TLR 4: Wikis

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Toll-like receptor 4

PDB rendering based on 2z64.
Available structures
2z62, 2z63, 2z64, 2z65, 2z66
Identifiers
Symbols TLR4; CD284; TOLL; hToll
External IDs OMIM603030 MGI96824 HomoloGene41317 GeneCards: TLR4 Gene
RNA expression pattern
PBB GE TLR4 221060 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7099 21898
Ensembl ENSG00000136869 ENSMUSG00000039005
UniProt O00206 Q3U4D4
RefSeq (mRNA) NM_138554 NM_021297
RefSeq (protein) NP_612564 NP_067272
Location (UCSC) Chr 9:
119.51 - 119.52 Mb
Chr 4:
66.31 - 66.33 Mb
PubMed search [1] [2]

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene.[1][2] TLR 4 is a toll-like receptor. It detects lipopolysaccharide on Gram-negative bacteria and is thus important in the activation of the innate immune system. TLR4 has also been designated as CD284 (cluster of differentiation 284).

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta, and in myelomonocytic subpopulation of the leukocytes. It has been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness. Also, several transcript variants of this gene have been found, but the protein coding potential of most of them is uncertain.[3]

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations


Contents

Interactions

TLR 4 has been shown to interact with TOLLIP,[4] Myd88[5][6][7][8] and Lymphocyte antigen 96.[9][10]

Drugs targeting TLR4

The lipid A analogon eritoran acts as a TLR4 antagonist. As of December 2009, it is being developed as a drug against severe sepsis.[11]

References

  1. ^ Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (Feb 1998). "A family of human receptors structurally related to Drosophila Toll". Proc Natl Acad Sci U S A 95 (2): 588–93. PMID 9435236.  
  2. ^ Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (Aug 1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity". Nature 388 (6640): 394–7. doi:10.1038/41131. PMID 9237759.  
  3. ^ "Entrez Gene: TLR4 toll-like receptor 4". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7099.  
  4. ^ Zhang, Guolong; Ghosh Sankar (Mar. 2002). "Negative regulation of toll-like receptor-mediated signaling by Tollip". J. Biol. Chem. (United States) 277 (9): 7059–65. doi:10.1074/jbc.M109537200. ISSN 0021-9258. PMID 11751856.  
  5. ^ Chuang, Tsung-Hsien; Ulevitch Richard J (May. 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nat. Immunol. (United States) 5 (5): 495–502. doi:10.1038/ni1066. ISSN 1529-2908. PMID 15107846.  
  6. ^ Doyle, Sean E; O'Connell Ryan, Vaidya Sagar A, Chow Edward K, Yee Kathleen, Cheng Genhong (Apr. 2003). "Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4". J. Immunol. (United States) 170 (7): 3565–71. ISSN 0022-1767. PMID 12646618.  
  7. ^ Rhee, S H; Hwang D (Nov. 2000). "Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase". J. Biol. Chem. (UNITED STATES) 275 (44): 34035–40. doi:10.1074/jbc.M007386200. ISSN 0021-9258. PMID 10952994.  
  8. ^ Fitzgerald, K A; Palsson-McDermott E M, Bowie A G, Jefferies C A, Mansell A S, Brady G, Brint E, Dunne A, Gray P, Harte M T, McMurray D, Smith D E, Sims J E, Bird T A, O'Neill L A (Sep. 2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature (England) 413 (6851): 78–83. doi:10.1038/35092578. ISSN 0028-0836. PMID 11544529.  
  9. ^ Re, Fabio; Strominger Jack L (Jun. 2002). "Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness". J. Biol. Chem. (United States) 277 (26): 23427–32. doi:10.1074/jbc.M202554200. ISSN 0021-9258. PMID 11976338.  
  10. ^ Shimazu, R; Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M (Jun. 1999). "MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4". J. Exp. Med. (UNITED STATES) 189 (11): 1777–82. ISSN 0022-1007. PMID 10359581.  
  11. ^ Tidswell, M; Tillis, W; Larosa, SP; Lynn, M; Wittek, AE; Kao, R; Wheeler, J; Gogate, J et al. (2010). "Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis". Critical care medicine 38 (1): 72–83. doi:10.1097/CCM.0b013e3181b07b78. PMID 19661804.  

Further reading

  • Lien E, Ingalls RR (2002). "Toll-like receptors.". Crit. Care Med. 30 (1 Suppl): S1–11. doi:10.1097/00003246-200201001-00001. PMID 11782555.  
  • Raetz CR, Whitfield C (2002). "Lipopolysaccharide endotoxins.". Annu. Rev. Biochem. 71: 635–700. doi:10.1146/annurev.biochem.71.110601.135414. PMID 12045108.  
  • Lin WJ, Yeh WC (2005). "Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock.". Shock 24 (3): 206–9. doi:10.1097/01.shk.0000180074.69143.77. PMID 16135957.  
  • Lorenz E (2007). "TLR2 and TLR4 expression during bacterial infections.". Curr. Pharm. Des. 12 (32): 4185–93. doi:10.2174/138161206778743547. PMID 17100621.  
  • Stoll LL, Denning GM, Weintraub NL (2007). "Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease.". Curr. Pharm. Des. 12 (32): 4229–45. doi:10.2174/138161206778743501. PMID 17100625.  
  • Rousseaux C, Desreumaux P (2007). "[The peroxisome-proliferator-activated gamma receptor and chronic inflammatory bowel disease (PPARgamma and IBD)]". J. Soc. Biol. 200 (2): 121–31. PMID 17151549.  
  • Szabo G, Dolganiuc A, Dai Q, Pruett SB (2007). "TLR4, ethanol, and lipid rafts: a new mechanism of ethanol action with implications for other receptor-mediated effects.". J. Immunol. 178 (3): 1243–9. PMID 17237368.  

External links

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