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Calcium-Independent Phospholipase A₂ Is Required for Human Monocyte Chemotaxis to Monocyte Chemoattractant Protein 1¹

Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195

Monocyte chemoattractant protein 1 (MCP-1) has an important influence on monocyte migration into sites of inflammation. Our understanding of the signal transduction pathways involved in the response of monocytes to MCP-1 is quite limited yet potentially significant for understanding and manipulating the inflammatory response. Prior studies have demonstrated a crucial regulatory role for cytosolic phospholipase A₂ (cPLA₂) in monocyte chemotaxis to MCP-1. In these studies we investigated the role for another PLA₂, calcium-independent PLA₂ (iPLA₂) in comparison to cPLA₂. Pharmacological inhibitors of PLA₂ were found to substantially inhibit chemotaxis. Using antisense oligodeoxyribonucleotide treatment we found that iPLA₂ expression is required for monocyte migration to MCP-1. Complete blocking of the chemotactic response was observed with inhibition of either iPLA₂ or cPLA₂ expression by their respective antisense oligodeoxyribonucleotide. In reconstitution experiments, lysophosphatidic acid completely restored MCP-1-stimulated migration in iPLA₂-deficient monocytes, whereas lysophosphatidic acid was without effect in restoring migration in cPLA₂-deficient monocytes. To the contrary, arachidonic acid fully restored migration of cPLA₂-deficient monocytes while having no effect on the iPLA₂-deficient monocytes. Additional studies revealed that neither enzyme appears to be upstream of the other indicating that iPLA₂ and cPLA₂ represent parallel regulatory pathways. These data demonstrate novel and distinct roles for these two phospholipases in this critical step in inflammation.

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