ArticleJournal of immunology (Baltimore, Md. : 1950)2012
The Asp299Gly polymorphism alters TLR4 signaling by interfering with recruitment of MyD88 and TRIF.
Article in Journal of immunology (Baltimore, Md. : 1950), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 5 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
72 citing papers in PubMed, 5 syntheses or guidelines pooled it, 138 citations in OpenAlex.
- The relationship between 896A/G (rs4986790) polymorphism ofFrontiers in genetics · 2022Pooled it
- Association of Toll-like 4 receptor gene polymorphism (rs4986790, rs4986791) with the risk of urinary tract infection: A systematic review and meta-analysis.The Kaohsiung journal of medical sciences · 2020Pooled it
- Association between TLR4 A299G polymorphism and pneumonia risk: a meta-analysis.Medical science monitor : international medical journal of experimental and clinical research · 2015Pooled it
- Toll-like receptor 4 D299G polymorphism in metabolic disorders: a meta-analysis.Molecular biology reports · 2013Pooled it
- The role of TLR4 896 A>G and 1196 C>T in susceptibility to infections: a review and meta-analysis of genetic association studies.PloS one · 2013Pooled it
- TLR4 896A/G and TLR9 1174G/A polymorphisms are associated with the risk of infectious mononucleosis.Scientific reports · 2020Trial
- Polymorphism in the TLR Adaptors of the Toll Signalling Pathway for Use in Livestock Breeding for Health Traits.International journal of molecular sciences · 2026Review
- GHSR and TLR4 collectively promote hepatic inflammation and aberrant repair in alveolar echinococcosis.Frontiers in immunology · 2026Article
- The Role of TLR2/TLR4 Receptors in Host Genetic Susceptibility to Recurrent Vulvovaginitis.Journal of fungi (Basel, Switzerland) · 2025Review
- Identification of novel amino acid variants in the Han Chinese population that impair toll-like receptor 4 signaling and confer hyporesponsiveness to lipopolysaccharide.Frontiers in immunology · 2025Article
- Allelic, Genotypic, and Haplotypic Analysis of Cytokine IL17A, IL17F, and Toll-like Receptor TLR4 Gene Polymorphisms in Metabolic-Dysfunction-Associated Steatotic Liver Disease: Insights from an Exploratory Study.Life (Basel, Switzerland) · 2024Article
- SNP Analysis of TLR4 Promoter and Its Transcriptional Factor Binding Profile in Relevance to Bovine Subclinical Mastitis.Biochemical genetics · 2024Article
- Article
- TRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and CaNature communications · 2022Article
- Association of D299G Polymorphism of TLR4 Gene and CagA Virulence Factor of H. pylori among the Iranian Patients with Colorectal Cancer.Medical journal of the Islamic Republic of Iran · 2022Article
- Article
- Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88.Innate immunity · 2021Article
- Association of TLR4 gene polymorphisms with sepsis after a burn injury: findings of the functional role of rs2737190 SNP.Genes and immunity · 2021Article
- TLR4 and TLR9 polymorphisms are not associated with either rheumatoid arthritis or systemic lupus erythematosus in Mexican patients.Molecular biology reports · 2021Article
- A mouse model of human TLR4 D299G/T399I SNPs reveals mechanisms of altered LPS and pathogen responses.The Journal of experimental medicine · 2021Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Asp(299)Gly (D299G) and, to a lesser extent, Thr(399)Ile (T399I) TLR4 polymorphisms have been associated with gram-negative sepsis and other infectious diseases, but the mechanisms by which they affect TLR4 signaling are unclear. In this study, we determined the impact of the D299G and T399I polymorphisms on TLR4 expression, interactions with myeloid differentiation factor 2 (MD2), LPS binding, and LPS-mediated activation of the MyD88- and Toll/IL-1R resistance domain-containing adapter inducing IFN-β (TRIF) signaling pathways. Complementation of human embryonic kidney 293/CD14/MD2 transfectants with wild-type (WT) or mutant yellow fluorescent protein-tagged TLR4 variants revealed comparable total TLR4 expression, TLR4-MD2 interactions, and LPS binding. FACS analyses with anti-TLR4 Ab showed only minimal changes in the cell-surface levels of the D299G TLR4. Cells transfected with D299G TLR4 exhibited impaired LPS-induced phosphorylation of p38 and TANK-binding kinase 1, activation of NF-κB and IFN regulatory factor 3, and induction of IL-8 and IFN-β mRNA, whereas T399I TLR4 did not cause statistically significant inhibition. In contrast to WT TLR4, expression of the D299G mutants in TLR4(-/-) mouse macrophages failed to elicit LPS-mediated induction of TNF-α and IFN-β mRNA. Coimmunoprecipitation revealed diminished LPS-driven interaction of MyD88 and TRIF with the D299G TLR4 species, in contrast to robust adapter recruitment exhibited by WT TLR4. Thus, the D299G polymorphism compromises recruitment of MyD88 and TRIF to TLR4 without affecting TLR4 expression, TLR4-MD2 interaction, or LPS binding, suggesting that it interferes with TLR4 dimerization and assembly of intracellular docking platforms for adapter recruitment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.