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Ceramide as a TLR4 agonist; a putative signalling intermediate between sphingolipid receptors for microbial ligands and TLR4.

Fischer, Hans LU ; Ellström, Patrik; Ekström-Holka, Kristina LU ; Gustafsson, Lotta LU ; Gustafsson, Mattias LU and Svanborg, Catharina LU (2007) In Cellular Microbiology 9(5). p.1239-1251
Abstract
Mucosal Toll-like receptors (TLRs) respond to pathogens, but remain inert to the indigenous flora, suggesting that the TLRs can receive pathogen-specific signals. For example, TLR4 signalling is activated in CD14-negative epithelial cells by P-fimbriated, uropathogenic Escherichia coli, but not by lipopolysaccharide. The fimbriae use glycosphingolipids as recognition receptors and there is release of ceramide, which is the membrane-anchoring domain of the receptors. In this study, ceramide was identified as a TLR4 agonist and as a putative signalling intermediate between the glycosphingolipid recognition receptors and TLR4. Exogenous ceramide activated a TLR4-dependent epithelial cell response, as shown by exposing stably transfected... (More)
Mucosal Toll-like receptors (TLRs) respond to pathogens, but remain inert to the indigenous flora, suggesting that the TLRs can receive pathogen-specific signals. For example, TLR4 signalling is activated in CD14-negative epithelial cells by P-fimbriated, uropathogenic Escherichia coli, but not by lipopolysaccharide. The fimbriae use glycosphingolipids as recognition receptors and there is release of ceramide, which is the membrane-anchoring domain of the receptors. In this study, ceramide was identified as a TLR4 agonist and as a putative signalling intermediate between the glycosphingolipid recognition receptors and TLR4. Exogenous ceramide activated a TLR4-dependent epithelial cell response, as shown by exposing stably transfected TLR4-positive or -negative human embryonal kidney cells to C2 and C6 ceramide. A similar, TLR4-dependent response occurred after deliberate release of endogenous long-chained ceramide with sphingomyelinase. Microbial ligands with glycosphingolipid specificity (P fimbriae or the B subunit of Shiga toxin) were shown to increase the levels of ceramide and to trigger a TLR4-dependent response in epithelial cells. The results show that ceramide activates TLR4 signalling and suggest that this mechanism might allow pathogens to elicit mucosal TLR4 responses by perturbing sphingolipid receptors for virulence ligands like P fimbriae. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cellular Microbiology
volume
9
issue
5
pages
1239 - 1251
publisher
Wiley-Blackwell
external identifiers
  • wos:000245506100014
  • scopus:34047276820
ISSN
1462-5814
DOI
10.1111/j.1462-5822.2006.00867.x
language
English
LU publication?
yes
id
4112b4e2-c416-460e-bac2-4f578227d453 (old id 164887)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17223929&dopt=Abstract
date added to LUP
2007-07-04 09:05:46
date last changed
2017-11-12 03:25:15
@article{4112b4e2-c416-460e-bac2-4f578227d453,
  abstract     = {Mucosal Toll-like receptors (TLRs) respond to pathogens, but remain inert to the indigenous flora, suggesting that the TLRs can receive pathogen-specific signals. For example, TLR4 signalling is activated in CD14-negative epithelial cells by P-fimbriated, uropathogenic Escherichia coli, but not by lipopolysaccharide. The fimbriae use glycosphingolipids as recognition receptors and there is release of ceramide, which is the membrane-anchoring domain of the receptors. In this study, ceramide was identified as a TLR4 agonist and as a putative signalling intermediate between the glycosphingolipid recognition receptors and TLR4. Exogenous ceramide activated a TLR4-dependent epithelial cell response, as shown by exposing stably transfected TLR4-positive or -negative human embryonal kidney cells to C2 and C6 ceramide. A similar, TLR4-dependent response occurred after deliberate release of endogenous long-chained ceramide with sphingomyelinase. Microbial ligands with glycosphingolipid specificity (P fimbriae or the B subunit of Shiga toxin) were shown to increase the levels of ceramide and to trigger a TLR4-dependent response in epithelial cells. The results show that ceramide activates TLR4 signalling and suggest that this mechanism might allow pathogens to elicit mucosal TLR4 responses by perturbing sphingolipid receptors for virulence ligands like P fimbriae.},
  author       = {Fischer, Hans and Ellström, Patrik and Ekström-Holka, Kristina and Gustafsson, Lotta and Gustafsson, Mattias and Svanborg, Catharina},
  issn         = {1462-5814},
  language     = {eng},
  number       = {5},
  pages        = {1239--1251},
  publisher    = {Wiley-Blackwell},
  series       = {Cellular Microbiology},
  title        = {Ceramide as a TLR4 agonist; a putative signalling intermediate between sphingolipid receptors for microbial ligands and TLR4.},
  url          = {http://dx.doi.org/10.1111/j.1462-5822.2006.00867.x},
  volume       = {9},
  year         = {2007},
}