Toll-like receptor 1 inhibits Toll-like receptor 4 signaling in endothelial cells

Abstract

Toll-like receptor 4 (TLR4) is the signal-transducing component of the LPS recognition complex and is essential for LPS-induced septic shock. Here we demonstrate that TLR1 has the capacity to abrogate TLR4 signaling. Human microvascular endothelial cells express TLR4 but not TLR1 and respond to LPS through TLR4. The ability of these cells to respond to LPS was lost, however, when they were transfected with TLR1. Inhibition was specific for TLR1 because TL5 failed to block TLR4 function. Moreover, TLR1 had no effect upon TNF-alpha signaling, indicating that TLR1 operated at a step upstream of the convergence between the two pathways. Inhibition of TLR4 signaling was mediated by the extracellular, but not cytoplasmic domain of TLR1. In addition, TLR1 physically associated with TLR4 in co-precipitation experiments. These findings suggest that TLR1 might restrain potentially dangerous innate response to LPS by binding to TLR4 and preventing the formation of active signaling complexes.

Host immune gene polymorphisms were associated with the prognosis of non‐small‐cell lung cancer in Chinese

“…TLR1 is important in regulating TLR responses 24. For example, TLR1 can associate with TLR4 to inhibit its signaling in endothelial cells,25 and TLR1 can associate with TLR2 to inhibit the TLR2‐mediated response to phenol‐soluble modulin 26. The SNP rs5743551 (5′FR), reported in the promoter region, alters a putative core binding site of the proto‐oncogene PU.1 (AAAAGGAG A AG)27 However, SNPs IL‐5R rs11713419 (5′‐UTR), TLR3 rs3775291 (Leu412Phe) were rarely mentioned in previous studies.…”

Gene Expression in Splenic CD4 and CD8 Cells From BALB/c Mice Immunized With Porphyromonas gingivalis

“…Myeloperoxidase produced by macrophages and neutrophils participates in antimicrobial defense, 66 and peptidoglycan recognition proteins are involved in the killing and degradation of these bacterial cell‐wall components 67 . CD14 expressed mainly by macrophages and TLR play central roles in innate immunity as receptors for bacterial lipopolysaccharide (LPS) 68,69 . TLR1 has been shown to associate with TLR2 to recognize various lipopeptides 70 and to be associated with and to abrogate TLR4 signaling to prevent innate responses to LPS 68 .…”

“…CD14 expressed mainly by macrophages and TLR play central roles in innate immunity as receptors for bacterial lipopolysaccharide (LPS) 68,69 . TLR1 has been shown to associate with TLR2 to recognize various lipopeptides 70 and to be associated with and to abrogate TLR4 signaling to prevent innate responses to LPS 68 . Tollip has been demonstrated to coimmunoprecipitate with TLR2 and TLR4 and may be an important constituent of both the TLR2‐ and TLR4‐signaling pathways 71 …”

Translational Mini-Review Series on Toll-like Receptors:
Networks regulated by Toll-like receptors mediate innate and adaptive immunity

“…TLR10 was the orphan member of the family, but recent work has demonstrated its ability to form homodimers and also heterodimers with TLR1 and TLR2, although specific ligands for these combinations have yet to be identified [21]. TLR4 acts essentially as a homodimer (although there is some evidence for heterodimerization with TLR1 [22] and TLR5 [23]), and it also recognizes an extensive range of agonists. The involvement of accessory proteins at the cell membrane may help to confer ligand specificity and responses (such as CD14, MD2 and CD11b/CD18 [24]).…”