Protein kinase C epsilon IS required for the induction of mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages

LPS induces in bone marrow macrophages the transient expression of mitogen- activated protein kinase (MAPK) phosphatase-1 (MKP-1). Because MKP-1 plays a crucial role in the attenuation of different MAPK cascades, we were inter ested in the characterization of the signaling mechanisms involved in the c ontrol of MKP-1 expression in LPS-stimulated macrophages, The induction of MKP-1 was blocked by genistein, a tyrosine kinase inhibitor, and by two dif ferent protein kinase C (PKC) inhibitors (GF109203X and calphostin C), We h ad previously shown that bone marrow macrophages express the isoforms PKC b eta I, epsilon, and zeta. Of all these, only PKC beta I and epsilon are inh ibited by GF109203X, The following arguments suggest that PKC epsilon is re quired selectively for the induction of MKP-1 by LPS, First, in macrophages exposed to prolonged treatment with PMA, MKP-1 induction by LPS correlates with the levels of expression of PKC epsilon but not with that of PKC beta I, Second, Go6976, an inhibitor selective for conventional PKCs, including PKC beta I, does not alter MKP-1 induction by LPS, Last, antisense oligonu cleotides that block the expression of PKC epsilon, but not those selective for PKC beta I or PKC zeta, inhibit MKP-1 induction and lead to an increas e of extracellular-signal regulated kinase activity during the macrophage r esponse to LPS, Finally, in macrophages stimulated with LPS we observed sig nificant activation of PKC epsilon, In conclusion, our results demonstrate an important role for PKC epsilon in the induction of MKP-1 and the subsequ ent negative control of MAPK activity in macrophages.