Disease relevance of TLR4

• TLR4 is critical for the response to lipopolysaccharide (LPS) of gram-negative bacteria, while TLR2 is important for response to gram-positive bacteria, bacterial peptides, and yeast zymosan [1].
• When LPS was administered to LPS-sensitive C3H/HeN and LPS-resistant C3H/HeJ mice, functional TLR4 expression in vivo was shown to be responsible for LPS-induced thrombocytopenia [2].
• We assessed if sequence variants of TLR4 were associated with the risk of prostate cancer [3].
• We investigated the roles of TLR2 and TLR4 in Propionibacterium acnes (P. acnes)-primed, LPS-induced liver damage using selective TLR ligands [4].
• These data demonstrate that the response to N. gonorrhoeae and other Gram-negative bacteria at the mucosal surface of the female genital tract occurs in the absence of endotoxin recognition and TLR4-mediated signaling [5].
• Altered TLR4 and adaptor protein expression might impair TLR4 signaling and explain the weak mucosal response to urinary tract infection in patients who develop ABU rather than symptomatic disease [6].
• These in vitro data indicate an anti-anabolic effect of TLR-4 in articular chondrocytes that may hamper cartilage repair in various joint diseases [7].
• We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis [8].

Psychiatry related information on TLR4

• Therefore, the purpose of this study was to determine the association between age, physical activity status, biomarkers of inflammation, and TLR4 [9].
• To investigate the role of TLR4 in the amyloidogenesis in vivo, we determined the amounts of cerebral Abeta in Alzheimer's disease mouse models with different genotypes of TLR4 using three distinct methods [10].

High impact information on TLR4

• Beta-defensins interact with CCR6; murine beta-defensin-2 in addition activates TLR4 [11].
• TLR4 belongs to a family of innate immunity receptors that possess a large extracellular domain of leucine-rich repeats, a single trans-membrane segment, and a smaller cytoplasmic signaling region that engages the adaptor protein MyD88 [12].
• Most significant has been the identification of the plasma membrane protein TLR4 as the lipid A signaling receptor of animal cells [12].
• This binding recruits a key adaptor MyD88 to TLR4, suggesting that there is crosstalk between the TLR signaling pathway and phospholipid metabolism [13].
• TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction [14].

Chemical compound and disease context of TLR4

• However, 8 of the 20 with poorly-differentiated gastric adenocarcinoma showed heterozygosity at the 135th position of the amino acid sequence of TLR4, and a mutation from threonine to alanine was found at this site [15].
• Seya et al. demonstrated that maturation of dendritic cells (DCs) and cytokine induction by the cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin (BCG-CWS) are induced via both TLR2 and TLR4 [16].
• Tumor necrosis factor alpha blockade treatment down-modulates the increased systemic and local expression of Toll-like receptor 2 and Toll-like receptor 4 in spondylarthropathy [17].
• A polysaccharide preparation obtained from Salmonella LPS was inactive in 293 cells expressing human CD14/TLR4/MD-2 even in combination with 516 [18].
• Furthermore, MCP-1 expression elicited by E. coli LPS was inhibitable with TLR4-specific antibody and polymyxin B [19].

Biological context of TLR4

• We demonstrate that THP activates myeloid DCs via Toll-like receptor-4 (TLR4) to acquire a fully mature DC phenotype [20].
• IFNgamma counteracted the LPS-induced downregulation of TLR4 [21].
• These results suggest that enhanced TLR4 expression underlies the long-known priming by IFNgamma of mononuclear phagocytes for pathogen recognition and killing as well as its synergism with LPS in macrophage activation [21].
• In conclusion, human activated HSCs utilize components of TLR4 signal transduction cascade to stimulate NF-kappaB and JNK and up-regulate chemokines and adhesion molecules [22].
• We genotyped 16 common (>5%) single nucleotide polymorphisms (SNP) discovered in a resequencing study spanning TLR4 to test for association between sequence variation in TLR4 and prostate cancer [3].

Anatomical context of TLR4

• Although some cellular responses are completely abolished in MyD88-deficient mice, TLR4, but not TLR9, can activate NF-kappa B and mitogen-activated protein kinases and induce dendritic cell maturation in the absence of MyD88 [23].
• We report here that RP105 expression was wide, directly mirroring that of TLR4 on antigen-presenting cells [24].
• CONCLUSIONS: This study shows the inflammation-dependent induction of TLR2 and TLR4 expression in intestinal macrophages [25].
• RESULTS: Immunohistochemistry revealed a significant increase in the TLR2 and TLR4 antigen expression on submucosal cells in inflamed intestinal mucosa compared with non-inflamed mucosa [25].
• The human monocyte response to crude bacterial LPS is composed of a TLR4-specific response to the pure LPS component and a TLR2-dependent response to associated lipopeptides [1].

Associations of TLR4 with chemical compounds

• TLR4 expression was confirmed by demonstrating murine platelet binding to lipopolysaccharide (LPS) [2].
• Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation [26].
• IFN-gamma regulates expression of the critical TLR4 co-receptor MD-2 through the Janus tyrosine kinase-STAT pathway [27].
• MD-2, a glycoprotein that is essential for the innate response to lipopolysaccharide (LPS), binds to both LPS and the extracellular domain of Toll-like receptor 4 (TLR4) [28].
• Deletion and alanine substitution experiments revealed that amino acids 151-153 and 273-275 were required for the TLR4-mediated activation [29].
• TLR4 signaling also led to increased serine phosphorylation of intestinal focal adhesion kinase (FAK) [30].
• The response to AP or lipopolysaccharide was significantly diminished in TLR4(-/-) and PAR2(-/-) macrophages, respectively, and SW620 colonic epithelial cells exhibited synergistic responses to co-stimulation with AP and lipopolysaccharide [31].
• The release of IL-1beta and TNF-alpha was significantly increased in monocytes from T1DM compared with controls and correlated with TLR2 and TLR4 expression (P < 0.005) [32].
• Using actinomycin to inhibit transcription, we found that Tat increased the half-life of TLR4 mRNA from approximately 25 to 60 min, and RNA gel-shift assays demonstrated direct binding of Tat to TLR4 mRNA [33].
• We also identified a pair of conserved hydrophobic residues (Phe-440 and Phe-463) in leucine-rich repeats 16 and 17 of the TLR4 ectodomain, which are essential for activation of TLR4 by LPS [34].

Physical interactions of TLR4

• MD-2 must be bound to TLR4 on the cell surface before binding can occur [35].
• Our findings implicate Btk as a Toll/interleukin-1 receptor domain-binding protein that is important for NFkappaB activation by TLR4 [36].
• These results suggest that TLR4 receptor complex is the molecular target of curcumin in addition to IKKbeta [37].
• This was supported by decreased IRAK-1:TRAF6 association in TLR4 induced but sustained presence of IRAK-1:TRAF6 complexes in TLR2- plus TLR4-stimulated monocytes after alcohol treatment [38].
• Rapid recycling of TLR4/CD14/MD-2 complexes between the Golgi and the plasma membrane was a prominent phenomenon [39].

Co-localisations of TLR4

• Both forms of MD-2 colocalized with TLR4 on the cell surface after transfection, but only the wild-type cDNA reverted the lipopolysaccharide (LPS) nonresponder phenotype [40].
• LPS was endocytosed by a receptor-mediated mechanism dependent on dynamin and clathrin and colocalized with TLR4 on early/sorting endosomes [41].

Regulatory relationships of TLR4

• Toll-like receptor (TLR)2 and TLR4 agonists regulate CCR expression in human monocytic cells [42].
• Excess teichoic acid, LTA-0, antibodies to phosphocholine, or antibodies to TLR4 did not inhibit the LTA-induced TLR2 stimulation [43].
• Inhibition was specific for TLR1 because TL5 failed to block TLR4 function [44].
• These data suggest that, upon NTHi infection, low numbers of bacteria binding LBP may activate TLR4-bearing cells, such as alveolar macrophages, and consequently induce an inflammatory response [45].
• These findings suggest that CXCR4 could exert local control of TLR4 and suggest the possibility of new therapeutic approaches to suppression of TLR4 function [46].
• Single mutants K122A and K132A each react with E.CD14 +/- TLR4 and promote TLR4-dependent cell activation by endotoxin suggesting that Phe(121) and Tyr(131) are needed for TLR4-independent transfer of endotoxin from CD14 to MD-2 and also needed for TLR4 activation by bound E.MD-2 [47].

Other interactions of TLR4

• IRF3 mediates a TLR3/TLR4-specific antiviral gene program [48].
• Moreover, cells of TLR2- and TLR4-deficient mice are activated by CpG-DNA, whereas cells of MyD88-deficient mice do not respond [49].
• We observed an induction of mRNA for TLR2, TLR4, and TLR5 in inflammation-associated macrophages [25].
• TLR1 and TLR4 expression were not significantly induced by B-cell activation [50].
• Activation was observed in cells transfected with both CD14 and TLR4 [51].

Analytical, diagnostic and therapeutic context of TLR4

• These differences suggest that another adapter must exist that can mediate MyD88-independent signaling in response to TLR4 ligation [23].
• Results show that human and murine platelets variably expressed TLR2, TLR4, and TLR9 by flow cytometry and Western blotting [2].
• A previous case-control study found a modest association of a polymorphism in the TLR4 gene [11381G/C, GG versus GC/CC: odds ratio (OR), 1.26] with risk of prostate cancer [3].
• However, neither lauric acid nor DHA affected the heterodimerization of TLR2 with TLR6 as well as the homodimerization of TLR4 as determined by co-immunoprecipitation assays in 293T cells in which these TLRs were transiently overexpressed [52].
• We further characterized by flow cytometry, biotinylation/precipitation, and confocal microscopy the intracellular localization of TLR4 in these cells [53].

References