Calcium-independent phospholipase A(2) is required for human monocyte chemotaxis to monocyte chemoattractant protein 1

Monocyte chemoattractant protein 1 (MCP-1) has an important influence on mo nocyte migration into sites of inflammation. Our understanding of the signa l transduction pathways involved in the response of monocytes to MCP-I is q uite limited yet potentially significant for understanding and manipulating the inflammatory response. Prior studies have demonstrated a crucial regul atory role for cytosolic phospholipase A(2) (cPLA(2)) in monocyte chemotaxi s to MCP-1. In these studies we investigated the role for another PLA(2), c alcium-independent PLA(2) (iPLA(2)) in comparison to cPLA(2). Pharmacologic al inhibitors of PLA, were found to substantially inhibit chemotaxis. Using antisense oligodeoxyribonucleotide treatment we found that iPLA(2) express ion is required for monocyte migration to MCP-I. Complete blocking of the c hemotactic response was observed with inhibition of either iPLA(2) or cPLA( 2) expression by their respective antisense oligodeoxyribonucleotide. In re constitution experiments, lysophosphatidic acid completely restored MCP-1-s timulated migration in iPLA(2)-deficient monocytes, whereas lysophosphatidi c acid was without effect in restoring migration in cPLA(2)-deficient monoc ytes. To the contrary, arachidonic acid fully restored migration of cPLA(2) -deficient monocytes while having no effect on the iPLA(2)-deficient monocy tes. Additional studies revealed that neither enzyme appears to be upstream of the other indicating that iPLA(2) and cPLA(2) represent parallel regula tory pathways. These data demonstrate novel and distinct roles for these tw o phospholipases in this critical step in inflammation.