title: PKC epsilon is involved in JNK activation that mediates LPS-induced TNF-alpha, which induces apoptosis in macrophages.
abstract: Lipopolysaccharide (LPS) is a powerful stimulator of macrophages and induces apoptosis in these cells. Using primary cultures of bone marrow-derived macrophages, we found that the autocrine production of tumor necrosis factor-alpha (TNF-alpha) has a major function in LPS-induced apoptosis. LPS activates PKC and regulates the different mitogen-activated protein kinases (MAPK). We aimed to determine its involvement either in the secretion of TNF-alpha or in the induction of apoptosis. Using specific inhibitors and mice with the gene for PKCepsilon disrupted, we found that LPS-induced TNF-alpha-dependent apoptosis is mostly mediated by PKCepsilon, which is not directly involved in the signaling mechanism of apoptosis but rather in the process of TNF-alpha secretion. In our cell model, all three MAPKs were involved in the regulation of TNF-alpha secretion, but at different levels. JNK mainly regulates TNF-alpha transcription and apoptosis, whereas ERK and p38 contribute to the regulation of TNF-alpha production, probably through posttranscriptional mechanisms. Only JNK activity is mediated by PKCepsilon in response to LPS and so plays a major role in TNF-alpha secretion and LPS-induced apoptosis. We demonstrated in macrophages that LPS involving PKCepsilon regulates JNK activity and produces TNF-alpha, which induces apoptosis.
authors.affiliation: Macrophage Biology Group, Biomedical Research Institute of Barcelona-Science Park, University of Barcelona, Josep Samitier 1-5, 08028 Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Comalada
authors.forename: Jordi
authors.initials: J
authors.lastname: Xaus
authors.forename: Annabel F
authors.initials: AF
authors.lastname: Valledor
authors.forename: Carlos
authors.initials: C
authors.lastname: López-López
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pennington
authors.forename: Antonio
authors.initials: A
authors.lastname: Celada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4; D008264:Macrophages / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism* / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D007211:Indoles; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008301:Maleimides; D014409:Tumor Necrosis Factor-alpha; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C070515:bisindolylmaleimide I