Summary of TLR4
Toll-like receptors play a role in recognizing pathogens and activating the innate immune response [R]. The TLR4 protein recognizes LPS (lipopolysaccharide, a component of gram-negative bacteria), as well as viral and internal proteins [R, R2, R3].
The Function of TLR4
Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634). 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).
Protein names
Recommended name:
Toll-like receptor 4Alternative name(s):
hTollCD antigen CD284
- RS10759932 (TLR4) ??
- RS11536879 (TLR4) ??
- RS11536891 (TLR4) ??
- RS11536897 (TLR4) ??
- RS1554973 (TLR4) ??
- RS1927902 (TLR4) ??
- RS1927911 (TLR4) ??
- RS1927914 (TLR4) ??
- RS2149356 (TLR4) ??
- RS4986790 (TLR4) ??
- RS4986791 (TLR4) ??
- RS5030717 (TLR4) ??
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Top Gene-Substance Interactions
TLR4 Interacts with These Diseases
| Disease | Score |
Fixes
If you have excess TLR4 activation, the following Inhibit TLR4: Nicotine [R], Resveratrol (humans w/ inflammation, obesity, diabetes) (R), Statins [R], LDN (R), TanshioneII (R), Grape Seed Extract (R), Cyanidin-3-O-²-glucoside (C3G) - typical anthocyanin (R), B-glucans/Nutritional Yeast (R), Tea Polyphenols/Jasmine Tea (R), VIP (R), Quercetin (R), Garlic (R), Angelica/decursin (R), EGCG (R), Coptis/Berberine (R), Cinnamon/Cinnamaldehyde (R), Curcumin (R), Ginkgo (R), Licorice (R), Walnut (R), Luteolin (R), Peony root (R), Panax Ginseng aq (s aureus mice, sepsis) (R), Panax notoginseng (DCs-inflammation) (R), Rhubarb (R), Salvia M (R), Tripterygium wilfordii (R), Ginger (R), Grape skin polyphenols (fat cells) (R)
Substances That Increase TLR4
| Substances | Interaction | Organism | Category |
Substances That Decrease TLR4
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Advanced Summary
TLR4 is a gene that codes for a member of the toll-like receptor protein family [R].
Toll-like receptors play a role in recognizing pathogens and activating the innate immune response [R].
The TLR4 protein recognizes LPS (lipopolysaccharide, a component of gram-negative bacteria), as well as viral and internal proteins [R, R2, R3]. Mutations in the TLR4 gene are associated with gram-negative bacterial and blood infections. [R , R2].
TLR4 interacts with the cellular proteins to initiate the immune response to LPS [R], which leads to the release of pro-inflammatory cytokines (such as IL-6, IL-8, and IL-1B) [R].
Although TLR4 is commonly activated by LPS, it can also be activated by fats and fatty acids [R].
Two SNPs in the TLR4 gene (TLR4 Asp299Gly and TLR4 Thr399Ile) were found to increase Candida blood infection rate (fungal infection caused by Candida albicans). Decreased pro-inflammatory cytokines and increased anti-inflammatory IL-10 production is thought to be the cause [R, R2].
The same SNPs were found to inhibit LPS responsiveness and increase exposure to gram- negative bacterial infections [R,R2].
Increased rate of sepsis progression occurred during gram-negative bacterial infections [R].
The TLR4 receptor is associated with binge drinking. An experimental study involving mice revealed that inhibition of TLR4 and GABA receptors caused a marked reduction in binge drinking [R].
Another animal study revealed that high levels of TLR4 are linked to an increased cancer growth rate in sleep-deprived mice. Also, when mice were genetically altered to produce no TLR4 receptors, normal cancer growth was observed [R].
From NCBI Gene: Age-related macular degeneration 10From UniProt: Macular degeneration, age-related, 10 (ARMD10): A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. [MIM:611488]
From NCBI Gene: 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] From UniProt: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634). 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). 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).
Conditions with Increased Gene Activity
| Condition | Change (log2fold) | Comparison | Species | Experimental variables | Experiment name |
|---|
Conditions with Decreased Gene Activity
| Condition | Change (log2fold) | Comparison | Species | Experimental variables | Experiment name |
|---|
Technical
The following transcription factors affect gene expression:
Tissue specificity:
Highly expressed in placenta, spleen and peripheral blood leukocytes. Detected in monocytes, macrophages, dendritic cells and several types of T-cells.
Gene Pathways:
Molecular Function:
- Lipopolysaccharide Binding
- Lipopolysaccharide Receptor Activity
- Receptor Activity
- Transmembrane Signaling Receptor Activity
Biological Processes:
- Activation Of Mapk Activity
- Toll-Like Receptor Signaling Pathway
- B Cell Proliferation Involved In Immune Response
- Nitric Oxide Production Involved In Inflammatory Response
- Regulation Of Dendritic Cell Cytokine Production
- Myd88-Dependent Toll-Like Receptor Signaling Pathway
- Myd88-Independent Toll-Like Receptor Signaling Pathway
- Inflammatory Response
- Immune Response
- I-Kappab Kinase/Nf-Kappab Signaling
- I-Kappab Phosphorylation
- Positive Regulation Of Platelet Activation
- Positive Regulation Of Gene Expression
- Astrocyte Development
- Detection Of Fungus
- Positive Regulation Of B Cell Proliferation
- Lipopolysaccharide-Mediated Signaling Pathway
- Response To Lipopolysaccharide
- Detection Of Lipopolysaccharide
- Interferon-Gamma Production
- Negative Regulation Of Interferon-Gamma Production
- Negative Regulation Of Interleukin-17 Production
- Negative Regulation Of Interleukin-23 Production
- Negative Regulation Of Interleukin-6 Production
- Negative Regulation Of Tumor Necrosis Factor Production
- Positive Regulation Of Chemokine Production
- Positive Regulation Of Interferon-Alpha Production
- Positive Regulation Of Interferon-Beta Production
- Positive Regulation Of Interferon-Gamma Production
- Positive Regulation Of Interleukin-1 Production
- Positive Regulation Of Interleukin-10 Production
- Positive Regulation Of Interleukin-12 Production
- Positive Regulation Of Interleukin-6 Production
- Positive Regulation Of Interleukin-8 Production
- Positive Regulation Of Tumor Necrosis Factor Production
- Negative Regulation Of Myd88-Independent Toll-Like Receptor Signaling Pathway
- Toll-Like Receptor 4 Signaling Pathway
- Trif-Dependent Toll-Like Receptor Signaling Pathway
- T-Helper 1 Type Immune Response
- Macrophage Activation
- Positive Regulation Of Nf-Kappab Import Into Nucleus
- Positive Regulation Of Tumor Necrosis Factor Biosynthetic Process
- Defense Response To Bacterium
- Positive Regulation Of Interleukin-12 Biosynthetic Process
- Innate Immune Response
- Positive Regulation Of Mhc Class Ii Biosynthetic Process
- Positive Regulation Of Interferon-Beta Biosynthetic Process
- Positive Regulation Of Interleukin-8 Biosynthetic Process
- Positive Regulation Of Nitric Oxide Biosynthetic Process
- Negative Regulation Of Osteoclast Differentiation
- Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
- Positive Regulation Of Jnk Cascade
- Interleukin-1 Beta Secretion
- Regulation Of Cytokine Secretion
- Positive Regulation Of Inflammatory Response
- Defense Response To Gram-Negative Bacterium
- Positive Regulation Of Nf-Kappab Transcription Factor Activity
- Positive Regulation Of Nitric-Oxide Synthase Biosynthetic Process
- Intestinal Epithelial Structure Maintenance
- Positive Regulation Of Macrophage Cytokine Production
- Necroptotic Process
- Negative Regulation Of Erk1 And Erk2 Cascade
- Positive Regulation Of Erk1 And Erk2 Cascade
- Positive Regulation Of Nucleotide-Binding Oligomerization Domain Containing 1 Signaling Pathway
- Positive Regulation Of Nucleotide-Binding Oligomerization Domain Containing 2 Signaling Pathway
- Cellular Response To Lipopolysaccharide
- Cellular Response To Lipoteichoic Acid
- Cellular Response To Mechanical Stimulus
- Apoptotic Signaling Pathway
- Positive Regulation Of Nlrp3 Inflammasome Complex Assembly