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Browse TLR4

Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Basic function annotation.
> Subcellular Location, Domain and Function
> Gene Ontology
> KEGG and Reactome Pathway
> Subcellular Location, Domain and Function
 
Subcellular Location Cell membrane Single-pass type I membrane protein Early endosome Note=Upon complex formation with CD36 and TLR6, internalized through dynamin-dependent endocytosis (PubMed:20037584). Colocalizes with RFTN1 at cell membrane and then together with RFTN1 moves to endosomes, upon lipopolysaccharide stimulation.
Domain PF13516 Leucine Rich repeat
PF13855 Leucine rich repeat
PF01582 TIR domain
Function

Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). 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. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). 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 (PubMed:16622205).

> Gene Ontology
 
Biological Process GO:0000187 activation of MAPK activity
GO:0001818 negative regulation of cytokine production
GO:0001819 positive regulation of cytokine production
GO:0001894 tissue homeostasis
GO:0001933 negative regulation of protein phosphorylation
GO:0002218 activation of innate immune response
GO:0002221 pattern recognition receptor signaling pathway
GO:0002224 toll-like receptor signaling pathway
GO:0002237 response to molecule of bacterial origin
GO:0002250 adaptive immune response
GO:0002263 cell activation involved in immune response
GO:0002274 myeloid leukocyte activation
GO:0002285 lymphocyte activation involved in immune response
GO:0002312 B cell activation involved in immune response
GO:0002322 B cell proliferation involved in immune response
GO:0002366 leukocyte activation involved in immune response
GO:0002367 cytokine production involved in immune response
GO:0002371 dendritic cell cytokine production
GO:0002440 production of molecular mediator of immune response
GO:0002443 leukocyte mediated immunity
GO:0002460 adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains
GO:0002521 leukocyte differentiation
GO:0002532 production of molecular mediator involved in inflammatory response
GO:0002537 nitric oxide production involved in inflammatory response
GO:0002573 myeloid leukocyte differentiation
GO:0002683 negative regulation of immune system process
GO:0002694 regulation of leukocyte activation
GO:0002696 positive regulation of leukocyte activation
GO:0002697 regulation of immune effector process
GO:0002699 positive regulation of immune effector process
GO:0002700 regulation of production of molecular mediator of immune response
GO:0002702 positive regulation of production of molecular mediator of immune response
GO:0002703 regulation of leukocyte mediated immunity
GO:0002718 regulation of cytokine production involved in immune response
GO:0002720 positive regulation of cytokine production involved in immune response
GO:0002730 regulation of dendritic cell cytokine production
GO:0002753 cytoplasmic pattern recognition receptor signaling pathway
GO:0002755 MyD88-dependent toll-like receptor signaling pathway
GO:0002756 MyD88-independent toll-like receptor signaling pathway
GO:0002757 immune response-activating signal transduction
GO:0002758 innate immune response-activating signal transduction
GO:0002761 regulation of myeloid leukocyte differentiation
GO:0002762 negative regulation of myeloid leukocyte differentiation
GO:0002764 immune response-regulating signaling pathway
GO:0006606 protein import into nucleus
GO:0006809 nitric oxide biosynthetic process
GO:0006913 nucleocytoplasmic transport
GO:0007249 I-kappaB kinase/NF-kappaB signaling
GO:0007252 I-kappaB phosphorylation
GO:0007254 JNK cascade
GO:0007586 digestion
GO:0007596 blood coagulation
GO:0007599 hemostasis
GO:0009306 protein secretion
GO:0009595 detection of biotic stimulus
GO:0009612 response to mechanical stimulus
GO:0009620 response to fungus
GO:0010001 glial cell differentiation
GO:0010543 regulation of platelet activation
GO:0010572 positive regulation of platelet activation
GO:0010669 epithelial structure maintenance
GO:0010934 macrophage cytokine production
GO:0010935 regulation of macrophage cytokine production
GO:0014002 astrocyte development
GO:0016046 detection of fungus
GO:0017038 protein import
GO:0021782 glial cell development
GO:0022600 digestive system process
GO:0030099 myeloid cell differentiation
GO:0030168 platelet activation
GO:0030193 regulation of blood coagulation
GO:0030194 positive regulation of blood coagulation
GO:0030277 maintenance of gastrointestinal epithelium
GO:0030316 osteoclast differentiation
GO:0030522 intracellular receptor signaling pathway
GO:0030888 regulation of B cell proliferation
GO:0030890 positive regulation of B cell proliferation
GO:0031098 stress-activated protein kinase signaling cascade
GO:0031334 positive regulation of protein complex assembly
GO:0031349 positive regulation of defense response
GO:0031503 protein complex localization
GO:0031663 lipopolysaccharide-mediated signaling pathway
GO:0032103 positive regulation of response to external stimulus
GO:0032147 activation of protein kinase activity
GO:0032386 regulation of intracellular transport
GO:0032388 positive regulation of intracellular transport
GO:0032479 regulation of type I interferon production
GO:0032481 positive regulation of type I interferon production
GO:0032490 detection of molecule of bacterial origin
GO:0032496 response to lipopolysaccharide
GO:0032497 detection of lipopolysaccharide
GO:0032602 chemokine production
GO:0032606 type I interferon production
GO:0032607 interferon-alpha production
GO:0032608 interferon-beta production
GO:0032609 interferon-gamma production
GO:0032611 interleukin-1 beta production
GO:0032612 interleukin-1 production
GO:0032613 interleukin-10 production
GO:0032615 interleukin-12 production
GO:0032620 interleukin-17 production
GO:0032627 interleukin-23 production
GO:0032635 interleukin-6 production
GO:0032637 interleukin-8 production
GO:0032640 tumor necrosis factor production
GO:0032642 regulation of chemokine production
GO:0032647 regulation of interferon-alpha production
GO:0032648 regulation of interferon-beta production
GO:0032649 regulation of interferon-gamma production
GO:0032652 regulation of interleukin-1 production
GO:0032653 regulation of interleukin-10 production
GO:0032655 regulation of interleukin-12 production
GO:0032660 regulation of interleukin-17 production
GO:0032667 regulation of interleukin-23 production
GO:0032675 regulation of interleukin-6 production
GO:0032677 regulation of interleukin-8 production
GO:0032680 regulation of tumor necrosis factor 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:0032872 regulation of stress-activated MAPK cascade
GO:0032874 positive regulation of stress-activated MAPK cascade
GO:0032943 mononuclear cell proliferation
GO:0032944 regulation of mononuclear cell proliferation
GO:0032946 positive regulation of mononuclear cell proliferation
GO:0033157 regulation of intracellular protein transport
GO:0033674 positive regulation of kinase activity
GO:0034121 regulation of toll-like receptor signaling pathway
GO:0034122 negative regulation of toll-like receptor signaling pathway
GO:0034127 regulation of MyD88-independent toll-like receptor signaling pathway
GO:0034128 negative regulation of MyD88-independent toll-like receptor signaling pathway
GO:0034142 toll-like receptor 4 signaling pathway
GO:0034504 protein localization to nucleus
GO:0035666 TRIF-dependent toll-like receptor signaling pathway
GO:0035872 nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
GO:0042035 regulation of cytokine biosynthetic process
GO:0042063 gliogenesis
GO:0042088 T-helper 1 type immune response
GO:0042089 cytokine biosynthetic process
GO:0042090 interleukin-12 biosynthetic process
GO:0042100 B cell proliferation
GO:0042107 cytokine metabolic process
GO:0042108 positive regulation of cytokine biosynthetic process
GO:0042113 B cell activation
GO:0042116 macrophage activation
GO:0042228 interleukin-8 biosynthetic process
GO:0042306 regulation of protein import into nucleus
GO:0042307 positive regulation of protein import into nucleus
GO:0042326 negative regulation of phosphorylation
GO:0042345 regulation of NF-kappaB import into nucleus
GO:0042346 positive regulation of NF-kappaB import into nucleus
GO:0042348 NF-kappaB import into nucleus
GO:0042533 tumor necrosis factor biosynthetic process
GO:0042534 regulation of tumor necrosis factor biosynthetic process
GO:0042535 positive regulation of tumor necrosis factor biosynthetic process
GO:0042742 defense response to bacterium
GO:0042990 regulation of transcription factor import into nucleus
GO:0042991 transcription factor import into nucleus
GO:0042993 positive regulation of transcription factor import into nucleus
GO:0043122 regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043254 regulation of protein complex assembly
GO:0043405 regulation of MAP kinase activity
GO:0043406 positive regulation of MAP kinase activity
GO:0043409 negative regulation of MAPK cascade
GO:0043410 positive regulation of MAPK cascade
GO:0044089 positive regulation of cellular component biogenesis
GO:0044546 NLRP3 inflammasome complex assembly
GO:0044744 protein targeting to nucleus
GO:0045075 regulation of interleukin-12 biosynthetic process
GO:0045084 positive regulation of interleukin-12 biosynthetic process
GO:0045088 regulation of innate immune response
GO:0045089 positive regulation of innate immune response
GO:0045342 MHC class II biosynthetic process
GO:0045346 regulation of MHC class II biosynthetic process
GO:0045348 positive regulation of MHC class II biosynthetic process
GO:0045350 interferon-beta biosynthetic process
GO:0045351 type I interferon biosynthetic process
GO:0045357 regulation of interferon-beta biosynthetic process
GO:0045359 positive regulation of interferon-beta biosynthetic process
GO:0045414 regulation of interleukin-8 biosynthetic process
GO:0045416 positive regulation of interleukin-8 biosynthetic process
GO:0045428 regulation of nitric oxide biosynthetic process
GO:0045429 positive regulation of nitric oxide biosynthetic process
GO:0045637 regulation of myeloid cell differentiation
GO:0045638 negative regulation of myeloid cell differentiation
GO:0045670 regulation of osteoclast differentiation
GO:0045671 negative regulation of osteoclast differentiation
GO:0045860 positive regulation of protein kinase activity
GO:0046209 nitric oxide metabolic process
GO:0046328 regulation of JNK cascade
GO:0046330 positive regulation of JNK cascade
GO:0046651 lymphocyte proliferation
GO:0046822 regulation of nucleocytoplasmic transport
GO:0046824 positive regulation of nucleocytoplasmic transport
GO:0048708 astrocyte differentiation
GO:0048871 multicellular organismal homeostasis
GO:0050663 cytokine secretion
GO:0050670 regulation of lymphocyte proliferation
GO:0050671 positive regulation of lymphocyte proliferation
GO:0050701 interleukin-1 secretion
GO:0050702 interleukin-1 beta secretion
GO:0050707 regulation of cytokine secretion
GO:0050708 regulation of protein secretion
GO:0050727 regulation of inflammatory response
GO:0050729 positive regulation of inflammatory response
GO:0050817 coagulation
GO:0050818 regulation of coagulation
GO:0050820 positive regulation of coagulation
GO:0050829 defense response to Gram-negative bacterium
GO:0050864 regulation of B cell activation
GO:0050865 regulation of cell activation
GO:0050867 positive regulation of cell activation
GO:0050871 positive regulation of B cell activation
GO:0050878 regulation of body fluid levels
GO:0051090 regulation of sequence-specific DNA binding transcription factor activity
GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity
GO:0051092 positive regulation of NF-kappaB transcription factor activity
GO:0051169 nuclear transport
GO:0051170 nuclear import
GO:0051222 positive regulation of protein transport
GO:0051249 regulation of lymphocyte activation
GO:0051251 positive regulation of lymphocyte activation
GO:0051403 stress-activated MAPK cascade
GO:0051767 nitric-oxide synthase biosynthetic process
GO:0051769 regulation of nitric-oxide synthase biosynthetic process
GO:0051770 positive regulation of nitric-oxide synthase biosynthetic process
GO:0060249 anatomical structure homeostasis
GO:0060729 intestinal epithelial structure maintenance
GO:0060907 positive regulation of macrophage cytokine production
GO:0061041 regulation of wound healing
GO:0061081 positive regulation of myeloid leukocyte cytokine production involved in immune response
GO:0061082 myeloid leukocyte cytokine production
GO:0070265 necrotic cell death
GO:0070266 necroptotic process
GO:0070302 regulation of stress-activated protein kinase signaling cascade
GO:0070304 positive regulation of stress-activated protein kinase signaling cascade
GO:0070371 ERK1 and ERK2 cascade
GO:0070372 regulation of ERK1 and ERK2 cascade
GO:0070373 negative regulation of ERK1 and ERK2 cascade
GO:0070374 positive regulation of ERK1 and ERK2 cascade
GO:0070391 response to lipoteichoic acid
GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway
GO:0070424 regulation of nucleotide-binding oligomerization domain containing signaling pathway
GO:0070426 positive regulation of nucleotide-binding oligomerization domain containing signaling pathway
GO:0070427 nucleotide-binding oligomerization domain containing 1 signaling pathway
GO:0070428 regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway
GO:0070430 positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway
GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway
GO:0070432 regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway
GO:0070434 positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway
GO:0070661 leukocyte proliferation
GO:0070663 regulation of leukocyte proliferation
GO:0070665 positive regulation of leukocyte proliferation
GO:0071214 cellular response to abiotic stimulus
GO:0071216 cellular response to biotic stimulus
GO:0071219 cellular response to molecule of bacterial origin
GO:0071222 cellular response to lipopolysaccharide
GO:0071223 cellular response to lipoteichoic acid
GO:0071260 cellular response to mechanical stimulus
GO:0071396 cellular response to lipid
GO:0071496 cellular response to external stimulus
GO:0071706 tumor necrosis factor superfamily cytokine production
GO:0071900 regulation of protein serine/threonine kinase activity
GO:0071902 positive regulation of protein serine/threonine kinase activity
GO:0072593 reactive oxygen species metabolic process
GO:0090303 positive regulation of wound healing
GO:0090316 positive regulation of intracellular protein transport
GO:0097300 programmed necrotic cell death
GO:0098542 defense response to other organism
GO:0098543 detection of other organism
GO:0098581 detection of external biotic stimulus
GO:1900046 regulation of hemostasis
GO:1900048 positive regulation of hemostasis
GO:1900180 regulation of protein localization to nucleus
GO:1900182 positive regulation of protein localization to nucleus
GO:1900225 regulation of NLRP3 inflammasome complex assembly
GO:1900227 positive regulation of NLRP3 inflammasome complex assembly
GO:1902105 regulation of leukocyte differentiation
GO:1902106 negative regulation of leukocyte differentiation
GO:1902532 negative regulation of intracellular signal transduction
GO:1902593 single-organism nuclear import
GO:1903034 regulation of response to wounding
GO:1903036 positive regulation of response to wounding
GO:1903409 reactive oxygen species biosynthetic process
GO:1903426 regulation of reactive oxygen species biosynthetic process
GO:1903428 positive regulation of reactive oxygen species biosynthetic process
GO:1903533 regulation of protein targeting
GO:1903555 regulation of tumor necrosis factor superfamily cytokine production
GO:1903556 negative regulation of tumor necrosis factor superfamily cytokine production
GO:1903557 positive regulation of tumor necrosis factor superfamily cytokine production
GO:1903706 regulation of hemopoiesis
GO:1903707 negative regulation of hemopoiesis
GO:1903829 positive regulation of cellular protein localization
GO:1904407 positive regulation of nitric oxide metabolic process
GO:1904589 regulation of protein import
GO:1904591 positive regulation of protein import
GO:1904951 positive regulation of establishment of protein localization
GO:2000377 regulation of reactive oxygen species metabolic process
GO:2000379 positive regulation of reactive oxygen species metabolic process
GO:2001057 reactive nitrogen species metabolic process
Molecular Function GO:0001530 lipopolysaccharide binding
GO:0001875 lipopolysaccharide receptor activity
GO:0008329 signaling pattern recognition receptor activity
GO:0038187 pattern recognition receptor activity
Cellular Component GO:0009897 external side of plasma membrane
GO:0010008 endosome membrane
GO:0043235 receptor complex
GO:0044440 endosomal part
GO:0046696 lipopolysaccharide receptor complex
GO:0098552 side of membrane
> KEGG and Reactome Pathway
 
KEGG hsa04064 NF-kappa B signaling pathway
hsa04066 HIF-1 signaling pathway
hsa04145 Phagosome
hsa04151 PI3K-Akt signaling pathway
hsa04620 Toll-like receptor signaling pathway
hsa04621 NOD-like receptor signaling pathway
Reactome R-HSA-166054: Activated TLR4 signalling
R-HSA-936964: Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon
R-HSA-1280218: Adaptive Immune System
R-HSA-1236975: Antigen processing-Cross presentation
R-HSA-109581: Apoptosis
R-HSA-5357769: Caspase activation via extrinsic apoptotic signalling pathway
R-HSA-983169: Class I MHC mediated antigen processing & presentation
R-HSA-1643685: Disease
R-HSA-5602358: Diseases associated with the TLR signaling cascade
R-HSA-5260271: Diseases of Immune System
R-HSA-1236974: ER-Phagosome pathway
R-HSA-937041: IKK complex recruitment mediated by RIP1
R-HSA-975163: IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation
R-HSA-5603041: IRAK4 deficiency (TLR2/4)
R-HSA-168256: Immune System
R-HSA-168249: Innate Immune System
R-HSA-140534: Ligand-dependent caspase activation
R-HSA-5602498: MyD88 deficiency (TLR2/4)
R-HSA-975155: MyD88 dependent cascade initiated on endosome
R-HSA-166166: MyD88-independent TLR3/TLR4 cascade
R-HSA-166058: MyD88
R-HSA-5357801: Programmed Cell Death
R-HSA-5686938: Regulation of TLR by endogenous ligand
R-HSA-168180: TRAF6 Mediated Induction of proinflammatory cytokines
R-HSA-975138: TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-937072: TRAF6 mediated induction of TAK1 complex
R-HSA-937061: TRIF-mediated TLR3/TLR4 signaling
R-HSA-2562578: TRIF-mediated programmed cell death
R-HSA-181438: Toll Like Receptor 2 (TLR2) Cascade
R-HSA-168164: Toll Like Receptor 3 (TLR3) Cascade
R-HSA-166016: Toll Like Receptor 4 (TLR4) Cascade
R-HSA-168181: Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168138: Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168179: Toll Like Receptor TLR1
R-HSA-168188: Toll Like Receptor TLR6
R-HSA-168898: Toll-Like Receptors Cascades
Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Literatures that report relations between TLR4 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.
> Text Mining
 
  Literatures describing the relation between TLR4 and anti-tumor immunity in human cancer.
PMID Cancer type Relation to immunity Evidence sentences
28179508Colon CarcinomaPromote immunity (infiltration)Tumor microenvironment colonization by engineered Salmonella appeared to induce the infiltration of abundant immune cells such as monocytes/macrophages and neutrophils via TLR4 signaling.
26928313Hepatocellular CarcinomaInhibit immunity (T cell function)TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD-1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals.
22583829Oral Cavity Squamous Cell CarcinomaInhibit immunityRole of toll-like receptor 4 on the immune escape of human oral squamous cell carcinoma and resistance of cisplatin-induced apoptosis.
18199559Skin Squamous Cell CarcinomaPromote immunity (T cell function)TLR4-deficient C3H/HeJ mice developed more tumors relative to the TLR4-normal C3H/HeN mice. Interestingly, the cell-mediated immune response was mediated by IFN-gamma in C3H/HeN mice and by interleukin (IL)-17 in C3H/HeJ mice. Moreover, C3H/HeN mice had elevated circulating levels of IFN-gamma following topical application of DMBA, whereas IL-17 was elevated in C3H/HeJ mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA skin tumorigenesis and that this is associated with differences in the T-cell subtype activated.
20826579Adrenal Cortex Carcinoma; AdenomaPromote immunity (T cell function)Real-time PCR analysis of human ACC (n=8), adenoma (n=8), and ACC cell lines (SW13, NCI-H295R, and HAC15) revealed a significant down-regulation of TLR4, MD2 (myeloid differentiation protein-2), and cluster of differentiation 14 (CD14) mRNA compared with normal human adrenal cortex and adrenocortical cells in primary culture. Western blot analysis of MAPK, AKT, activator protein-1, and nuclear factor-κB signaling revealed that the ACC cell lines are unresponsive to lipopolysaccharide action. Restoration of TLR4 signaling by stable transfection of TLR4-CD14 plasmid into NCI-H295R cells sensitized them to lipopolysaccharide incubation as shown by nuclear factor-κB activation and decreased cell viability and induced apoptosis in these cells
19881547Colorectal CarcinomaPromote immunityThe knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele.
19826413Ovarian CarcinomaInhibit immunity (T cell function)In MyD88(+) SCOV3 cells, LPS or PTX binding to TLR4 induced IRAK4 activation and cJun phosphorylation, activated the NF-kappaB pathway and promoted interleukin (IL)-8, IL-6, vascular endothelial growth factor and monocyte chemotactic protein-1 production and resistance to drug-induced apoptosis. Silencing of TLR4 in SCOV3 cells with small interference RNA resulted in phosphorylated-cJun (p-cJun) downregulation and a loss of PTX resistance. In PTX-sensitive, MyD88(neg) A2780 cells, TLR4 stimulation upregulated TRIF, and TLR4 silencing eliminated this effect.
17974996Prostate Carcinoma; MelanomaPromote immunityWe show that (a) activating TLR4 signaling in two different tumor cell lines in vitro modifies the tumor outgrowth in vivo; (b) this effect is not due to a direct consequence of TLR4 signaling on the proliferation/apoptosis balance of the tumor cells; (c) the T-cell compartment is somehow involved in the described phenomenon because the inhibitory effect observed is not seen in athymic nude mice; and (d) tumor-infiltrating lymphocytes purified from tumors induced by TLR4-activated cells show strong induction of IFN gamma transcript in detriment of interleukin-10 transcript, suggesting a change in their functionality.
29661854Skin CarcinomaInhibit immunity immunotherapy targetGiven the tremendous cancer burden incurred by NMSC, further exploration of the use of TLR4 antagonists in NMSC chemoprevention strategies is certainly warranted.
23904461MelanomaPromote immunity (T cell function); essential for immunotherapyAutologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.
21455984Other Mammary Carcinoma of MousePromote immunityCell mediated immune responses through TLR4 prevents DMBA-induced mammary carcinogenesis in mice. T cells of TLR4 deficient mice produced elevated levels of IL-17 and lower levels of IFN-γ relative to WT mice. IL-12 secreted by CD11c(+) cells was higher in WT mice, whereas greater amounts of IL-23 were produced by CD11c(+) cells from TLR4 deficient mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA induced mouse mammary tumorigenesis and efforts to divert the cell-mediated immune response may, therefore, prove to be beneficial in the prevention of mammary tumors.
29270668Rectal CarcinomaPromote immunityThe better outcome is likely due to the release of HMGB1, which triggers the maturation of dendritic cells (DCs) via TLR4 activation, and the subsequent recruitment of PD-1+?tumor-infiltrating lymphocytes to the tumor site, where they participate in immune-scavenging.
24321786Lung CarcinomaInhibit immunityHere we show that autophagy induced by TLR4 or TLR3 activation enhances various cytokine productions through promoting TRAF6 (TNF receptor-associated factor 6, E3 ubiquitin protein ligase) ubiquitination and thus facilitates migration and invasion of lung cancer cells. Remarkably, inhibition of autophagy by chemical or genetic approaches blocked TLR4- or TLR3-induced Lys63 (K63)-linked ubiquitination of TRAF6 that was essential for activation of MAPK and NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathways, both of which were involved in the increased production of the cytokines.
22915070Mantle Cell LymphomaInhibit immunity; Candidate for immunotherapy targetThe activation of TLR4 signaling in MCL cells by LPS induced MCL proliferation and up-regulated the secretion of cytokines like interleukin-6 (IL-6), IL-10, and vascular endothelial growth factor (VEGF). Knockdown of TLR4 on MCL cells abrogated the effect of LPS on MCL cells in term of cell growth or secretion of the cytokines and evasion of the immune system. Thus, TLR4 signaling molecules may be novel therapeutic targets in patients with MCL.
22139376MelanomaPromote immunityIFNβ produced by TLR4-activated tumor cells is involved in improving the antitumoral immune response. Transcriptional analysis showed that TLR4 activation on B16 cells induced changes in the expression of type I IFN and type I IFN-related genes. Most importantly, culture supernatants from LPS-B16 cells improved the maturation of bone marrow-derived dendritic cells (BMDC) from TLR4-deficient mice, upregulating the expression of interleukin-12 and costimulatory molecules on those cells.
20675592Hepatocellular CarcinomaInhibit immunityTumor cell-released TLR4 ligands stimulate Gr-1+CD11b+F4/80+ cells to induce apoptosis of activated T cells. Blockade of TLR4 signaling could further reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells and enhance the suppressive effect of 4-1BBL/soluble form of programmed death-1 on tumor growth.
21949133Lung CarcinomaPromote immunityActivation of Toll-like receptor 4 (TLR4) triggers the innate immune response and leads to the induction of adaptive immunity. TLR4 agonists are known to function as immunostimulants and exhibit promising therapeutic potential for cancer immunotherapy.
Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.
> High-throughput Screening
  Statistical results of TLR4 in screening data sets for detecting immune reponses.
PMID Screening System Cancer Type Cell Line Data Set Statistical Results Relation to immunity
29301958CRISPR-Cas9 melanomaB16F10Pmel-1 T cell NA/NSNA/NS
29301958CRISPR-Cas9 melanomaB16F10OT-1 T cell NA/NSNA/NS
28783722CRISPR-Cas9 melanomaMel6242CT-CRISPR NA/NSNA/NS
28723893CRISPR-Cas9 melanomaB16GVAX+Anti-PD1 NA/NSNA/NS
28723893CRISPR-Cas9 melanomaB16GVAX NA/NSNA/NS
25691366RNAiBreast cancerMCF7Luc-CTL assay NA/NSNA/NS
24476824shRNAmelanomaB16Primary screen NA/NSNA/NS
24476824shRNAmelanomaB16Secondary screen NA/NSNA/NS
Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets.
> Expression difference between responders and non-responders
> Mutation difference between responders and non-responders
> Expression difference between responders and non-responders
 
Points in the above scatter plot represent the expression difference of TLR4 in various data sets.
No PMID Cancer type Group Drug # Res # NRes Log2 (Fold Change) P value Anno
126997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)1412-0.1650.687
226997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)650.0770.946
326997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)87-0.350.718
428552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 9160.2350.636
528552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 59-0.6360.721
628552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 471.340.567
729033130MelanomaallAnti-PD-1 (nivolumab) 2623-0.150.752
829033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 15110.1720.915
929033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 1112-0.5280.769
1029301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 480.6130.526
1129301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 2001
1229301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 281.1540.458
1329443960Urothelial cancerallAnti-PD-L1 (atezolizumab) 68230-0.3380.0037
> Mutation difference between responders and non-responders
 
Points in the above scatter plot represent the mutation difference of TLR4 in various data sets.
No PMID Cancer type Group Drug # Res # NRes % Mut/Res % Mut/NRes % Diff (R vs NR) Pval Anno
125765070Non-small cell lung cancer (NSCLC)allAnti-PD-1 (pembrolizumab) 141714.35.98.40.576
225765070Non-small cell lung cancer (NSCLC)smokingAnti-PD-1 (pembrolizumab) 1032033.3-13.31
325765070Non-small cell lung cancer (NSCLC)non-smokingAnti-PD-1 (pembrolizumab) 4140001
426359337MelanomaallAnti-CTLA-4 (ipilimumab) 27737.411-3.60.725
526359337MelanomaBRAFiAnti-CTLA-4 (ipilimumab) 0140001
626359337Melanomanon-BRAFiAnti-CTLA-4 (ipilimumab) 27597.413.6-6.20.495
726997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)211723.817.66.20.709
826997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)8637.516.720.80.58
926997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)131115.418.2-2.81
1028552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 91611.16.24.91
1128552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 592011.18.91
1228552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 470001
1329033130MelanomaallAnti-PD-1 (nivolumab) 382710.57.43.11
1429033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 22139.17.71.41
1529033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 161412.57.15.41
1629301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 11130001
1729301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 610001
1829301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 5120001
Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TLR4. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.
> Lymphocyte
 
Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TLR4. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TLR4.
> Immunoinhibitor
> Immunostimulator
> MHC molecule
> Immunoinhibitor
 
> Immunostimulator
 
> MHC molecule
 
Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TLR4. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene.
> Chemokine
> Receptor
> Chemokine
 
> Receptor
 
Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Distribution of TLR4 expression across immune and molecular subtypes.
> Immune subtype
> Molecular subtype
> Immune subtype
 
> Molecular subtype
 
Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Associations between TLR4 and clinical features.
> Overall survival analysis
> Cancer stage
> Tumor grade
> Overall survival
 
> Stage
 
> Grade
 
Summary
SymbolTLR4
Nametoll-like receptor 4
Aliases hToll; CD284; TLR-4; ARMD10; TOLL; homolog of Drosophila toll; CD antigen CD284
Chromosomal Location9q33.1
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Drugs targeting TLR4 collected from DrugBank database.
> Drugs from DrugBank database
 

  Details on drugs targeting TLR4.
ID Name Drug Type Targets #Targets
DB01183NaloxoneSmall MoleculeCES1, CREB1, ESR1, OPRD1, OPRK1, OPRM1, TLR47
DB027673-Hydroxy-Myristic AcidSmall MoleculeLY96, TLR42
DB03017Lauric AcidSmall MoleculeADH5, C8G, GLTP, GM2A, HNF4A, LTF, LY96, PLA2G2A, PLA2G2D, PPARA, ......12
DB04933EritoranSmall MoleculeTLR41
DB05475GolotimodSmall MoleculeTLR2, TLR4, TLR7, TLR94
DB08231Myristic acidSmall MoleculeABL1, ARF1, ARF6, ECI2, FKBP1A, GM2A, GUCA1A, HNF4A, INS, LY96, NC ......20
DB13615MifamurtideSmall MoleculeNOD2, TLR42