InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Gene: TLR4

Summary

InnateDB Gene

IDBG-82738.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

TLR4

Gene Name

toll-like receptor 4

Synonyms

ARMD10; CD284; TLR-4; TOLL

Species

Homo sapiens

Ensembl Gene

ENSG00000136869

Encoded Proteins

IDBP-82746

toll-like receptor 4

IDBP-241495

toll-like receptor 4

Protein Structure

Useful resources

Stemformatics EHFPI ImmGen

InnateDB Annotation

Summary

PMID 18326860

TLR4 is activated by LPS and this recognition activates the Src family kinases, Src, Fyn and Yes, which in turn contribute to tyrosine phosphorylation of Zonula adherens proteins to open the endothelial paracellular pathway.

PMID 15852007

TLR4 binding to microbial ligands can be inhibited by CD180 and its helper molecule, LY86, via direct interactions with the TLR4 signalling complex.

PMID 10196138

TLR4 is involved in lipopolysaccharide (LPS) signaling and serves as a cell-surface co-receptor for CD14, leading to LPS-mediated NF-kappaB activation and subsequent cellular events.

PMID 20037584

TLR4-TLR6-Cd36 activation is a common molecular mechanism by which atherogenic lipids and amyloid-beta stimulate sterile inflammation.

PMID 20133493

TLR4 dimerize and enable rapid signal transduction against LPS stimulation on membrane-associated CD14-expressing cells.

PMID 20360853

TLR4 and TLR9 have both non-redundant and cooperative roles in lung innate responses during Gram-negative bacterial pneumonia and are both critical for IL-17 driven antibacterial host response.

PMID 20826541

TLR4 mediates LPS-induced muscle catabolism via coordinate activation of the ubiquitin-proteasome and the autophagy-lysosomal pathways. TLR4 activation by LPS induces C2C12 myotube atrophy via up-regulating autophagosome formation and the expression of ubiquitin ligase atrogin-1/MAFbx and MuRF1.

PMID 21442393

TLR4 transfection of eukaryotic host cells using bacterial vectors, or bactofection, was shown to reduce E. coli colonization in the kidney and the bladder in an animal model of urinary tract infection. (Demonstrated in murine model)

PMID 21464300

TLR4 is involved in the transmission of ER stress from tumour cells to macrophages, promoting a pro-inflammatory program in the tumour microenvironment, thus facilitating tumour progression. (Demonstrated in murine model)

PMID 21518783

TLR4 deficient murine macrophages results in the complete abrogation of TNF-alpha production during Leishmania panamensis infection. The endosomal TLR4 plays a crucial role in the activation of host macrophages and controlling the early stages of parasitic infection. (Demonstrated in murine model)

PMID 21615666

Epithelial TLR4 activation facilitates the transcytosis of non-cytolytic uropathogenic E. coli across intact collecting duct cell layers to invade the renal interstitium in experimental urinary tract infections.

PMID 21712422

TLR4:LY96 functions as intracellular LPS sensor and triggers a unique set of LPS responses upon recognition of phagocytosed bacteria in macrophages. (Demonstrated in murine model)

PMID 21730052

TLR4 on dendritic cell surfaces binds to HSPA14 and induces a robust Th1 response via the MAPK and NFkB signalling pathways. (Demonstrated in mouse)

PMID 21738466

TLR4 recognizes Clostridium difficile surface layer proteins and induces the maturation of dendritic cells to activate the innate and adaptive immune response. (Demonstrated in mouse)

PMID 21775438

TLR4 and HSPD1 mediate myocardial ischemia-activated innate immune signalling, which plays an important role in mediating apoptosis and inflammation during ischemia/reperfusion (I/R). (Demonstrated in murine model)

PMID 22096480

TLR4 and TLR2 are crucial for in vivo recognition of Chlamydia pneumoniae. Tlr4/2 double-deficient mice were unable to control pneumonia caused by C. pneumoniae. (Demonstrated in mice)

PMID 22354030

TLR4 translocates to membrane lipid rafts in a ceramide-dependent manner in Helicobacter pylori infected gastric epithelial cells.

PMID 22396536

TLR4 is involved in cell-cell contact signalling between activated apoptotic lymphocytes and dendritic cells (DC) during the maturation of DCs.

PMID 22433865

Synthetic triacylated lipid A-molecules have the potent ability to selectively antagonize TLR4 and inhibit anti-bacterial immunity.

PMID 22593572

The poxviral protein A46 directly inhibits TLR4 signalling by disrupting receptor complex formation.

PMID 22962435

A human TLR4 polymorphism (D299G/T399I) impairs TLR4::LY96 dimerization and results in a dampened host response to bacterial lipids.

PMID 22951730

TLR4 is an important regulator of wound inflammation and is essential for early skin wound healing. (Demonstrated in mice)

PMID 24265315

TIR domain-contaning protein from Brucella melitensis, TcpB, disrupts the receptor-adaptor interaction between TLR4 and TIRAP.

PMID 25371197

ECSIT binds to MAP3K7 and TRAF6 to form a complex that plays a pivotal role in activating TLR4-mediated NF-kB signalling.

PMID 25505274

The TLR4/S100A8 axis is important in the activation of monocytes.

PMID 26082489

Endotoxin tolerance re-programs TLR4 signalling via suppression of PELI1, a positive regulator of MyD88- and TIR domain-containing adapter inducing IFN-β (TRIF)-dependent signalling that promotes K63-linked polyubiquitination of IRAK1, TBK1, and TAK1.

PMID 26610398

H. pylori infection induces the expression and activation of components of NLRP3 inflammasomes in neutrophils and this activation is independent of a functional type IV secretion system, TLR2 and TLR4.

PMID 26310831

PELI3 is involved in endotoxin tolerance and functions as a negative regulator of TLR2/4 signalling.

InnateDB Annotation from Orthologs

Summary

PMID 19923461

[Mus musculus] Signaling crosstalk during sequential Tlr4 and Tlr9 activation amplifies the inflammatory response of mouse macrophages.

PMID 20385881

[Mus musculus] Tlr4 and Tlr2 activate murine macrophages and this activation is negatively regulated by a Lyn/PI3K module and promoted by SHIP1.

PMID 21442393

[Mus musculus] Tlr4 transfection of eukaryotic host cells using bacterial vectors, or bactofection, was shown to reduce E. coli colonization in the kidney and the bladder in an animal model of urinary tract infection.

PMID 21464300

[Mus musculus] Tlr4 is involved in the transmission of ER stress from tumour cells to macrophages, promoting a pro-inflammatory program in the tumour microenvironment, thus facilitating tumour progression.

PMID 21518783

[Mus musculus] Tlr4 deficient murine macrophages results in the complete abrogation of TNF-alpha production during Leishmania panamensis infection. The endosomal Tlr4 plays a cruical role in the activation of host macrophages and controlling the early stages of parasitic infection.

PMID 21615666

[Mus musculus] Epithelial Tlr4 activation facilitates the transcytosis of non-cytolytic uropathogenic E. coli across intact collecting duct cell layers to invade the renal interstitium in experimental urinary tract infections.

PMID 21712422

[Mus musculus] Tlr4:Ly96 functions as intracellular LPS sensor and triggers a unique set of LPS responses upon recognition of phagocytosed bacteria in macrophages.

PMID 21730052

[Mus musculus] Tlr4 on dendritic cell surfaces binds to Hspa14 and induces a robust Th1 response via the MAPK and NFkB signalling pathways.

PMID 21738466

[Mus musculus] Tlr4 recognizes Clostridium difficile surface layer proteins and induces the maturation of dendritic cells to activate the innate and adaptive immune response.

PMID 21775438

[Mus musculus] Tlr4 and Hspd1 mediate myocardial ischemia-activated innate immune signalling, which plays an important role in mediating apoptosis and inflammation during ischemia/reperfusion (I/R).

PMID 22096480

[Mus musculus] Tlr4 and Tlr2 are crucial for in vivo recognition of Chlamydia pneumoniae. Tlr4/2 double-deficient mice were unable to control pneumonia caused by C. pneumoniae.

PMID 22354030

[Mus musculus] Tlr4 translocates to membrane lipid rafts in a ceramide-dependent manner in Helicobacter pylori infected gastric epithelial cells. (Demonstrated in human)

PMID 22396536

[Mus musculus] Tlr4 is involved in cell-cell contact signalling between activated apoptotic lymphocytes and dendritic cells (DC) during the maturation of DCs. (Demonstrated in human)

PMID 22433865

[Mus musculus] Synthetic triacylated lipid A-molecules have the potent ability to selectively antagonize Tlr4 and inhibit anti-bacterial immunity. (Demonstrated in human)

PMID 22593572

[Mus musculus] The poxviral protein A46 directly inhibits Tlr4 signalling by disrupting receptor complex formation. (Demonstrated in human)

PMID 22962435

[Mus musculus] A human TLR4 polymorphism (D299G/T399I) impairs TLR4::LY96 dimerization and results in a dampened host response to bacterial lipids. (Demonstrated in human)

PMID 22951730

[Mus musculus] Tlr4 is an important regulator of wound inflammation and is essential for early skin wound healing.

PMID 24101501

[Mus musculus] Milk oligosaccharide sialyl(α2,3)lactose modulates mucosal immunity by inducing inflammation through TLR4 signaling

PMID 24423728

[Mus musculus] Itgam (Cd11b) fine tunes the balance between adaptive and innate immune responses initiated by LPS by modulating the trafficking and signalling functions of Tlr4 in a cell-type-specific manner.

PMID 24163408

[Mus musculus] Nod1 and Nod2 synergize with Tlr4 in dendritic cells to increase IL12 production and enhance invariant natural killer T (iNKT) cell activation, and are important regulators of the IFN gamma response by iNKT cells during S. typhimurium and L. monocytogenes infections.

PMID 25022365

[Mus musculus] Rab8a interacts with Pik3cg to regulate Akt signalling generated by surface Tlr4.

PMID 25389373

[Mus musculus] High-potency Tlr4 agonists can act as clinically useful vaccine adjuvants by selectively activating Ticam1-dependent immunostimulatory signalling events and only weakly activating potentially harmful Myd88-dependent inflammatory responses.

PMID 25448706

[Mus musculus] Myd88 and Ticam1 pathways differently regulate Tlr4-induced immune responses in B cells.

PMID 25483963

[Mus musculus] Autophagy causes PELI3 degradation during Tlr4-signalling, subsequently inhibiting Il1b expression and impairing the hyperinflammatory phase during sepsis.

PMID 25549946

[Mus musculus] Tmem126a upregulates genes involved in antigen presentation; such as Icam1, MHC II, Cd86 and Cd40, via the Tlr4 signal transduction pathway.

PMID 25548220

[Mus musculus] Ticam1 but not Myd88 signalling is critical for the Trl4 protective adjuvant effect in neonates; where Ticam1(-/-) but not Myd88(-/-) neonates are highly susceptible to Escherichia coli peritonitis and bacteremia.

PMID 25736436

[Mus musculus] Wdfy1 is a crucial adaptor protein in the Tlr3/4 signalling pathway. Wdfy1 interacts with Tlr3 and Tlr4 and mediates the recruitment of Ticam1 to these receptors.

PMID 25801433

[Mus musculus] Lipopolysaccharide-mediated myeloid Anpep (CD13) expression governs internalization of Tlr4 and negatively regulates Tlr4 signalling, thereby balancing the innate response by maintaining the inflammatory equilibrium critical to innate immune regulation.

PMID 26081153

[Mus musculus] Psen2 deficiency is paralleled by reduced transcription of Tlr4 mRNA and loss of LPS-induced Tlr4 mRNA transcription regulation.

PMID 26310831

[Mus musculus] Peli3 is involved in endotoxin tolerance and functions as a negative regulator of Tlr2/4 signalling.

Entrez Gene

Summary

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor has been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

Gene Information

Type

Protein coding

Genomic Location

Chromosome 9:117704332-117716871

Strand

Forward strand

Band

q33.1

Transcripts

ENST00000355622	ENSP00000363089
ENST00000394487	ENSP00000377997
ENST00000472304
ENST00000490685

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 91 experimentally validated interaction(s) in this database.
They are also associated with 38 interaction(s) predicted by orthology.

Experimentally validated
Total	91 [view]
Protein-Protein	81 [view]
Protein-DNA	4 [view]
Protein-RNA	1 [view]
DNA-DNA	3 [view]
RNA-RNA	2 [view]
DNA-RNA	0

Predicted by orthology
Total	38 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0001530	lipopolysaccharide binding
GO:0001875	lipopolysaccharide receptor activity
GO:0004872	receptor activity
GO:0004888	transmembrane signaling receptor activity
GO:0005515	protein binding

Biological Process

GO:0000187	activation of MAPK activity
GO:0002218	activation of innate immune response
GO:0002224	toll-like receptor signaling pathway
GO:0002322	B cell proliferation involved in immune response
GO:0002537	nitric oxide production involved in inflammatory response
GO:0002755	MyD88-dependent toll-like receptor signaling pathway
GO:0002756	MyD88-independent toll-like receptor signaling pathway
GO:0006955	immune response
GO:0007165	signal transduction
GO:0007249	I-kappaB kinase/NF-kappaB signaling
GO:0007252	I-kappaB phosphorylation
GO:0009617	response to bacterium
GO:0010572	positive regulation of platelet activation
GO:0016046	detection of fungus
GO:0030890	positive regulation of B cell proliferation
GO:0031663	lipopolysaccharide-mediated signaling pathway
GO:0032496	response to lipopolysaccharide
GO:0032497	detection of lipopolysaccharide
GO:0032609	interferon-gamma production
GO:0032689	negative regulation of interferon-gamma production
GO:0032700	negative regulation of interleukin-17 production
GO:0032707	negative regulation of interleukin-23 production
GO:0032715	negative regulation of interleukin-6 production
GO:0032720	negative regulation of tumor necrosis factor production
GO:0032722	positive regulation of chemokine production
GO:0032727	positive regulation of interferon-alpha production
GO:0032728	positive regulation of interferon-beta production
GO:0032729	positive regulation of interferon-gamma production
GO:0032732	positive regulation of interleukin-1 production
GO:0032733	positive regulation of interleukin-10 production
GO:0032735	positive regulation of interleukin-12 production
GO:0032755	positive regulation of interleukin-6 production
GO:0032757	positive regulation of interleukin-8 production
GO:0032760	positive regulation of tumor necrosis factor production
GO:0032874	positive regulation of stress-activated MAPK cascade
GO:0034134	toll-like receptor 2 signaling pathway
GO:0034138	toll-like receptor 3 signaling pathway
GO:0034142	toll-like receptor 4 signaling pathway
GO:0035666	TRIF-dependent toll-like receptor signaling pathway
GO:0038123	toll-like receptor TLR1:TLR2 signaling pathway
GO:0038124	toll-like receptor TLR6:TLR2 signaling pathway
GO:0042088	T-helper 1 type immune response
GO:0042116	macrophage activation
GO:0042346	positive regulation of NF-kappaB import into nucleus
GO:0042535	positive regulation of tumor necrosis factor biosynthetic process
GO:0042742	defense response to bacterium
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB signaling
GO:0045084	positive regulation of interleukin-12 biosynthetic process
GO:0045087	innate immune response (InnateDB)
GO:0045348	positive regulation of MHC class II biosynthetic process
GO:0045359	positive regulation of interferon-beta biosynthetic process
GO:0045416	positive regulation of interleukin-8 biosynthetic process
GO:0045429	positive regulation of nitric oxide biosynthetic process
GO:0045671	negative regulation of osteoclast differentiation
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0046330	positive regulation of JNK cascade
GO:0050671	positive regulation of lymphocyte proliferation
GO:0050707	regulation of cytokine secretion
GO:0050727	regulation of inflammatory response
GO:0050729	positive regulation of inflammatory response
GO:0050829	defense response to Gram-negative bacterium
GO:0051092	positive regulation of NF-kappaB transcription factor activity
GO:0051770	positive regulation of nitric-oxide synthase biosynthetic process
GO:0060729	intestinal epithelial structure maintenance
GO:0060907	positive regulation of macrophage cytokine production
GO:0070373	negative regulation of ERK1 and ERK2 cascade
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:0070430	positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway
GO:0070434	positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway
GO:0071222	cellular response to lipopolysaccharide
GO:0071223	cellular response to lipoteichoic acid
GO:0071260	cellular response to mechanical stimulus

Cellular Component

GO:0005737	cytoplasm
GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0009897	external side of plasma membrane
GO:0010008	endosome membrane
GO:0016021	integral component of membrane
GO:0046696	lipopolysaccharide receptor complex
GO:0048471	perinuclear region of cytoplasm