• Korean Journal of Food Science and Technology
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• v.40 no.3
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• pp.332-336
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• 2008

Ginger is widely used as a traditional herbal medicine. Both ginger and its extracts have been used to treat many chronic inflammatory conditions via the inhibition of nuclear factor-kappa B (NF-${\kappa}B$) activation, which results in the suppression of cyclooxygenase-2 (COX-2) expression. However, the mechanisms as to how ginger extracts mediate their health effects are largely unknown. Toll-like receptors (TLRs) trigger anti-microbial innate immune responses, recognizing conserved microbial structural molecules that are known as pathogen-associated molecular patterns. All TLR signaling pathways culminate in the activation of NF-${\kappa}B$. The activation of NF- ${\kappa}B$ leads to the induction of inflammatory gene products, including cytokines and COX-2. This study reports the biochemical evidence that 6-shogaol, an active compound in ginger, inhibits NF-${\kappa}B$ activation and COX-2 expression induced by TLR2, TLR3, and TLR4 agonists. Furthermore, 6-shogaol inhibited NF-${\kappa}B$ activation induced by the following downstream signaling components of the TLRs: MyD88, $IKK{\beta}$, and p65. These results imply that ginger can modulate immune responses that could potentially modify the risk of many chronic inflammatory diseases.

• The Korean Journal of Food And Nutrition
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• v.27 no.6
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• pp.1141-1146
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• 2014

The purpose of this study is to investigate the effects of arabinoxylan rice bran and endurance exercise training on TLR4 mediated protein expression in LPS-treated rats. The results showed that TLR4 as an important protein in the inflammatory response against lipopolysaccharide was shown to be significantly lower in both arabinoxylan supplement with exercise group and exercise group, thus the arabinoxylan rice bran had a higher inhibitory activity than arabinoxylan supplement group. However, $NF-{\kappa}B$ and MyD88 protein expression was not changed in arabinoxylan supplement with exercise training group, whereas $NF-{\kappa}B$ significantly decreased in 4 weeks of exercise training group. These results suggest that the supplement of arabinoxylan rice bran with exercise is likely to contribute to inflammation response and the arabinoxylan rice bran can be used as a possible safe alternative to the immunotherapeutic intervention.

• Biomedical Science Letters
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• v.27 no.3
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• pp.177-181
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• 2021

Allergy is an immune response that appears in certain people, and reactions such as coughing, shortness of breath, and hives occur. The immune system plays an important role in homeostasis and host defense, and allergies cause hypersensitivity reactions when an imbalance of immunity occurs. Mutations in the TLR genes are associated with autoimmune conditions such as allergies and asthma. It has been reported that a locus in the TLR1-TLR6-TLR10 region may be associated with atopic sensitization or allergy. Therefore, the purpose of this study was to select an allergy patient group and a healthy control group to determine how the genetic mutation of TLR1 affects the onset of disease. This study was conducted in 709 patients and 5,025 control groups out of 10,956 patients with data from KARE and HEXA cohorts. As a result of logistic regression analysis of 6 SNPs selected from the TLR1 gene, only rs117033348 showed a statistically significant correlation (P = 0.002356). The influence of rs117033348 was examined using PolyPhen-2, and a significant result was shown. Therefore, it can be predicted that the G base in rs117033348 will have an influence on the human body. In addition, Geography of Genetic Variants browser was used to confirm the geographical distribution of allele frequencies for the TLR1 gene. Although it was found that there was a large racial difference in the prevalence of TLR1 SNP, it could be confirmed that the polymorphism of rs117033348 conducted in this study was only specific in East Asia when compared with each race.

• BMB Reports
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• v.52 no.6
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• pp.373-378
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• 2019

The nucleotide-binding and oligomerization domain (NOD) is an innate pattern recognition receptor that recognizes pathogen- and damage-associated molecular patterns. The 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) is a matrix degradation product found in the synovial fluids of patients with osteoarthritis (OA). We investigated whether NOD2 was involved in 29-kDa FN-f-induced pro-catabolic gene expression in human chondrocytes. The expression of mRNA and protein was measured using quantitative real-time polymerase chain reaction (qrt-PCR) and Western blot analysis. Small interfering RNAs were used for knockdown of NOD2 and toll-like receptor 2 (TLR-2). An immunoprecipitation assay was performed to examine protein interactions. The NOD2 levels in human OA cartilage were much higher than in normal cartilage. NOD1 and NOD2 expression, as well as pro-inflammatory cytokines, including interleukin-1beta (IL-$1{\beta}$) and tumor necrosis factor-alpha (TNF-${\alpha}$), were upregulated by 29-kDa FN-f in human chondrocytes. NOD2 silencing showed that NOD2 was involved in the 29-kDa FN-f-induced expression of TLR-2. Expressions of IL-6, IL-8, matrix metalloproteinase (MMP)-1, -3, and -13 were also suppressed by TLR-2 knockdown. Furthermore, NOD2 and TLR-2 knockdown data demonstrated that both NOD2 and TLR-2 modulated the expressions of their adaptors, receptorinteracting protein 2 (RIP2) and myeloid differentiation 88, in 29-kDa FN-f-treated chondrocytes. 29-kDa FN-f enhanced the interaction of NOD2, RIP2 and transforming growth factor beta-activated kinase 1 (TAK1), an indispensable signaling intermediate in the TLR-2 signaling pathway, and activated nuclear factor-${\kappa}B$ (NF-${\kappa}B$), subsequently leading to increased expressions of pro-inflammatory cytokines and cartilage-degrading enzymes. These results demonstrate that 29-kDa FN-f modulated pro-catabolic responses via cross-regulation of NOD2 and TLR-2 signaling pathways.

• International Journal of Industrial Entomology and Biomaterials
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• v.42 no.1
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• pp.1-6
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• 2021

Toll-like receptor (TLR) is responsible for the recognition of foreign protein. Accordingly, TLR is mainly expressed in the immune associated cells. When foreign protein such as silk sericin is considered for the graft, the response of TLR should be considered. TLR is not all or none responsive receptor. TLR can be activated differently by the intensity of the input. Silk sericin is easily fragmented. The protein conformation of silk sericin is different to the degumming method. TLR response to silk sericin may be different to the degumming method. Consequently, objective tailored extraction method should be investigated and developed.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2807-2812
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• 2012

The purpose of this study was to examine the effect of a Toll-like receptor 5 (TLR5) agonist, CBLB502, on the growth and radiosensitivity of A549 lung cancer cells in vivo. Expression of myeloid differentiation factor 88 (MyD88) or TLR5 was stably knocked down in human lung cancer cells (A549) using lentivirus expressing short hairpin RNA targeting human MyD88 or TLR5. Lack of MyD88 or TLR5 expression enhanced tumor growth in mouse xenografts of A549 lung cancer cells. CBLB502 inhibited the growth of A549 lung cancer cells, not A549-MyD88-KD cells in vivo in the murine xenograft model. Our results showed that the inhibition of A549 by CBLB502 in vivo was realized through regulating the expression of neutrophil recruiting cytokines and neutrophil infiltration. Finally, we found that activation of TLR5 signaling did not affect the radiosensitivity of tumors in vivo.

• Molecules and Cells
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• v.38 no.1
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• pp.26-32
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• 2015

Toll-like receptors (TLR) 7 and 9 transduce a cellular signal through the MyD88-dependent pathway and induce the production of inflammatory mediators against microbial nucleotide components. The repeated stimulation of TLR4 leads to endotoxin tolerance, but the molecular mechanisms of tolerance induced through the costimulation of individual TLR has not yet been established, although endosomal TLRs share signaling pathways with TLR4. In the present study, mouse macrophages were simultaneously stimulated with the TLR7 agonist, gardiquimod (GDQ), and the TLR9 agonist, CpG ODN 1826, to examine the mechanism and effector functions of macrophage tolerance. Compared with individual stimulation, the costimulation of both TLRs reduced the secretion of TNF-${\alpha}$ and IL-6 through the delayed activation of the NF-${\kappa}B$ pathway; notably, IL-10 remained unchanged in costimulated macrophages. This tolerance reflected the early induction of suppressor of cytokine signaling-1 (SOCS-1), according to the detection of elevated TNF-${\alpha}$ secretion and restored NF-${\kappa}B$ signaling in response to the siRNA-mediated abrogation of SOCS-1 signaling. In addition, the restimulation of each TLRs using the same ligand significantly reduced the expression of both TLRs in endosomes. These findings revealed that the costimulation of TLR7 and TLR9 induced macrophage tolerance via SOCS-1, and the restimulation of each receptor or both TLR7 and TLR9 downregulated TLR expression through a negative feedback mechanisms that protects the host from excessive inflammatory responses. Moreover, the insufficient and impaired immune response in chronic viral infection might also reflect the repeated and simultaneous stimulation of those endosomal TLRs.

• Biomolecules & Therapeutics
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• v.24 no.4
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• pp.387-394
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• 2016

Sepsis, a serious clinical problem, is characterized by a systemic inflammatory response to infection and leads to organ failure. Toll-like receptor (TLR) signaling is intimately implicated in hyper-inflammatory responses and tissue injury during sepsis. Histone deacetylase (HDAC) inhibitors have been reported to exhibit anti-inflammatory properties. The aim of this study was to investigate the hepatoprotective mechanisms of trichostatin A (TSA), a HDAC inhibitor, associated with TLR signaling pathway during sepsis. The anti-inflammatory properties of TSA were assayed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP), a clinically relevant model of sepsis. The mice were intraperitoneally received TSA (1, 2 or 5 mg/kg) 30 min before CLP. The serum and liver samples were collected 6 and 24-h after CLP. TSA inhibited the increased production of tumor necrosis factor (TNF)-${\alpha}$ and interleukin (IL)-6 in LPS-stimulated RAW264.7 cells. TSA improved sepsis-induced mortality, attenuated liver injury and decreased serum TNF-${\alpha}$ and IL-6 levels. CLP increased the levels of TLR4, TLR2 and myeloid differentiation primary response protein 88 (MyD88) protein expression and association of MyD88 with TLR4 and TLR2, which were attenuated by TSA. CLP increased nuclear translocation of nuclear factor kappa B and decreased cytosolic inhibitor of kappa B ($I{\kappa}B$) protein expression, which were attenuated by TSA. Moreover, CLP decreased acetylation of $I{\kappa}B$ kinase (IKK) and increased association of IKK with $I{\kappa}B$ and TSA attenuated these alterations. Our findings suggest that TSA attenuates liver injury by inhibiting TLR-mediated inflammatory response during sepsis.

• Journal of Animal Science and Technology
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• v.62 no.3
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• pp.385-395
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• 2020

Polyinosinic:polycytidylic acid (poly[I:C]) can stimulate Toll-like receptor 3 (TLR3) signaling pathways. In this study, DF-1 cells were treated with poly(I:C) at various concentrations and time points to examine the comparative expression patterns of innate immune response genes. The viability of DF-1 cells decreased from 77.41% to 38.68% when cells were treated different dose of poly(I:C) from 0.1 ㎍/mL to 100 ㎍/mL for 24 h respectively. The expressions of TLR3, TLR4, TLR7, TLR15, TLR21, IL1B, and IL10 were increased in dose- and time-dependent manners by poly(I:C) treatment. On the contrary, the expression patterns of interferon regulatory factors 7 (IRF7), Jun proto-oncogene, AP-1 transcription factor subunit (JUN), Nuclear Factor Kappa B Subunit 1 (NF-κB1), and IL8L2 were varied; IRF7 and IL8L2 were increasingly expressed whereas the expressions of JUN and NF-κB1 were decreased in a dose-dependent manner after they were early induced. In time-dependent analysis, IRF7 expression was significantly upregulated from 3 h to 24 h, whereas JUN and NF-κB1 expressions settled down from 6 h to 24 h after poly(I:C) treatment although they were induced at early time from 1 h to 3 h. Poly(I:C) treatment rapidly increased the expression of IL8L2 from 3 h to 6 h with a plateau at 6 h and then the expression of IL8L2 was dramatically decreased until 24 h after poly(I:C) treatment although the expression level was still higher than the non-treated control. These results may provide the basis for understanding host response to viral infection and its mimicry system in chickens.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.3
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• pp.225-231
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• 2014

In this study we aim to extensively investigate the anti-influenza virus immune responses in human pharyngeal epithelial cell line (Hep-2) and evaluate the protective role of Toll-like receptor (TLR) ligands in seasonal influenza A H1N1 (sH1N1) infections in vitro. We first investigated the expression of the TLRs and cytokines genes in resting and sH1N1 infected Hep-2 cells. Clear expressions of TLR3, TLR9, interleukin (IL)-6, tumour necrosis factor (TNF)-${\alpha}$ and interferon (IFN)-${\beta}$ were detected in resting Hep-2 cells. After sH1N1 infection, a ten-fold of TLR3 and TLR9 were elicited. Concomitant with the TLRs activation, transcriptional expression of IL-6, TNF-${\alpha}$ and IFN-${\beta}$ were significantly induced in sH1N1-infected cells. Pre-treatment of cells with poly I:C (an analog of viral double-stranded RNA) and CpG-ODN (a CpG-motif containing oligodeoxydinucleotide) resulted in a strong reduction of viral and cytokines mRNA expression. The results presented indicated the innate immune response activation in Hep-2 cells and affirm the antiviral role of Poly I:C and CpG-ODN in the protection against seasonal influenza A viruses.