Cyclic AMP-independent activation of neutrophil-like HL-60 cells by prostaglandin E2

The role of cAMP in mediating prostaglandin E2 (PGE2)-stimulated aggregation of neutrophil-like HL-60 cells has been investigated. Although the EP2 receptors appear to couple to Gs-proteins, PGE2 stimulated HL-60 cell aggregation appears to be a cAMP-independent process. This response to PGE2 in independent of calcium and tyrosine kinase activity, appears to involve activation of phosphatidylinositol 3-kinase which is negatively regulated by phosphatidic acid generated from phospholipase D activity, and is partially dependent on protein kinase C activity. In contrast, although the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) produces a similar aggregation response to PGE2, FMLP uses a distinct intracellular signalling pathway. The aggregation response to FMLP involves activation of Gi-proteins, is partially dependent on extracellular calcium, is negatively regulated by protein kinase C, and is independent of phosphatidylinositol 3-kinase, phospholipase D and tyrosine kinase activity. The possibility exists that EP2 receptor activation leads to Gs-dependent, but cAMP-independent, stimulation of phosphatidylinositol 3-kinase activity in HL-60 cells.