Phosphatidyl inositol-3-phosphate kinase mediates CD14 dependent signaling.
Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is an important mediator of innate immunity and septic shock, but the exact mechanisms mediating cellular LPS recognition and the subsequent translation to inflammatory gene expression remain incompletely understood. CD14 has been established as a receptor that confers high sensitivity to LPS in cells of the myeloid lineage, probably by presenting LPS to Toll receptors. We use an anti CD14 blocking antibody to define a LPS stimulus that activates only this high affinity component of the LPS receptor and then examine CD14 dependent signaling events that are activated in response to LPS stimulation. We describe a novel LPS activated signaling pathway in human PBMC that leads to cytokine production and is mediated by PI3 kinase through Ras and the MEK/ERK cassette. Moreover, we show the PI3 kinase effectors PKB and PKC(zeta) are also activated by PI3 kinase in a CD14 dependent manner in LPS stimulated human PBMC. Thus, PI3 kinase appears to be an essential component in LPS signal transduction.
O'Toole
Tom
T
Laboratory of Experimental Medicine, G2-130, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Peppelenbosch
Maikel P
MP
D000911:Antibodies, Monoclonal / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism; D000099221:Protein Kinase C zeta
D000911:Antibodies, Monoclonal; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins; D000099221:Protein Kinase C zeta