TLR4 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the TLR4 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | TLR4 |
|---|---|
| Full Name | Toll Like Receptor 4 |
| Gene Type | protein coding |
| Chromosomal Location | 9q33.1 |
| NCBI Gene ID | 7099 ncbi.nlm.nih.gov/gene/7099 |
| Ensembl ID | ENSG00000136869 |
| UniProt ID | O00206 |
| OMIM ID | 603030 |
| HGNC ID | 11849 |
| Aliases | CD284, TOLL, hToll |
Description
The TLR4 gene encodes Toll-like receptor 4, a transmembrane protein that plays a central role in the innate immune system. It recognizes pathogen-associated molecular patterns (PAMPs), most notably lipopolysaccharide (LPS) from Gram-negative bacteria, and triggers signaling cascades that lead to the production of pro-inflammatory cytokines and type I interferons. TLR4 is also involved in the recognition of damage-associated molecular patterns (DAMPs) and has been implicated in various inflammatory and autoimmune diseases.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Sepsis | TLR4 mediates the inflammatory response to LPS; altered TLR4 signaling can influence susceptibility to septic shock. | ClinVar, OMIM |
| Atherosclerosis | TLR4 activation by oxidized LDL and other DAMPs promotes vascular inflammation and plaque progression. | OMIM, PubMed |
| Asthma | TLR4 polymorphisms may affect airway inflammation and response to environmental triggers. | ClinVar, OMIM |
| Inflammatory Bowel Disease | TLR4 variants are associated with altered gut mucosal immunity and increased risk of IBD. | OMIM, PubMed |
| Neuropathic Pain | TLR4 activation in microglia contributes to pain hypersensitivity; modulation is a therapeutic target. | PubMed |
| Cancer | TLR4 signaling can promote tumor progression and metastasis in certain cancers, though context-dependent. | COSMIC, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Blood | 12.4 | Medium |
| Spleen | 8.9 | Low |
| Lung | 6.2 | Low |
| Liver | 4.1 | Low |
| Brain | 2.3 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| THP-1 (monocyte) | 15.2 | High expression; LPS-responsive |
| A549 (lung epithelial) | 3.4 | Low expression |
| HepG2 (liver) | 1.8 | Very low |
| MCF7 (breast) | 0.5 | Not detected |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs4986790 (D299G) | Missense | ~5-10% in European populations | Reduced LPS responsiveness; associated with increased risk of sepsis and hyporesponsiveness to inhaled LPS. |
| rs4986791 (T399I) | Missense | ~5-10% in European populations | Often co-occurs with D299G; similar functional impact on LPS signaling. |
| rs7873784 (3'UTR) | Regulatory | Variable | May affect TLR4 expression and disease susceptibility. |
| C119A (p.Pro40His) | Missense | Rare | Reported in a patient with meningococcal meningitis; functional impact unclear. |
Mutation functional classification
Loss of Function (LOF)
The D299G and T399I variants are well-documented to impair LPS-induced signaling, leading to reduced cytokine production and increased susceptibility to Gram-negative infections.
Gain of Function (GOF)
Some rare variants may enhance TLR4 signaling, potentially contributing to hyperinflammatory states, but evidence is limited.
Dominant Negative (DN)
No dominant-negative mutations have been clearly established for TLR4; however, certain variants may exert a dominant-negative effect on receptor dimerization.
View complete mutation data：
Gene Ontology (GO)
| • lipopolysaccharide binding | • transmembrane signaling receptor activity |
| • protein homodimerization activity | • innate immune response |
| • inflammatory response | • signal transduction |
| • cell surface receptor signaling pathway | • positive regulation of NF-kappaB transcription factor activity |
Pathways
• Toll-like receptor signaling pathway
• NF-kappaB signaling
• MAPK signaling
• MyD88-dependent pathway
• TRIF-dependent pathway
• Innate Immune System
Protein Summary
TLR4 is a type I transmembrane glycoprotein consisting of an extracellular leucine-rich repeat (LRR) domain, a transmembrane domain, and an intracellular Toll/interleukin-1 receptor (TIR) domain. It functions as a pattern recognition receptor (PRR) that recognizes LPS in complex with MD-2 and CD14. Upon ligand binding, TLR4 dimerizes and recruits adaptor proteins (MyD88 or TRIF) to activate downstream signaling cascades, leading to the expression of pro-inflammatory cytokines and type I interferons. TLR4 is expressed on various immune cells, including macrophages, dendritic cells, and monocytes, as well as on non-immune cells like endothelial and epithelial cells. Its dysregulation is implicated in numerous diseases, making it a key therapeutic target.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TLR4 Knockout HEK293 Cell Line | EDJ-KQ1491 | Human | 7099 | Details Get a Quote |
| TLR4 Knockout HeLa Cell Line | EDJ-KQ21090 | Human | 7099 | Details Get a Quote |
| TLR4 Knockout HCT 116 Cell Line | EDJ-KQ18233 | Human | 7099 | Details Get a Quote |
| TLR4 Knockout THP-1 Cell Line | EDJ-KZ511 | Human | 7099 | Details Get a Quote |
| TLR4 Knockout A-549 Cell Line | EDJ-KQ63149 | Human | 7099 | Details Get a Quote |
| TLR4 Knockout THP-1 Cell Line | EDJ-KQ78091 | Human | 7099 | Details Get a Quote |
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