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

Immunol Cell Biol. 2011 Feb;89(2):268-74. doi: 10.1038/icb.2010.91. Epub 2010 Jul 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling / drug effects
  • Caspase 3 / metabolism
  • Enzyme Activation / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Inflammation Mediators / metabolism*
  • Interleukin-6 / biosynthesis*
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Lipopolysaccharides / pharmacology*
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Mice
  • Models, Biological
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Toll-Like Receptor 4 / metabolism*


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IL6 protein, human
  • Inflammation Mediators
  • Interleukin-6
  • Lipopolysaccharides
  • Toll-Like Receptor 4
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • MAP Kinase Kinase Kinase 5
  • MAP3K5 protein, human
  • Caspase 3