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

Pchejetski, Dmitri, Nunes, Joao, Coughlan, Karen, Lall, Harjinder, Pitson, Stuart M, Waxman, Jonathan and Sumbayev, Vadim V (2011) 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. Immunology and Cell Biology, 89 (2). pp. 268-74. ISSN 1440-1711

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: animals,calcium signaling,caspase 3,enzyme activation,humans,hypoxia-inducible factor 1, alpha subunit,inflammation mediators,interleukin-6,intracellular space,lipopolysaccharides,map kinase kinase kinase 5,mice,models, biological,phosphotransferases (alcohol group acceptor),toll-like receptor 4
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 16 Dec 2014 10:04
Last Modified: 21 Apr 2020 23:41
URI: https://ueaeprints.uea.ac.uk/id/eprint/51535
DOI: 10.1038/icb.2010.91

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