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PKC epsilon is involved in JNK activation that mediates LPS-induced TNF-alpha, which induces apoptosis in macrophages.
- Source :
-
American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2003 Nov; Vol. 285 (5), pp. C1235-45. Date of Electronic Publication: 2003 Jul 16. - Publication Year :
- 2003
-
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.
- Subjects :
- Animals
Apoptosis drug effects
Bone Marrow Cells drug effects
Bone Marrow Cells enzymology
Bone Marrow Cells metabolism
Cells, Cultured
DNA Fragmentation drug effects
DNA Fragmentation physiology
Indoles pharmacology
Isoenzymes antagonists & inhibitors
Isoenzymes metabolism
MAP Kinase Kinase 4
Maleimides pharmacology
Mice
Mice, Inbred BALB C
Protein Kinase C antagonists & inhibitors
Protein Kinase C-epsilon
Apoptosis physiology
JNK Mitogen-Activated Protein Kinases
Lipopolysaccharides pharmacology
Macrophages metabolism
Mitogen-Activated Protein Kinase Kinases metabolism
Mitogen-Activated Protein Kinase Kinases physiology
Protein Kinase C metabolism
Tumor Necrosis Factor-alpha biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6143
- Volume :
- 285
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Cell physiology
- Publication Type :
- Academic Journal
- Accession number :
- 12867362
- Full Text :
- https://doi.org/10.1152/ajpcell.00228.2003