GRANULOCYTE-COLONY-STIMULATING FACTOR ACTIVATES PROTEIN-KINASE-A IN GRANULOCYTIC BUT NOT MONOCYTIC PRECURSORS OR NEUTROPHILS

Granulocyte colony-stimulating factor (G-CSF) regulates survival, prol iferation, differentiation, and activation of myeloid cells, G-CSF-R s ignaling mechanisms other than tyrosine kinase activation have not bee n documented. We explored the potential involvement of cAMP-dependent protein kinase A (PKA) in G-CSF-R signal transduction, In this report, we provide the first direct evidence of PKA modulation by G-CSF-R, G- CSF treatment of granulocytic precursor cell lines (HL-60, NFS-60, KG- 1) resulted in PKA activation, measured by phosphorylation of Kemptide , a peptide substrate. In contrast, the myelomonocytic cell lines (WEH I-3B,U-937) and peripheral blood neutrophils (PMNC) showed a rapid dec rease in PKA activity in response to G-CSF, H-89, a specific inhibitor of PKA, blocked G-CSF-induced PKA activation in HL-60 cells but did n ot affect ligand-induced downmoduIation of G-CSF-R. Indomethacin, an i nhibitor of the cyclooxygenase pathway and prostaglandin synthesis, di d not inhibit PKA induction in G-CSF-treated HL-60 cells. Our results demonstrate the involvement of PKA in G-CSF-R signal transduction and suggest a lineage-restricted, developmental stage-specific regulation of this pathway in myeloid cells.