Multiple eicosanoid-activated nonselective cation channels regulate B-lymphocyte adhesion to integrin ligands.
Arachidonic acid (AA) is a substrate for a variety of proinflammatory mediators, which are generated by cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P-450 (CYP450) enzymes. COX (e.g., PGs and prostacyclins) and LOX (e.g., leukotrienes) products have well-established proinflammatory roles; however, little is known about the functions of CYP450 products in leukocytes. We previously found that mechanical strain generated by subjecting lymphocytes to hypotonic challenge triggered AA production and that two CYP450 products of AA, 5,6-epoxyeicosatrienoic acid (5,6-EET) and 20-hydroxyeicosatetraenoic acid (20-HETE), as well as a product of LOX, 5-(S)-hydroperoxyeicosatetrenoic acid (5-HPETE), induced Ca(2+) entry into primary B cells. The main goal of the present studies, therefore, was to define the biophysically properties of eicosanoid-activated channels responsible for Ca(2+) entry and the physiological consequences of activating these channels, including their role in mechanical signaling. We found that 5,6-EET, 20-HETE, and 5-HPETE each activated distinct Ca(2+)-permeant nonselective cation channels (NSCCs) in primary B cells. These NSCCs each regulate plasma membrane potential and B-cell adhesion to integrin ligands ICAM-1 and VCAM-1. Thus our data demonstrate that proinflammatory mediators produced in response to osmotic and/or physical stress play a direct role in regulating the B-cell membrane potential and their adhesion to specific ECM proteins. These results not only have important implications for understanding normal mechanisms of B-cell activation, differentiation, and trafficking but also point to novel targets for modulating the pathogenesis of B-cell-mediated inflammatory diseases.
Liu
Xiaohong
X
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 368E Old Vet Bldg., 3800 Spruce St., Philadelphia, PA 19104, USA.
Zhu
Peimin
P
Freedman
Bruce D
BD
D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015777:Eicosanoids / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D008024:Ligands; D008564:Membrane Potentials; D011485:Protein Binding / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D015777:Eicosanoids; D007473:Ion Channels; D008024:Ligands; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002118:Calcium