| | | | | association of an additional component, MD-2 which |
| Toll-like receptor 4 (TLR4) often designated as CD284 | | | | together can initiate two major intracellular signaling |
| (cluster of differentiation 284) is a class I | | | | pathways, MyD88-dependent and TRIF-dependent |
| transmembrane receptor belonging to the large | | | | (MyD88-independent). The MyD88-dependent pathway |
| homologous family of Toll like receptors. TLR4 | | | | requires the recruitment of TIRAP and MyD88 via |
| expressed on the surface of immune system cells, is | | | | homophilic TIR-TIR interactions and activates nuclear |
| activated by exposure to lipopolysaccharides derived | | | | factor (NF)-?B, activator protein-1 (AP-1) and interferon |
| from the outer membrane of Gram negative bacteria | | | | regulatory factor 5 (IRF5), which induce inflammatory |
| and thus forms part of the innate immune response in | | | | cytokine expression such as IL-6, IL-12, and TNF?. The |
| mammals. (1) TLR4 was initially cloned as the human | | | | TRIF-dependent pathway requires the recruitment of |
| homolog of Drosophila Toll (dToll) and thus was first | | | | TRAM and TRIF and activates IRF3, in addition to |
| named hToll. Like all other members of the TLR family, | | | | NF-?B and AP-1, which induce type I interferon (IFN) |
| TLR4 is composed of an extracellular domain | | | | expression. TLR4 can also activate various other |
| containing multiple leucine-rich repeats (LRRs), a | | | | signaling molecules, including phosphatidylinositol-3 |
| transmembrane region, and a cytoplasmic tail | | | | kinase (PI-3K) and MAP3Ks such as MEKK3, TPL2, |
| containing the conserved TIR domain. TLR4 maps to | | | | and ASK1. (5,6) The TLR4 complex also recognizes a |
| chromosome 9q32-33. It shows a high degree of | | | | few other bacterial PAMPs including LTA. Further, the |
| similarity to dToll over the entire aminoacid sequence. | | | | TLR4 complex recognizes viruses including respiratory |
| The TLR4 sequence encodes an 839 aminoacid | | | | syncytial virus (RSV), hepatitis C virus (HCV), and |
| protein with 22 N-terminal LRR regions and a | | | | mouse mammary tumor virus (MMTV). The TLR4 |
| calculated molecular weight of 90 kDa. TLR4 is most | | | | complex can also recognize endogenous ligands, for |
| closely related to TLR1 and TLR6 each with 25% | | | | example, heat shock proteins, fibrinogen, fibronectin, |
| overall aa sequence identity. Several transcript variants | | | | surfactant protein A (SP-A), and ?-defensins. TLR4 |
| of this gene have been found, but the protein coding | | | | also forms heterodimers both with TLR5, which |
| potential of most of them is uncertain. | | | | presumably enhances its activity, and also with TLR1, |
| | | | | which inhibits its activity. (7, 8) |
| In vivo, TLR4 mRNA is expressed as a single | | | | |
| transcript, and found at highest levels in spleen and | | | | Mutations in TLR4 gene have been associated with |
| PBLs. (2, 3) Of the PBL populations, TLR4 is | | | | differences in LPS responsiveness. |
| expressed by B cells, DCs, monocytes, macrophages, | | | | A recently discovered Asp299Gly TLR4 |
| granulocytes, and T cells. Other reports suggest that | | | | polymorphism has been identified that confer |
| TLR4 is only expressed in myelomonocytic cells and is | | | | differences in the inflammatory response elicited by |
| highest in mononuclear cells. In vitro, TLR4 mRNA and | | | | bacterial lipopolysaccharide and is associated with a |
| protein expression is upregulated in THP-1 cells upon | | | | decreased risk of atherosclerosis. (9) |
| PMA-induced differentiation. TLR4 is moderately | | | | |
| upregulated by autocrine IFN-?, IL-1?. TLR4 mRNA | | | | Reference: |
| expression in THP-1 cells is unaffected by exposure to | | | | 1. Ricardo et al. PLoS ONE. 2007; 2(8): e788. |
| both Gram-positive and Gram-negative bacteria. Ex | | | | 2. Medzhitov, R. et al. (1997) Nature 388:394. |
| vivo, granulocyte, and especially monocyte, TLR4 | | | | 3. Rock, F.L. et al. (1998) Proc. Natl. Acad. Sci. USA |
| expression is upregulated upon exposure to | | | | 95:588. |
| Gram-negative bacteria. (4) | | | | 4. Zarember, K.A. & P.J. Godowski (2002) J. Immunol. |
| | | | | 168:554. |
| TLR4 is critical for host defense against | | | | 5. Myeong Sup Lee Vol. 76: 447-480 Annual Review |
| gram-negative bacteria in both mice and humans. Upon | | | | of Biochemistry |
| recognition of its ligand LPS, TLR4 undergoes | | | | 6. Yong-Chen Lu doi:10.1016/j.cyto.2008.01.006 Article |
| dimerization, and recent studies suggest that this | | | | in press |
| causes concerted conformational changes in the | | | | 7. Spitzer, J.H. et al. (2002) Eur. J. Immunol. 32:1182. |
| receptor leading to self association of the cytoplasmic | | | | 8. Mizel, S.B. et al. (2003) J. Immunol. 170:6217. |
| Toll/Interleukin 1 receptor (TIR) signalling domain. Ligand | | | | 9. N Engl J Med 2002; 347:1978-1980, Dec 12, 2002. |
| recognition by TLR4 requires the extracellular | | | | |