Lipopolysaccharide induces jun N-terminal kinase activation in macrophages by a novel Cdc42/Rac-independent pathway involving sequential activation of protein kinase C zeta and phosphatidylcholine-dependent phospholipase C.
The activation of kinases of the mitogen-activated protein kinase superfamily initiated by lipopolysaccharide (LPS) plays an important role in transducing inflammatory signals. The pathway leading to the induction of stress-activated protein kinases in macrophages stimulated with LPS was investigated. The activation of Jun N-terminal kinases (JNK) by LPS is herbimycin sensitive. Using specific inhibitors, it was shown that the pathway involves the activation of phosphoinositide 3-kinase (PI 3-K). However, in contrast to previous reports, the small GTPases Cdc42 and Rac are not required downstream of PI 3-K for JNK activation. Instead, the phosphoinositides produced by PI 3-K stimulate protein kinase C (PKC) zeta activation through PDK1. In turn, activation of this atypical PKC leads to the stimulation of phosphatidylcholine phospholipase C (PC-PLC) and acidic sphingomyelinase (ASMase). It is therefore proposed that PKCzeta regulates the PC-PLC/ASMase pathway, and it is hypothesized that the resultant ceramide accumulation mediates the activation of the SEK/JNK module by LPS.
Procyk
K J
KJ
Section of Cell Biology and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Vienna, Austria.
Rippo
M R
MR
Testi
R
R
Hofmann
F
F
Parker
P J
PJ
Baccarini
M
M
D000730:Androstadienes / Q000494:pharmacology; D016227:Benzoquinones; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4; D008264:Macrophages / Q000201:enzymology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism*; D000077191:Wortmannin; D020764:cdc42 GTP-Binding Protein / Q000502:physiology
D000730:Androstadienes; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011809:Quinones; D017828:Rifabutin; D013108:Sphingomyelin Phosphodiesterase; D010738:Type C Phospholipases; D000077191:Wortmannin; D020764:cdc42 GTP-Binding Protein; C020754:herbimycin; C105598:phosphatidylcholine-specific phospholipase C