The Journal of Experimental Medicine
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Published online January 21, 2008
doi:10.1084/jem.20071243
The Journal of Experimental Medicine, Vol. 205, No. 2, 347-359
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Mishra et al.
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ARTICLE

 iPLA2β: front and center in human monocyte chemotaxis to MCP-1

Ravi S. Mishra1, Kevin A. Carnevale2, and Martha K. Cathcart1,3

1 Department of Cell Biology, Cleveland Clinic, Cleveland, OH 44195
2 Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine,Columbia, SC 29208
3 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195

CORRESPONDENCE Martha K. Cathcart: cathcam{at}ccf.org

Monocyte chemoattractant protein-1 (MCP-1) directs migration of blood monocytes to inflamed tissues. Despite the central role of chemotaxis in immune responses, the regulation of chemotaxis by signal transduction pathways and their in vivo significance remain to be thoroughly deciphered. In this study, we examined the intracellular location and functions of two recently identified regulators of chemotaxis, Ca2+-independent phospholipase (iPLA2β) and cytosolic phospholipase (cPLA2{alpha}), and substantiate their in vivo importance. These enzymes are cytoplasmic in unstimulated monocytes. Upon MCP-1 stimulation, iPLA2β is recruited to the membrane-enriched pseudopod. In contrast, cPLA2{alpha} is recruited to the endoplasmic reticulum. Although iPLA2β or cPLA2{alpha} antisense oligodeoxyribonucleotide (ODN)–treated monocytes display reduced speed, iPLA2β also regulates directionality and actin polymerization. iPLA2β or cPLA2{alpha} antisense ODN–treated adoptively transferred mouse monocytes display a profound defect in migration to the peritoneum in vivo. These converging observations reveal that iPLA2β and cPLA2{alpha} regulate monocyte migration from different intracellular locations, with iPLA2β acting as a critical regulator of the cellular compass, and identify them as potential targets for antiinflammatory strategies.

Abbreviations used: AA, arachidonic acid; AACOCF3, arachidonyl trifluoromethyl ketone; BEL, bromoenol lactone; CCR2, CC chemokine receptor 2; cPLA2, cytosolic phospholipase; DIC, differential interference contrast; iPLA2, Ca2+-independent phospholipase; LPA, lysophosphatidic acid; MCP-1, monocyte chemoattractant protein-1; ODN, oligodeoxyribonucleotide; PA, phosphatidic acid; PDI, protein disulfide isomerase; PI3K, phosphatidylinositol 3-kinase; PLD, phospholipase D; PtdIns(3,4,5)P3, phosphatidylinositol (3,4,5) triphosphate; TBS, Tricine-buffered saline.


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