Disease relevance of TLR1

• Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice [1].
• We show that whole Gram-positive bacteria, sPGN and LTA induce the activation of NF-kappaB in HEK293 cells expressing TLR2 but not in cells expressing TLR1 or TLR4 [2].
• Lipoproteins from Borrelia burgdorferi, the agent of Lyme disease, activate inflammatory cells through TLR2 and TLR1 [3].
• In CD, we found a negative association between ileal disease involvement and TLR1 S602I (P = .03, OR [95% CI] 0.522 [0.286-0.950]) [4].
• An association between nonsynonymous variants in the TLR1, -2, and -6 genes and extensive colonic disease in UC and CD was found [4].

Psychiatry related information on TLR1

• Activation of the TLR/IL-1R signaling pathway by foreign bacterial DNA may be one way to initiate innate defense mechanisms against infectious pathogens in vivo [5].
• These results suggest that TLR signalling pathway(s) may be involved in clearance of Abeta-deposits in the brain and that TLRs can be a therapeutic target for Alzheimer's disease [6].
• Circulating RF was induced in response to chronic alcohol consumption; the latter probably involved Toll-like receptor ligation [7].

High impact information on TLR1

• Other mutations, induced by the random germ line mutagen ENU (N-ethyl-N-nitrosourea), have disclosed key molecules in the TLR signaling pathways and helped us to construct a reasonably sophisticated portrait of the afferent innate immune response [8].
• GENETIC ANALYSIS OF HOST RESISTANCE: Toll-Like Receptor Signaling and Immunity at Large [8].
• IPCs display plasma cell morphology, selectively express Toll-like receptor (TLR)-7 and TLR9, and are specialized in rapidly secreting massive amounts of type 1 interferon following viral stimulation [9].
• PTX3 is produced by a variety of cells and tissues, most notably dendritic cells and macrophages, in response to Toll-like receptor (TLR) engagement and inflammatory cytokines [10].
• Upon recognition of microbial products, Toll-like receptors (TLRs) recruit distinct combinations of adaptors to induce TLR-specific gene expression [11].

Chemical compound and disease context of TLR1

• Recently, lipopolysaccharide (LPS), a major biologically active agent of Gram-negative bacteria, was shown to mediate cellular activation by a member of the human Toll-like receptor family, Toll-like receptor (TLR) 2 [2].
• Human Langerhans Cells Express a Specific TLR Profile and Differentially Respond to Viruses and Gram-Positive Bacteria [12].
• It was reported recently that histamine induced Toll-like receptor (TLR)2 and TLR4 expression in endothelial cells and enhanced their sensitivity to Gram-positive and Gram-negative bacteria; and that TLRs were expressed in airway epithelial cells and that several inflammatory mediators modulated their expression [13].
• Liposomal amphotericin B activates antifungal resistance with reduced toxicity by diverting Toll-like receptor signalling from TLR-2 to TLR-4 [14].
• In contrast, LAM isolated from M. tuberculosis or Mycobacterium bovis bacillus Calmette-Guérin failed to induce TLR-dependent activation [15].

Biological context of TLR1

• TLR1 transfection of HeLa cells, which express neither TLR1 nor TLR2, was not sufficient to confer responsiveness to several microbial extracts [16].
• Furthermore, lipoprotein analogs whose acylation was modified were preferentially recognized by TLR1 [17].
• The TLR6 gene, as well as the TLR1 gene, mapped to the proximal region of murine chromosome 5 within 1.7cM of each other [18].
• The higher expression of TLR1 and TLR9 on CD5+ B cells compared to CD5- B cells may reflect the role of B1 cells in more primitive, less specific antibody responses [19].
• The TLR6-TLR1-TLR10 gene cluster may play a role in prostate cancer risk, although further functional studies are needed to pinpoint the disease-associated variants in this gene cluster [20].

Anatomical context of TLR1

• TLR1 and TLR3 were only detectable in blood monocytes [21].
• Neutrophils expressed TLR1, 2, 4, 5, 6, 7, 8, 9, and 10-all the TLRs except TLR3 [22].
• An in vitro study in THP1 cells suggested that this relative increase in hsTLR1 might be attributable to a direct effect of mycobacterial components because it could be mimicked by mycobacterial preparations in the absence of IFN-gamma or T cells and by the TLR1/2 agonist Pam3CysK4 [23].
• In addition, unlike TLR1 and TLR6, TLR10 was expressed in a highly restricted fashion as a highly N-glycosylated protein, which we detected in B cell lines, B cells from peripheral blood, and plasmacytoid dendritic cells from tonsil [24].
• Macrophages from TLR1-deficient (TLR1(-/-)) mice showed impaired proinflammatory cytokine production in response to the 19-kDa lipoprotein and a synthetic triacylated lipopeptide [17].

Associations of TLR1 with chemical compounds

• Examination of chimeric receptors, generated by domain exchange between TLR1 and -6, has revealed that leucine-rich repeats 9-12 of the extracellular domain enable these receptors to discriminate between structurally similar lipopeptides [25].
• However, examination of a wide variety of lipopeptide derivatives indicates that recognition by human TLR1 and -2 does not strictly correlate with the number or position of the acyl chains on the modified cysteine residue [25].
• Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin [26].
• Monocyte TLRs were upregulated in vivo (TLR1 and 2), and in vitro (TLR1, 2 and 4) 8 h after LPS bolus (P < 0.05 versus baseline) [27].
• Inhibition of neutrophil apoptosis by TLR agonists in whole blood: involvement of the phosphoinositide 3-kinase/Akt and NF-kappaB signaling pathways, leading to increased levels of Mcl-1, A1, and phosphorylated Bad [28].

Physical interactions of TLR1

• Taken together, TLR1 interacts with TLR2 to recognize the lipid configuration of the native mycobacterial lipoprotein as well as several triacylated lipopeptides [17].
• In order to mediate cellular response to lipopolysaccharide (LPS), Toll-like receptor (TLR) 4 must interact with MD-2, a secreted protein [29].
• TLR-ligand binding results in cell signal transduction and subsequent production of various proinflammatory cytokines such as IL-1 and TNF-alpha [30].
• The activity of the secreted material was significantly reduced by anti-CD14 monoclonal antibodies suggesting that the active protein (or proteins) was binding to the CD14/Toll-like receptor (TLR)4 complex [31].
• BACKGROUND: This study aimed to investigate the interrelationship of in vivo expression of lipopolysaccharide-binding protein (LBP) and membrane-bound CD14 (mCD14) in human gingival tissues as well as the coexpression of Toll-like receptors (TLR) 2 and 4 in association with periodontal conditions [32].

Regulatory relationships of TLR1

• The TLR2-mediated response to this modulin was enhanced by TLR6 but inhibited by TLR1, indicating a functional interaction between these receptors [26].
• In particular, expression of TLR3 transcripts is restricted to DC that are the only elements which express the full TLR repertoire [33].
• Inhibition was specific for TLR1 because TL5 failed to block TLR4 function [34].
• Lipopolysaccharide (LPS) is an agonist for Toll-like receptor (TLR) 4 and expresses many genes including NF-kappaB- and interferon regulatory factor (IRF)-3/IFN-inducible genes in macrophages and dendritic cells (DCs) [35].
• PTX3 production was induced by TLR ligands, CD40 ligand, and interleukin (IL)-1beta and was suppressed by dexamethasone, 1alpha, 25-dihydroxivitamin D3, and prostaglandin E2 [36].

Other interactions of TLR1

• TLR1 and TLR4 expression were not significantly induced by B-cell activation [37].
• The lack of sensitization to TLR2 ligands by P. acnes correlated with no increase in hepatic TLR1 or TLR6 mRNA [38].
• An increased level of hsTLR1 mRNA was found in both CD3- (p = 0.0078) and CD4+ cells (p = 0.028), resulting in an increased ratio of hsTLR1 mRNA to TLR1 and to TLR6 mRNA [23].
• In addition, selective regulation of TLR7 expression in PDC and B cells by CpG ODN revealed TLR7 as a candidate TLR potentially involved in modulating the recognition of CpG motifs [39].
• These results demonstrate that TLR1 through TLR5 mRNAs are differentially expressed and regulated in human leukocytes [33].

Analytical, diagnostic and therapeutic context of TLR1

• Human colonic epithelial cells isolated by laser capture microscopy and IEC lines (Caco-2, T84, HT-29) were analyzed for expression of TLR2, TLR6, TLR1, and Toll inhibitory protein (Tollip) mRNA by RT-PCR and quantitative real-time PCR [40].
• RESULTS: Human articular chondrocytes mainly expressed TLR1, 2, 5 by RT-PCR [41].
• Interleukin-12 (IL-12) is a heterodimeric cytokine produced by dendritic cells (DCs) in response to Toll-like receptor (TLR) ligation [42].
• Using flow cytometry, we investigated the effect of TLR agonists on human polymorphonuclear neutrophil (PMN) apoptosis in whole blood [28].
• ASMCs were stimulated with TLR ligands, and chemokine release was measured by means of ELISA [43].

References