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Am J Physiol Lung Cell Mol Physiol 295: L326-L335, 2008. First published May 23, 2008; doi:10.1152/ajplung.00393.2007
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Cytosolic phospholipase A2{alpha} activation induced by S1P is mediated by the S1P3 receptor in lung epithelial cells

Li-Yuan Chen, Grzegorz Woszczek, Sahrudaya Nagineni, Carolea Logun, and James H. Shelhamer

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland

Submitted 20 September 2007 ; accepted in final form 19 May 2008

Cytosolic phospholipase A2{alpha} (cPLA2{alpha}) activation is a regulatory step in the control of arachidonic acid (AA) liberation for eicosanoid formation. Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator involved in the regulation of many important proinflammatory processes and has been found in the airways of asthmatic subjects. We investigated the mechanism of S1P-induced AA release and determined the involvement of cPLA2{alpha} in these events in A549 human lung epithelial cells. S1P induced AA release rapidly within 5 min in a dose- and time-dependent manner. S1P-induced AA release was inhibited by the cPLA2{alpha} inhibitors methyl arachidonyl fluorophosphonate (MAFP) and pyrrolidine derivative, by small interfering RNA-mediated downregulation of cPLA2{alpha}, and by inhibition of S1P-induced calcium flux, suggesting a significant role of cPLA2{alpha} in S1P-mediated AA release. Knockdown of the S1P3 receptor, the major S1P receptor expressed on A549 cells, inhibited S1P-induced calcium flux and AA release. The S1P-induced calcium flux and AA release was associated with sphingosine kinase 1 (Sphk1) expression and activity. Furthermore, Rho-associated kinase, downstream of S1P3, was crucial for S1P-induced cPLA2{alpha} activation. Our data suggest that S1P acting through S1P3, calcium flux, and Rho kinase activates cPLA2{alpha} and releases AA in lung epithelial cells. An understanding of S1P-induced cPLA2{alpha} activation mechanisms in epithelial cells may provide potential targets to control inflammatory processes in the lung.

eicosanoid; calcium flux; airway inflammation


Address for reprint requests and other correspondence: J. H. Shelhamer, Critical Care Medicine Dept., National Institutes of Health, Warren Grant Magnuson Clinical Center, Bldg. 10, Rm. 2C145, 9000 Rockville Pike, Bethesda, MD 20892 (e-mail: jshelhamer{at}cc.nih.gov)






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