Calcium-Independent Phospholipase A sub(2) Is Required for Human Monocyte Chemotaxis to Monocyte Chemoattractant Protein 1

• Published in: The Journal of immunology (1950) Vol. 167; no. 6; pp. 3414 - 3421
• Main Authors: Carnevale, KA, Cathcart, M K
• Format: Journal Article
• Language: English
• Published: 15.09.2001
• Subjects: Monocyte chemoattractant protein 1
• ISSN: 0022-1767

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 A sub(2) (cPLA sub(2)) in monocyte chemotaxis to MCP-1. In these studies we investigated the role for another PLA sub(2), calcium-independent PLA sub(2) (iPLA sub(2)) in comparison to cPLA sub(2). Pharmacological inhibitors of PLA sub(2) were found to substantially inhibit chemotaxis. Using antisense oligodeoxyribonucleotide treatment we found that iPLA sub(2) expression is required for monocyte migration to MCP-1. Complete blocking of the chemotactic response was observed with inhibition of either iPLA sub(2) or cPLA sub(2) expression by their respective antisense oligodeoxyribonucleotide. In reconstitution experiments, lysophosphatidic acid completely restored MCP-1-stimulated migration in iPLA sub(2)-deficient monocytes, whereas lysophosphatidic acid was without effect in restoring migration in cPLA sub(2)-deficient monocytes. To the contrary, arachidonic acid fully restored migration of cPLA sub(2)-deficient monocytes while having no effect on the iPLA sub(2)-deficient monocytes. Additional studies revealed that neither enzyme appears to be upstream of the other indicating that iPLA sub(2) and cPLA sub(2) represent parallel regulatory pathways. These data demonstrate novel and distinct roles for these two phospholipases in this critical step in inflammation.