Monocyte chemotactic protein (MCP)-1, a member of the C-C (or ) branch of the chemokine superfamily, at chemotactic concentrations, induced a rapid release of [H]arachidonic acid but not of [C]oleic acid from prelabeled human monocytes. This effect was associated with an increase in the intensity of the immunoreactive band corresponding to the phosphorylated form of cytosolic phospholipase A (cPLA). To address the role of cPLA in the induction of monocyte chemotaxis, cells were treated with a specific antisense oligonucleotide. Monocytes cultured in the presence of 10 µM antisense oligonucleotide for 48 h showed a marked decrease (57 ± 5%; n = 4) of cPLA expression, as evaluated by Western blot analysis and a nearly complete inhibition (81.8 ± 4.2%; n = 3) of [H]arachidonic acid release in MCP-1-stimulated cells. Monocyte chemotaxis in response to MCP-1 also was inhibited in a concentration-dependent manner by cPLA antisense oligonucleotide (IC = 1.9 ± 1.1 µM; n = 3), with complete inhibition observed between 3 and 10 µM. No inhibition of chemotactic response was observed in monocytes treated with a control oligonucleotide. Monocyte migration in response to MCP-3, RANTES (regulated on activation normal T cells expressed and secreted), and MIP-1/LD78 also was inhibited (>70%) in antisense oligonucleotide-treated cells. On the contrary, the chemotactic response elicited by formyl-methionyl-leucyl-phenylalanine and C5a, two ``classical'' chemotactic agonists, was minimally affected (<20%) by antisense oligonucleotide treatment. These data show that cPLA plays a major role in [H]arachidonic acid release by MCP-1 in human monocytes and provide direct evidence for the involvement of cPLA in C-C chemokine-induced monocyte chemotaxis.

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