Abstract
We examined the functional role and mechanisms by which activation of cysteinyl leukotriene-1 receptor (cysLT1R) regulates β2-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 cysLT1R was identified both in PMNs and in eosinophils by immunofluorescence analysis. Total cysLT1R protein was substantially greater in eosinophils than in PMNs as determined by Western blot analysis. However, leukotriene D4 (LTD4) upregulated β2-integrin adhesion of PMNs to ICAM-1 with high efficacy in a time- and concentration-dependent manner. Upregulated β2-integrin adhesion of PMNs was related temporally and quantitatively to phosphorylation of 85-kDa cytosolic group IVa phospholipase A2 (gIVaPLA2). Augmented LTD4-induced adhesion was blocked significantly by montelukast, a cysLT1R antagonist. Trifluoromethylketone (a gIVaPLA2 inhibitor) blocked β2-integrin adhesion caused by LTD4 activation, as did anti-CD18 monoclonal antibody directed against β2-integrin on the PMN surface.
Our data demonstrate that LTD4 causes phosphorylation of gIVaPLA2 and upregulation of β2-integrin adhesion to ICAM-1 or ICAM-1 surrogate through cysLT1R activation. Activation of gIVaPLA2 is a critical step through which β2-integrin adhesion is upregulated by the cysLT1R expressed on the surface membrane of human PMN.
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