Toll-Like Receptor 4

Alternative Names

  • TLR4
  • Toll, Drosophila, Homolog of
  • Toll
  • Endotoxin Hyporesponsiveness
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OMIM Number

603030

Gene Map Locus
9q33.1

Description

The toll-like receptors (TLRs) are type I transmembrane proteins characterized by an extracellular domain containing leucine-rich repeats (LRRs) and a cytoplasmic tail that contains a conserved region called the Toll/IL-1 receptor (TIR) domain.  These proteins have a key role in the innate immune system.  They exist in the cells of lymphoid tissues and non-lymphoid tissues.  Expression levels of different types of TLRs in tissues and cells vary considerably.  At least 13 members of the TLR family have been identified.  TLR4 is predominantly activated by lipopolysaccharide, and also it senses endogenous ligands including hyaluronic acid, oxidized low-density lipoprotein, and heat-shock proteins.  Binding of TLR4 with its ligand triggers a cascade of cellular signals through the Toll/interleukin (IL)-1 receptor (TIR), leading to the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signal transduction pathways, consequently inducing expression of inflammatory genes.

Molecular Genetics

The TLR4 gene is located on 9q33.1 chromosome; it has three coding exons spanning 13 kb within the genomic DNA.  The encoded protein has 839 amino acids and weighs about 96 kDa.  Polymorphisms of the TLR4 gene are associated with age-related macular degeneration 10, delayed progression of liver fibrosis and reduced risk of development of hepatocellular carcinoma.  Two common single nucleotide polymorphisms have been identified in the coding region of the TLR4 gene at exon 3 that lead to amino acid exchanges in positions 299 (Asp299Gly) and 399 (Thr399Ile).  These polymorphisms have been associated with hyporesponsiveness to inhaled lipopolysaccharide (LPS).

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Azzam et al. (2012) analyzed three common NOD2 mutations (Leu1007fsinsC, Arg702Trp, Gly908Arg), as well as TLR4 (Thr399II) and CD4 159C/T gene promoter polymorphism, to investigate the contribution of these variants to the predisposition to Crohn’s disease among Saudi population.  Forty six Saudi with CD and 50 matched controls were included in the study.  The genotype mutant frequencies for TLR4 Thr399Ile were 8.7% for the patients and 8% for the controls.  The authors found no evidence to suggest that the TLR4 (Thr399Il) polymorphism could be a risk factor for Crohn's disease.

Semlali et al. (2016) analyzed the association between TLR4 polymorphisms and the risk of colon cancer in the Saudi population.  A total of 115 colon cancer affected patients and 102 healthy controls were recruited for the study.  A qRT-PCR analysis revealed that the expression of TLR4 gene was significantly higher in colon cancer tissues than normal tissues (p<0.001).  The expression levels of cytokines (IL-1b1, IL-6, IL-8, IL-17) were also significantly higher in these tissues.  Immuno-staining studies confirmed these finding by revealing higher levels of TLR4 protein and cytokines in colon cancer tissues as compared to normal tissues.  The polymorphisms rs10759931, rs2770150, rs10759932 and rs4986790 were studied.  The variant rs10759931 showed a strong association with colon cancer irrespective of gender or age [p<0.00001, OR=0.086 (0.04-0.18)].  The polymorphism rs2770150 was associated with an increased risk of colon cancer in women over the age of 50 [p<0.00084, OR=0.188 (0.074-0.48)] and was linked to the post-menopausal decrease in levels of female sex hormones.  The other two variants did not show any association with colon cancer.

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