The involvement of sphingosine kinase 1 in LPS-induced Toll-like receptor 4-mediated accumulation of HIF-1α protein, activation of ASK1 and production of the pro-inflammatory cytokine IL-6.
Toll-like receptors (TLRs) lie in the core of resistance to infectious diseases allowing host immune cells to specifically detect pathogens by recognising their specific molecular patterns. Cell membrane-associated TLR4 (recognises lipopolysaccharide (LPS) of Gram-negative bacteria) and endosomal TLR7/8 (recognise viral single-stranded RNA) are known to activate hypoxia inducible factor-1α (HIF-1α) protein (necessary for cellular adaptation to the inflammatory stress) via redox-dependent mechanism. TLR4 triggers the cross talk between HIF-1α and apoptosis signal-regulating kinase 1 (ASK1), whereas TLR7/8 activates HIF-1α in the ASK1-independent manner. Here, we report that in THP-1 and RAW264.7 macrophages, ligand-induced activation of the TLR4 but not TLR7/8 induces activation and transcriptional upregulation of sphingosine kinase 1 (SphK1) in extracellular signal-regulating kinase and phospholipase C-1γ/PI3 kinase-dependent manner. TLR4-mediated SphK1 activation was found to be critical for the redox-dependent activation of HIF-1α and ASK1, as well as for the prevention of LPS-induced activation of caspase 3 and the expression of pro-inflammatory cytokine interleukin-6.
Pchejetski
Dmitri
D
Department of Oncology, Hammersmith hospital, Imperial College London, London, UK. d.pshezhetskiy@imperial.ac.uk
Nunes
Joao
J
Coughlan
Karen
K
Lall
Harjinder
H
Pitson
Stuart M
SM
Waxman
Jonathan
J
Sumbayev
Vadim V
VV
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000099157:Sphingosine Kinase
D053148:Caspase 3; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D048848:MAP Kinase Kinase Kinase 5; D017853:Phosphotransferases (Alcohol Group Acceptor); D051197:Toll-Like Receptor 4; D000099157:Sphingosine Kinase; C497442:HIF1A protein, human; C508600:IL6 protein, human; C482858:MAP3K5 protein, human