PI3 kinase and direct S-nitrosation are involved in down-regulation of apoptosis signal-regulating kinase 1 during LPS-induced Toll-like receptor 4 signalling.
Toll-like receptor 4 (TLR4) is the human pattern recognition receptor that detects lipopolysaccharide (LPS) shared by Gram-negative bacteria. TLR4 is expressed in different cell types including myeloid cells, the key effectors of innate immune reactions. Apoptosis signal-regulating kinase 1 (ASK1), the upstream kinase of MAP kinase-dependent apoptotic pathway has recently been found to be selectively required for p38 MAP kinase activation/cytokine production during TLR4 signalling. However, the activity of this enzyme has to be down-regulated to protect the cells against apoptosis. In the present study we have found that inhibition of PI3 kinase by LY294002 in THP-1 cells exposed to LPS attenuated down-regulation of ASK1 activity followed by programmed cell death. In addition, nitric oxide produced in response to exposure of THP-1 cells to LPS was found to S-nitrosate and therefore, down-regulate ASK1 activity.
Sumbayev
Vadim V
VV
Medway School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent ME4 4TB, United Kingdom. V.Sumbayev@kent.ac.uk
D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D015538:Nitrosation / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002867:Chromones; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009025:Morpholines; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D009569:Nitric Oxide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D053148:Caspase 3