Macrophage colony-stimulating factor induces the expression of mitogen-activated protein kinase phosphatase-1 through a protein kinase C-dependent pathway

M-CSF triggers the activation of extracellular signal-regulated protein kin ases (ERK)-1/2. We show that inhibition of this pathway leads to the arrest of bone marrow macrophages at the G(0)G(1) phase of the cell cycle without inducing apoptosis. M-CSF induces the transient expression of mitogen-acti vated protein kinase phosphatase-1 (MKP-1), which correlates with the inact ivation of ERK-1/2, Because the time course of ERK activation must be finel y controlled to induce cell proliferation, we studied the mechanisms involv ed in the induction of MKP-1 by M-CSF. Activation of ERK-1/2 is not require d for this event. Therefore, M-CSF activates ERK-1/2 and induces MKP-1 expr ession through different pathways. The use of two protein kinase C (PKC) in hibitors (GF109203X and calphostin C) revealed that M-CSF induces MKP-1 exp ression through a PKC-dependent pathway. We analyzed the expression of diff erent PKC isoforms in bone marrow macrophages, and we only detected PKC bet a I, PKC epsilon, and PKC zeta, PKC zeta is not inhibited by GF109203X/calp hostin C. Of the other two isoforms, PKC epsilon is the best candidate to m ediate MKP-1 induction. Prolonged exposure to PMA slightly inhibits MKP-1 e xpression in response to M-CSF, In bone marrow macrophages, this treatment leads to a complete depletion of PKC beta I, but only a partial down-regula tion of PKC epsilon, Moreover, no translocation of PKC beta I or PKC zeta f rom the cytosol to particulate fractions was detected in response to M-CSF, whereas PKC epsilon was constitutively present at the membrane and underwe nt significant activation in M-CSF-stimulated macrophages. In conclusion, w e remark the role of PKC, probably isoform epsilon, in the negative control of ERK-1/2 through the induction of their specific phosphatase.