials: SR
authors.lastname: McColl
authors.forename: P
authors.initials: P
authors.lastname: Kubes
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D018845:CD11 Antigens; D018821:CD18 Antigens; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology; D005449:Fluorenes / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D016023:Integrins / Q000032:analysis*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000737:chemistry*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D005449:Fluorenes; D006873:Hydroquinones; D016023:Integrins; C080486:N-(9H-(fluoren-9-ylmethoxy)carbonyl)glycine; D014443:Tyrosine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011493:Protein Kinase C; D005998:Glycine; C048212:erbstatin