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GROWTH, DIFFERENTIATION, AND APOPTOSIS

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

¹Macrophage Biology Group, Biomedical Research Institute of Barcelona-Science Park, University of Barcelona, Barcelona 08028, Spain; and ²Imperial 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

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