title: Attenuated translocation of group IVa phospholipase A2 and up-regulated annexin-1 synthesis by glucocorticoid blocks beta 2-integrin adhesion in neutrophils.
abstract: We examined the effect of glucocorticoid stimulation in blocking beta 2-integrin adhesion of polymorphonuclear leukocytes (PMNs) isolated from human subjects. Surface expression of CD11b and ERK-1/2-mediated gIVaPLA2 phosphorylation, which are required for beta 2-integrin adhesion, were not affected by treatment with < or =10(-6) M fluticasone propionate (FP) for PMNs activated by either 10(-7) M LTB4 or 30 ng/ml TNF-alpha and caused no significant blockade of beta 2-integrin adhesion in vitro. Baseline expression of annexin-1 (ANXA1) synthesis was increased only after 10(-6) M FP for PMNs; by contrast, comparable increase in ANXA1 expression was demonstrated in human eosinophils from the same subjects with 10(-8) M FP. Viability of PMNs was verified by propidium iodide and by the persistence of beta 2-integrin adhesion in treated groups. Exogenous administration of ANXA1 mimetic peptide fragment blocked significantly and comparably the beta 2-integrin adhesion in PMNs activated by LTB4 and TNF-alpha and in eosinophils activated by IL-5. Translocation of gIVaPLA2 from the cytosol to the nucleus also was refractory for activated PMNs treated with > or =10(-7) M FP; by contrast, complete blockade of nuclear translocation of cytosolic gIVaPLA2 was effected by 10(-9) M FP in eosinophils. Our data indicate that the cell surface ANXA1 synthesis is capable of blocking beta 2-integrin adhesion in both PMNs and eosinophils. However, in contrast to eosinophils, FP does not cause either substantial ANXA1 synthesis or nuclear transport of cytosolic gIVaPLA2 in PMNs and thus does not block beta2-integrin adhesion, a necessary step for granulocyte cell migration in vivo.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Angelo Y
authors.initials: AY
authors.lastname: Meliton
authors.forename: Nilda M
authors.initials: NM
authors.lastname: Munoz
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Zhu
authors.forename: Alan R
authors.initials: AR
authors.lastname: Leff
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000328:Adult; D000730:Androstadienes / Q000494:pharmacology*; D017305:Annexin A1 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects*; D002467:Cell Nucleus / Q000201:enzymology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D003600:Cytosol / Q000201:enzymology; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D000068298:Fluticasone; D054513:Group IV Phospholipases A2; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000097:blood; D015848:Interleukin-5 / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000730:Androstadienes; D017305:Annexin A1; D018821:CD18 Antigens; D015848:Interleukin-5; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C096153:annexin A1 peptide (2-26); D007975:Leukotriene B4; D000068298:Fluticasone; D048049:Extracellular Signal-Regulated MAP Kinases; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human