Leukotriene D4 activates {beta}2-integrin adhesion in human polymorphonuclear leukocytes.
We examined the functional role and mechanisms by which activation of cysteinyl leukotriene-1 receptor (cysLT(1)R) regulates beta(2)-integrin adhesion to intercellular adhesion molecule (ICAM)-1 in human polymorphonuclear leukocytes (PMNs) in vitro. Human peripheral blood PMNs and eosinophils were isolated separately from the same mildly atopic donors. Surface expression of cysLT(1)R was identified both in PMNs and in eosinophils by immunofluorescence analysis. Total cysLT(1)R protein was substantially greater in eosinophils than in PMNs as determined by Western blot analysis. However, leukotriene D(4) (LTD(4)) upregulated beta(2)-integrin adhesion of PMNs to ICAM-1 with high efficacy in a time- and concentration-dependent manner. Upregulated beta(2)-integrin adhesion of PMNs was related temporally and quantitatively to phosphorylation of 85-kDa cytosolic group IVa phospholipase A2 (gIVaPLA2). Augmented LTD(4)-induced adhesion was blocked significantly by montelukast, a cysLT(1)R antagonist. Trifluoromethylketone (a gIVaPLA2 inhibitor) blocked beta(2)-integrin adhesion caused by LTD(4) activation, as did anti-CD18 monoclonal antibody directed against beta(2)-integrin on the PMN surface. Our data demonstrate that LTD(4) causes phosphorylation of gIVaPLA2 and upregulation of beta(2)-integrin adhesion to ICAM-1 or ICAM-1 surrogate through cysLT(1)R activation. Activation of gIVaPLA2 is a critical step through which beta(2)-integrin adhesion is upregulated by the cysLT(1)R expressed on the surface membrane of human PMN.
Meliton
A Y
AY
Dept of Medicine, M6076, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Muñoz
N M
NM
Osan
C M
CM
Meliton
L N
LN
Leff
A R
AR
D018821:CD18 Antigens / Q000096:biosynthesis* / Q000235:genetics*; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D017998:Leukotriene D4 / Q000378:metabolism*; D008024:Ligands; D008856:Microscopy, Fluorescence / Q000379:methods; D009504:Neutrophils / Q000378:metabolism*; D010766:Phosphorylation
D018821:CD18 Antigens; D008024:Ligands; D018799:Intercellular Adhesion Molecule-1; D017998:Leukotriene D4