TLR4
Synonyms
EC:3.2.2.6, TLR4, Toll Like Receptor 4, Toll-Like Receptor 4, HToll, Homolog Of Drosophila Toll, CD284 Antigen, ARMD10, CD284, TLR-4, TOLL, Toll Like Receptor 4 Protein
Description
Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. It cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) and acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. It is also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni2+. Responses triggered by Ni2+ require non-conserved histidines and are, therefore, species-specific. Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. It binds electronegative LDL (LDL-) and mediates the cytokine release induced by LDL. Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor.
KO Status
F1 (+/-)
Drug Information
Launched drug: 1
Drugs in clinical trials: 10
Latest Research Phase: Approved
Drug Name
Code
Phase
Company
Indications
Clinical Trials
Ibudilast
AV-411, KC-404, MN-166
Approved
Diabetic Neuropathies, Multiple Sclerosis, Chronic Progressive, Multiple Sclerosis, Pneumonia, Viral, Asthma, Neuralgia, Amyotrophic Lateral Sclerosis
EB-05
EB-05
Phase 3 Clinical
Edesa Biotech
Coronavirus Disease 2019 (COVID-19), Respiratory Distress Syndrome, Adult
NI-0101
NI-0101
Phase 2 Clinical
Novimmune
Arthritis, Rheumatoid
ApTOLL
Phase 2 Clinical
aptaTargets SL
Stroke
Glucopyranosyl lipid A
G-100, ID-G100
Phase 2 Clinical
Immune Design, Merck
Carcinoma, Merkel Cell, Influenza A virus infections, Sarcoma, Lymphoma, Non-Hodgkin
PEPA-10
PEPA-10
Phase 2 Clinical
Immunovo
Neoplasms
DMT-210
DMT-200, DMT-210, DMT-220, SIG-990
Phase 2 Clinical
Signum Dermalogix
Rosacea, Dermatitis, Atopic
Anti-HERV-W humanized monoclonal antibodies (GeNeuro)
GNN-001, GNbAC-1, GENHP-01
Phase 2 Clinical
Geneuro
Multiple Sclerosis, Relapsing-Remitting, Diabetes Mellitus, Type 1, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, Multiple Sclerosis
Resatorvid
CLI-095, TAK-242
Phase 2 Clinical
Takeda Pharmaceutical Co Ltd
Shock, Septic, Sepsis, Acute-On-Chronic Liver Failure
House dust mite allergy ultra-short course therapy (Allergy Therapeutics)
Phase 1 Clinical
Allergy Therapeutics
Rhinitis, Allergic
References
Title
Authors
Source
A human homologue of the Drosophila Toll protein signals activation of adaptive immunity
Medzhitov R., Preston-Hurlburt P., Janeway C.A. Jr.,
Nature 388:394-397(1997)
A family of human receptors structurally related to Drosophila Toll
Rock F.L., Hardiman G., Timans J.C., Kastelein R.A., Bazan J.F.,
Proc. Natl. Acad. Sci. U.S.A. 95:588-593(1998)
Phylogenetic variation and polymorphism at the Toll-like receptor 4 locus (TLR4)
Smirnova I., Poltorak A., Chan E.K.L., McBride C., Beutler B.,
Genome Biol. 1:RESEARCH002.1-RESEARCH002.10(2000)
TLR4 mutations are associated with endotoxin hyporesponsiveness in humans
Arbour N.C., Lorenz E., Schutte B.C., Zabner J., Kline J.N., Jones M., Frees K., Watt J.L., Schwartz D.A.,
Nat. Genet. 25:187-191(2000)
Natural selection in the TLR-related genes in the course of primate evolution
Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., Kimura A.,
Immunogenetics 60:727-735(2008)
The heterogeneous allelic repertoire of human Toll-Like receptor (TLR) genes
Georgel P., Macquin C., Bahram S.,
PLoS ONE 4:E7803-E7803(2009)
Complete sequencing and characterization of 21,243 full-length human cDNAs
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., Sugano S.,
Nat. Genet. 36:40-45(2004)
DNA sequence and analysis of human chromosome 9
Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., Bagguley C.L., Dunham I.,
Nature 429:369-374(2004)
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)
The MGC Project Team,
Genome Res. 14:2121-2127(2004)
Signal peptide prediction based on analysis of experimentally verified cleavage sites
Zhang Z., Henzel W.J.,
Protein Sci. 13:2819-2824(2004)