PKC{epsilon} is involved in JNK activation that mediates LPS-induced TNF-{alpha}, which induces apoptosis in macrophages

• Published in: American Journal of Physiology: Cell Physiology 2003-11, Vol.285 (5), p.C1235
• Main Authors: Comalada, Monica, Xaus, Jordi, Valledor, Annabel F, Lopez-Lopez, Carlos, Pennington, Daniel J, Celada, Antonio
• Format: Article
• Language: English
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00228.2003

1 Macrophage Biology Group, Biomedical Research Institute of Barcelona-Science Park, University of Barcelona, Barcelona 08028, Spain; and 2 Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom Submitted 3 June 2003 ; accepted in final form 15 July 2003 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- (TNF- ) 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- or in the induction of apoptosis. Using specific inhibitors and mice with the gene for PKC disrupted, we found that LPS-induced TNF- -dependent apoptosis is mostly mediated by PKC , which is not directly involved in the signaling mechanism of apoptosis but rather in the process of TNF- secretion. In our cell model, all three MAPKs were involved in the regulation of TNF- secretion, but at different levels. JNK mainly regulates TNF- transcription and apoptosis, whereas ERK and p38 contribute to the regulation of TNF- production, probably through posttranscriptional mechanisms. Only JNK activity is mediated by PKC in response to LPS and so plays a major role in TNF- secretion and LPS-induced apoptosis. We demonstrated in macrophages that LPS involving PKC regulates JNK activity and produces TNF- , which induces apoptosis. cellular activation; protein kinases/phosphatases; signal transduction Address for reprint requests and other correspondence: A. Celada, Biomedical Research Institute of Barcelona-Science Park, Josep Samitier 1-5, 08028 Barcelona, Spain (E-mail: acelada{at}ub.edu ).