ArticlePloS one2014
The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 2 of them syntheses that pooled it.
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Who cites it
15 citing papers in PubMed, 2 syntheses or guidelines pooled it, 24 citations in OpenAlex.
- Pooled it
- Associations between TLR4 Polymorphisms and Open Angle Glaucoma: A Meta-Analysis.BioMed research international · 2019Pooled it
- T cell-intrinsic PRR signaling in immunity and pathology.Acta biochimica et biophysica Sinica · 2026Review
- The Role of TLR2/TLR4 Receptors in Host Genetic Susceptibility to Recurrent Vulvovaginitis.Journal of fungi (Basel, Switzerland) · 2025Review
- The Promise of Single-Cell RNA Sequencing to Redefine the Understanding of Crohn's Disease Fibrosis Mechanisms.Journal of clinical medicine · 2023Review
- Article
- Association of Toll-like receptor-4 polymorphism with SARS CoV-2 infection in Kurdish Population.Human gene (Amsterdam, Netherlands) · 2022Article
- Toll-like receptor 4 (TLR4) antagonists as potential therapeutics for intestinal inflammation.Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology · 2021Review
- A mouse model of human TLR4 D299G/T399I SNPs reveals mechanisms of altered LPS and pathogen responses.The Journal of experimental medicine · 2021Article
- Comprehensive assessment of association between TLR4 gene polymorphisms and cancer risk: a systematic meta-analysis.Oncotarget · 2017Article
- Structure-Activity Relationship in TLR4 Mutations: Atomistic Molecular Dynamics Simulations and Residue Interaction Network Analysis.Scientific reports · 2017Article
- Epigenetics and innate immunity: the 'unTolld' story.Immunology and cell biology · 2016Review
- Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious diseases.Clinical and experimental immunology · 2015Review
- Mechanisms of Microbe-Host Interaction in Crohn's Disease: Dysbiosis vs. Pathobiont Selection.Frontiers in immunology · 2015Review
- Association of TLR-4 896A/G, TLR-4 1196C/T, and TLR-9 C/T polymorphism with schizophrenia in Indian Bengalee patient.Indian journal of psychiatryArticle
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Dysregulated Toll-Like Receptor (TLR) signalling and genetic polymorphisms in these proteins are linked to many human diseases. We investigated TLR4 functional variants D299G and T399I to assess the impact on LPS-induced responsiveness in comparison to wild-type TLR4. The mechanism by which this occurs in unclear as these SNPs do not lie within the lipid A binding domain or dimerisation sites of the LPS-TLR4/MD2 receptor complexes. Transfection of TLR4D299G, TLR4T399I or TLR4D299G. T399I into HEK cells resulted in constitutive activation of an NF-κB reporter gene and a blunting of the LPS-induced reporter activation compared to WT-TLR4. Unstimulated human monocyte/macrophages, from patients with the D299G and T399I SNPs demonstrated a downregulation of many genes, particularly Tram/Trif signalling pathway constitutents compared to the TLR4 wild-type subjects supporting the concept of basal receptor activity. Monocyte/macrophages from carriers of the TLR4 D299G and T399I polymorphisms stimulated with LPS showed >6 fold lower levels of NF-κB and ∼12 fold higher IFN-β gene expression levels compared to wild-type subjects (P<0.05; MWU test) and dramatically altered resultant cytokine profiles. We conclude that these TLR4 SNPs affect constitutive receptor activity which impacts on the hosts ability to respond to LPS challenge leading to a dysregulated sub-optimal immune response to infection.
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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.