CAMP ENHANCES CSF-1-INDUCED ERK ACTIVITY AND C-FOS MESSENGER-RNA EXPRESSION VIA A MEK-DEPENDENT AND RAS-INDEPENDENT MECHANISM IN MACROPHAGES

Inhibition of MAPK by elevated intracellular cAMP has often been corre lated with suppression of growth factor-induced proliferation. However , in murine bone marrow-derived macrophages (BMM) we show that the cAM P analogue, 8-bromo cAMP (8BrcAMP) (1mM), despite being a dramatic G1 phase proliferation inhibitor, increased ERK activity both in the abse nce and presence of CSF-1; these increases were blocked by PD98059 (10 0 mu M) suggesting MEK dependence. In contrast, CSF-l-stimulated p21(R as) activity was blocked by 8BrcAMP thus correlating with the inhibiti on of proliferation. This is the first report to indicate that elevate d intracellular cAMP can activate ERK activity while inhibiting prolif eration and the data support the concept in CSF-l-treated macrophages of Ras-independent activation of ERK activity. It was also found that the acute but not the sustained elevation of c-fos mRNA expression due to 8BrcAMP was also MEK dependent indicating that there are separate pathways controlling c-fos mRNA expression in BMM. (C) 1998 Academic P ress.