TLR4- cluster of differentiation 284

Stephen Jones

Posted Date: Thursday, July 03, 2008 | Viewed: 63

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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 large homologous family of Toll like receptors. TLR4 expressed on the surface of immune system cells, is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and thus forms part of the innate immune response in mammals. (1) TLR4 was initially cloned as the human homolog of Drosophila Toll (dToll) and thus was first named hToll. Like all other members of the TLR family, TLR4 is composed of an extracellular domain containing multiple leucine-rich repeats (LRRs), a transmembrane region, and a cytoplasmic tail containing the conserved TIR domain. TLR4 maps to chromosome 9q32-33. It shows a high degree of similarity to dToll over the entire aminoacid sequence. The TLR4 sequence encodes an 839 aminoacid protein with 22 N-terminal LRR regions and a calculated molecular weight of 90 kDa. TLR4 is most closely related to TLR1 and TLR6 each with 25% overall aa sequence identity. Several transcript variants of this gene have been found, but the protein coding potential of most of them is uncertain.

In vivo, TLR4 mRNA is expressed as a single transcript, and found at highest levels in spleen and PBLs. (2, 3) Of the PBL populations, TLR4 is expressed by B cells, DCs, monocytes, macrophages, granulocytes, and T cells. Other reports suggest that TLR4 is only expressed in myelomonocytic cells and is highest in mononuclear cells. In vitro, TLR4 mRNA and protein expression is upregulated in THP-1 cells upon PMA-induced differentiation. TLR4 is moderately upregulated by autocrine IFN-γ, IL-1β. TLR4 mRNA expression in THP-1 cells is unaffected by exposure to both Gram-positive and Gram-negative bacteria. Ex vivo, granulocyte, and especially monocyte, TLR4 expression is upregulated upon exposure to Gram-negative bacteria. (4)

TLR4 is critical for host defense 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 receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR) signalling domain. Ligand recognition by TLR4 requires the extracellular association of an additional component, MD-2 which together can initiate two major intracellular signaling pathways, MyD88-dependent and TRIF-dependent (MyD88-independent). The MyD88-dependent pathway requires the recruitment of TIRAP and MyD88 via homophilic TIR-TIR interactions and activates nuclear factor (NF)-κB, activator protein-1 (AP-1) and interferon regulatory factor 5 (IRF5), which induce inflammatory cytokine expression such as IL-6, IL-12, and TNFα. The TRIF-dependent pathway requires the recruitment of TRAM and TRIF and activates IRF3, in addition to NF-κB and AP-1, which induce type I interferon (IFN) expression. TLR4 can also activate various other signaling molecules, including phosphatidylinositol-3 kinase (PI-3K) and MAP3Ks such as MEKK3, TPL2, and ASK1. (5,6) The TLR4 complex also recognizes a few other bacterial PAMPs including LTA. Further, the TLR4 complex recognizes viruses including respiratory syncytial virus (RSV), hepatitis C virus (HCV), and mouse mammary tumor virus (MMTV). The TLR4 complex can also recognize endogenous ligands, for example, heat shock proteins, fibrinogen, fibronectin, surfactant protein A (SP-A), and β-defensins. TLR4 also forms heterodimers both with TLR5, which presumably enhances its activity, and also with TLR1, which inhibits its activity. (7, 8)

Mutations in TLR4 gene have been associated with differences in LPS responsiveness.
A recently discovered Asp299Gly TLR4 polymorphism has been identified that confer differences in the inflammatory response elicited by bacterial lipopolysaccharide and is associated with a decreased risk of atherosclerosis. (9)

Reference:
1. Ricardo et al. PLoS ONE. 2007; 2(8): e788.
2. Medzhitov, R. et al. (1997) Nature 388:394.
3. Rock, F.L. et al. (1998) Proc. Natl. Acad. Sci. USA 95:588.
4. Zarember, K.A. & P.J. Godowski (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 press
7. Spitzer, J.H. et al. (2002) Eur. J. Immunol. 32:1182.
8. Mizel, S.B. et al. (2003) J. Immunol. 170:6217.
9. N Engl J Med 2002; 347:1978-1980, Dec 12, 2002.

Article Tags: toll-like receptors

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TLR4- cluster of differentiation 284

Stephen Jones

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