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 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.
Valledor
A F
AF
Departament de Fisiologia (Biologia del Macròfag), Facultat de Biologia, Fundació August Pi i Sunyer, Universitat de Barcelona, Spain.
Xaus
J
J
Comalada
M
M
Soler
C
C
Celada
A
A
D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D004306:Dose-Response Relationship, Immunologic; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology*; D008565:Membrane Proteins / Q000302:isolation & purification / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009687:Nuclear Proteins / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013379:Substrate Specificity / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D015534:Trans-Activators; D050882:CREB-Binding Protein; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases