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

• Published in: The Journal of immunology (1950) 2000-01, Vol.164 (1), p.29-37
• Main Authors: Valledor, A F, Xaus, J, Comalada, M, Soler, C, Celada, A
• Format: Article
• Language: English
• Subjects: Bone Marrow Cells - enzymology; Bone Marrow Cells - immunology; Cell Cycle Proteins; CREB-Binding Protein; Dose-Response Relationship, Immunologic; Dual Specificity Phosphatase 1; Enzyme Activation - immunology; Enzyme Induction - immunology; Immediate-Early Proteins - antagonists & inhibitors; Immediate-Early Proteins - biosynthesis; Immediate-Early Proteins - genetics; Isoenzymes - genetics; Isoenzymes - metabolism; Isoenzymes - physiology; Lipopolysaccharide Receptors - metabolism; lipopolysaccharides; Lipopolysaccharides - immunology; Lipopolysaccharides - metabolism; Macrophage Activation - immunology; Macrophages - enzymology; Macrophages - immunology; MAP kinase; Membrane Proteins - isolation & purification; Membrane Proteins - physiology; Mitogen-Activated Protein Kinases - antagonists & inhibitors; MKP-1 protein; Nuclear Proteins - metabolism; Oligonucleotides, Antisense - pharmacology; Phosphoprotein Phosphatases; Phosphorylation; Promoter Regions, Genetic - immunology; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein Kinase C - physiology; Protein Kinase C-epsilon; Protein kinase C^e; Protein Phosphatase 1; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - biosynthesis; Protein Tyrosine Phosphatases - genetics; Response Elements - immunology; Signal Transduction - immunology; Substrate Specificity - immunology; Trans-Activators - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.164.1.29

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 interested in the characterization of the signaling mechanisms involved in the control of MKP-1 expression in LPS-stimulated macrophages. The induction of MKP-1 was blocked by genistein, a tyrosine kinase inhibitor, and by two different protein kinase C (PKC) inhibitors (GF109203X and calphostin C). We had previously shown that bone marrow macrophages express the isoforms PKC beta I, epsilon, and zeta. Of all these, only PKC beta I and epsilon are inhibited by GF109203X. The following arguments suggest that PKC epsilon is required 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, Gö6976, an inhibitor selective for conventional PKCs, including PKC beta I, does not alter MKP-1 induction by LPS. Last, antisense oligonucleotides 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 increase of extracellular-signal regulated kinase activity during the macrophage response to LPS. Finally, in macrophages stimulated with LPS we observed significant activation of PKC epsilon. In conclusion, our results demonstrate an important role for PKC epsilon in the induction of MKP-1 and the subsequent negative control of MAPK activity in macrophages.