TLR4
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Toll-like receptor-4 (TLR4) is the endotoxin receptor.
The sepsis syndrome is thought to occur when microbial products activate Toll-like receptors stimulating widespread inflammation, in turn causing organ failure, shock and death. Not only microbial substances but also endogenous molecules can trigger Toll-like receptors.
Toll-like receptor-4 (TLR4), the endotoxin receptor, is constitutively suppressed. The first step in sepsis could be the release of Toll-like receptor-4 from suppression.
TLR4 signaling pathway
TLR4 activates both the MyD88- and the TRIF-dependent pathways. TIRAP and TRAM are required for the activation of the MyD88- and the TRIF-dependent pathways, respectively. MyD88 recruits TRAF6 and members of the IRAK family. TRAF6, together with Ubc13 and Uev1A, activates the TAK1 complex via K63-linked ubiquitination (Ub).
The activated TAK1 complex then activates the IKK complex consisting of IKK?, IKK? and NEMO, which catalyzes the phosphorylation of I?B proteins (P). I?Bs are destroyed by the proteasome-dependent pathway, allowing NF-?B (RelA?p50 heterodimer) to translocate into the nucleus (canonical pathway).
Simultaneously, the TAK1 complex activates the MAPK pathway, which results in the phosphorylation (P) and activation of AP-1. NF-?B and AP-1 control inflammatory responses through the induction of inflammatory cytokines. TRIF recruits TRAF3, which then interacts with TBK1 and IKKi. These kinases mediate phosphorylation of IRF3 (P).
Phosphorylated IRF3 dimerizes and translocates into the nucleus to regulate transcription. TRIF also interacts with TRAF6 and RIP1, which mediate NF-?B activation.
Activation of the IRF3, NF-?B and MAPK pathways is required for induction of type I IFN, particularly IFN-?. There are two types of NF-?B activation in TLR4 signaling: the MyD88-dependent pathway, which mediates early phase activation of NF-?B and the TRIF-dependent pathway, which mediates the late phase activation of NF-?B.
Pathology
variants in
- endotoxin hyporesponsiveness
- age-related macular degeneration (as ARMD10, MIM.611488)
- colorectal adenocarcinomas (16879199)
See also
TLRs
Reviews
Brunn GJ, Platt JL. The etiology of sepsis: turned inside out. Trends Mol Med. 2005 Nov 17; PMID: 16298551
References
Boraska Jelavic, T.; Barisic, M.; Drmic Hofman, I.; Boraska, V.; Vrdoljak, E.; Peruzovic, M.; Hozo, I.; Puljiz, Z.; Terjic, J. : Microsatelite (sic) GT polymorphism in the toll-like receptor 2 is associated with colorectal cancer. Clin. Genet. 70: 156-160, 2006. PubMed ID : 16879199
Kiechl, S.; Lorenz, E.; Reindl, M.; Wiedermann, C. J.; Oberhollenzer, F.; Bonora, E.; Willeit, J.; Schwartz, D. A. : Toll-like receptor 4 polymorphisms and atherogenesis. New Eng. J. Med. 347: 185-192, 2002. PubMed ID : 12124407
Michelsen, K. S.; Wong, M. H.; Shah, P. K.; Zhang, W.; Yano, J.; Doherty, T. M.; Akira, S.; Rajavashisth, T. B.; Arditi, M. : Lack of toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Nat. Acad. Sci. 101: 10679-10684, 2004. PubMed ID : 15249654