Therapeutic Targeting of Toll-Like Receptors for Infectious and Inflammatory Diseases and Cancer

O’Neill, Luke A. J.; Bryant, Clare E.; Doyle, Sarah

doi:10.1124/pr.109.001073

Cited by 390 publications

(368 citation statements)

References 222 publications

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“…required for the induction of BMP-2 expression by oxLDL as TLR2 and TLR4 utilize this shared signaling pathway (34).…”

Section: Discussionmentioning

confidence: 99%

Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

Shi

et al. 2011

Journal of Biological Chemistry

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Vascular calcification is a common complication in atherosclerosis. Bone morphogenetic protein-2 (BMP-2) plays an important role in atherosclerotic vascular calcification. The aim of this study was to determine the effect of oxidized low density lipoprotein (oxLDL) on BMP-2 protein expression in human coronary artery endothelial cells (CAECs), the roles of Toll-like receptor (TLR) 2 and TLR4 in oxLDL-induced BMP-2 expression, and the signaling pathways involved. Human CAECs were stimulated with oxLDL. The roles of TLR2 and TLR4 in oxLDLinduced BMP-2 expression were determined by pretreatment with neutralizing antibody, siRNA, and overexpression. Stimulation with oxLDL increased cellular BMP-2 protein levels in a dose-dependent manner (40 -160 g/ml). Pretreatment with neutralizing antibodies against TLR2 and TLR4 or silencing of these two receptors reduced oxLDL-induced BMP-2 expression. Overexpression of TLR2 and TLR4 enhanced the cellular BMP-2 response to oxLDL. Furthermore, oxLDL was co-localized with TLR2 and TLR4. BMP-2 expression was associated with activation of nuclear factor-B (NF-B), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase (ERK)1/2. Inhibition of NF-B and ERK1/2 reduced BMP-2 expression whereas inhibition of p38 MAPK had no effect. In conclusion, oxLDL induces BMP-2 expression through TLR2 and TLR4 in human CAECs. The NF-B and ERK1/2 pathways are involved in the signaling mechanism. These findings underscore an important role for TLR2 and TLR4 in mediating the BMP-2 response to oxLDL in human CAECs and indicate that these two immunoreceptors contribute to the mechanisms underlying atherosclerotic vascular calcification.Calcification in intima is often associated with atherosclerosis. Atherosclerotic calcification of coronary artery is a significant risk for the unsuccessful coronary intervention and balloon-induced coronary artery dissection (1), and calcification is found to be an indicator of plaque instability (2). Although inhibition of atherosclerotic calcification might be a promising approach to stabilize atherosclerotic plaques, the molecular mechanism(s) underlying atherosclerotic vascular calcification remains incompletely understood.It is known that oxLDL 2 accumulation in the vascular wall provokes the development of atherosclerosis and vascular calcification (3). BMP-2 is an osteogenic factor. It is expressed in calcified human atherosclerotic plaque. Cells from the atherogenic aortic wall express BMP-2 in vitro and formed calcified nodules with prolonged culture (4). The BMP-2 mRNA level increased after oxLDL stimulation in human CAECs (5). However, it remains unclear whether oxLDL up-regulates BMP-2 protein levels in CAECs. Further, the signaling mechanism that regulates the cellular BMP-2 response to oxLDL is unknown.Accumulating evidence indicates that atherosclerosis is an inflammatory process involving a network of vascular cells, monocytes, and T lymphocytes. Proinflammatory mediators, including cytokines, chemokines, and growth factors...

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“…required for the induction of BMP-2 expression by oxLDL as TLR2 and TLR4 utilize this shared signaling pathway (34).…”

Section: Discussionmentioning

confidence: 99%

Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

Shi

et al. 2011

Journal of Biological Chemistry

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“…A toll-like receptor (TLR) family on intestinal epithelial cells plays an important role in recognizing the intestine foreigners, which subsequently initiates the inflammation response Kawai & Akira 2009;O'Neill et al 2009;Lavelle et al 2010). MyD88 is the main adaptor molecule of TLRs; most of signal transduction of TLRs needs MyD88 to activate the downstream molecules, and finally leads nuclear factors such as NF-κB enter into nuclear and regulate inflammatory cytokines expression.…”

Section: Introductionmentioning

confidence: 99%

The inflammation regulation effects ofEnterococcus faeciumHDRsEf1 on human enterocyte-like HT-29 cells

Tian

Yang

et al. 2016

Animal Cells and Systems

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Enterococcus faecium HDRsEf1 strain used as a probiotic to inhibit intestine inflammation and improve animal growth performance has been proved by our research team; however, it remains unclear how HDRsEf1 was recognized by intestine cells and how it activates the downstream pathway which benefit intestine health. In this study, HDRsEf1 was used to stimulate HT-29 cell line to partially uncover the intestine benefit mechanism of HDRsEf1. The results of cell viability assays showed that HDRsEf1 had no toxicity on HT-29 at concentrations up to 1 × 10 8 CFU/mL, HDRsEf1 could upregulate the TLR1, TLR2, and TLR6 mRNA level, especially TLR2, and significantly downregulate the mRNA level of TLR4, TLR5, TLR7, TLR8, but did not significantly affect the mRNA or protein level of MyD88, which suggests that HDRsEf1 activates the TLR2 pathway in an MyD88-independent pattern. HDRsEf1 could significantly downregulate the mRNA level of pro-inflammatory factors IL-1β, IL-6, IL-8, IL-12p35, IL-17, and TNF-α and did not affect the anti-inflammatory factors IL-10, PPAR-γ, and TSLP; besides HDRsEf1 did not upregulate the degradation of IκB in HT-29 cells. By contrast, enterohemorrhagic E. coli (EHEC) O157:H7 strongly up-regulated the mRNA level of pro-inflammatory factors IL-1β, IL-6, IL-8, IL-23, and TNF-α, downregulated obviously anti-inflammatory factor PPAR-ɣ, and obviously upregulated the degradation of IκB, which suggested that HDRsEf1 may act as an antagonist to regulate intestine inflammation response to intestine pathogen. These findings shed a light on the intestine benefit mechanism of HDRsEf1. ARTICLE HISTORY

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“…According to crystal structures, TLRs form homo-or heterodimeric signaling complexes interacting with the single PAMP molecule [3][4][5][6][7]. The medical and biological significance of toll-like receptor (TLR) signaling is obvious, since the disregulation of the TLR system may cause various autoimmune diseases and septic shock [8][9][10][11], and some therapeutic strategies targeting TLRs have already emerged [8,11,12].…”

Section: Introductionmentioning

confidence: 99%

Toll‐like receptor 3 transmembrane domain is able to perform various homotypic interactions: An NMR structural study

2014

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Edited by Christian Griesinger Keyword:Toll-like receptor Transmembrane domain Spatial structure Dimerization Free energy a b s t r a c t Toll-like receptors (TLRs) take part in both the innate and adaptive immune systems. The role of the transmembrane domain in TLR signaling is still elusive, while its importance for the TLR activation was clearly demonstrated. In the present study the ability of the TLR3 transmembrane domain to form dimers and trimers in detergent micelles was shown by solution NMR spectroscopy. Spatial structures and free energy magnitudes were determined for the TLR3 transmembrane domain in dimeric and trimeric states, and two possible surfaces that may be used for the helix-helix interaction by the full-length TLR3 were revealed. Structured summary of protein interactions:TLR3-TM and TLR3-TM bind by nuclear magnetic resonance (1, 2)

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Therapeutic Targeting of Toll-Like Receptors for Infectious and Inflammatory Diseases and Cancer

Cited by 390 publications

References 222 publications

Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

Oxidized Low Density Lipoprotein Induces Bone Morphogenetic Protein-2 in Coronary Artery Endothelial Cells via Toll-like Receptors 2 and 4

The inflammation regulation effects ofEnterococcus faeciumHDRsEf1 on human enterocyte-like HT-29 cells

Toll‐like receptor 3 transmembrane domain is able to perform various homotypic interactions: An NMR structural study

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