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Toll-like receptor 4 (TLR4) often designated as CD284 (cluster of differentiation 284) is a class I transmembrane receptor belonging to the family of homologous Toll-like receptors. TLR4 expressed on the surface of immune cells, is activated by exposure to lipopolysaccharide outer membrane of Gram-negative bacteria and is therefore part of the innate immune response mammals. (1) TLR4 was initially cloned as the human homologue of Drosophila Toll (dToll) and therefore was first appointed hToll. Like all other members of the TLR family, TLR4 is composed of an extracellular domain containing leucine-rich repeats multiple (PRRS), a region transmembrane and cytoplasmic tail containing the conserved TIR domain. Maps TLR4 to chromosome 9q32-33. It shows a high degree of similarity to any sequence amino acids dToll period. The sequence encodes a TLR4 protein of 839 amino acids with 22 N-terminal region and a PBA molecular weight calculated 90 kDa. TLR4 is most closely related to TLR1 and TLR6 each with 25% AA sequence identity. Transcripts of several variants of this gene have been found, but the potential of coding for proteins most of them is uncertain.

In vivo, TLR4 mRNA is expressed in a speech unique, and is the highest level of the rate and LSP. (2, 3) populations of PBL, TLR4 is expressed in B cells, the developing countries, monocytes, macrophages, granulocytes and T lymphocytes Other reports suggest that TLR4 is expressed only in myelomonocytic cells and is increased in mononuclear cells. In vitro, TLR4 mRNA and protein expression is increased in THP-1 PMA-induced cell differentiation. TLR4 is moderately stimulated by autocrine IFN-γ, IL-1β. TLR4 mRNA expression in THP-1 cells is not affected by exposure to Gram-positive and gram-negative. Ex vivo of granulocytes monocytes and, especially, the expression of TLR4 is upregulated on exposure to gram-negative bacteria. (4)

TLR4 is essential for protection against Gram-negative bacteria, in both mice and humans. Upon recognition of its ligand LPS, TLR4 undergoes dimerization, and recent studies suggest that this causes concerted conformational changes in the receiver which leads to the association of cytoplasmic line / interleukin 1 receptor (TIR) signaling domain. TLR4 ligand recognition requires the association extracellular component of an additional MD-2 that can unite to launch two channels major intracellular signaling, MyD88-dependent and TRIF-dependent (MyD88-independent). The MyD88-dependent pathways requires the recruitment of TIRAP and MyD88 TIR through homophilic interactions between TIR and activates factor nuclear (NF)-kB, activator protein-1 (AP-1) and interferon regulatory factor 5 (IRF5), which induce expression of inflammatory cytokines such as IL-6, IL-12 and TNFa. The TRIF-dependent pathways requires the recruitment TRAM and TRIF and activates IRF3 in addition to NF-kB and AP-1 that induces interferon Type I (IFN) expression. TLR4 can also activate several other signaling molecules, including phosphatidylinositol-3 kinase (PI-3K) and MAP3Ks as MEKK3, TPL2, and ASK1. (5.6) The complex TLR4 also recognizes some other PAMPs including bacterial LTA. Additionally, TLR4 recognizes the complex viruses, including respiratory syncytial virus (RSV) Hepatitis C (HCV) virus and mouse mammary tumor (MMTV). The complex also TLR4 may recognize endogenous ligands such as proteins heat shock, fibrinogen, fibronectin, surfactant protein (SP-A) and β-defensins. TLR4 also heterodimers with both TLR5, which supposedly increases their activity, and also with TLR1, which inhibits its activity. (7,

TLR4 mutations are in genes associated with differences in LPS responsiveness.

A recently discovered polymorphisms TLR4 Asp299Gly has been identified that confer the differences in the inflammatory response induced by bacterial lipopolysaccharide and is associated with reduced risk atherosclerosis. (9)

Reference:

1. Ricardo et al. PLoS ONE. 2007, 2 (8): e788.

lang = "EN"> 2. Medzhitov, R. et al. (1997) Nature 388:394.

3. Rock, FL et al. (1998) Proc. Natl. Acad. Sci USA 95:588.

4. Zaremba, KA & Godowski PJ (2002) J. Immunol. 168:554.

5. Myeong Sup Lee vol. 76: 447-480 Annual Review of Biochemistry

6. Yong-Chen Lu doi: 10.1016/j.cyto.2008.01.006 article in the press

lang = "DE"> 7. Spitzer, JH et al (2002). Eur J Immunol. 32:1182.

8. Mizel, SB et al. (2003) J. Immunol. 170:6217.

9. N Engl J Med 2002, 347:1978-1980, December 12, 2002.

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