• Asian Pacific Journal of Cancer Prevention
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• 제13권12호
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• pp.6409-6413
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• 2012

The innate immune system coordinates the inflammatory response to pathogens. To do so, its cells must discriminate self from non-self utilizing receptors that identify molecules synthesized exclusively by microbes. Toll-like receptors have a crucial role in the detection of microbial infection in mammals and insects. In mammals, they have evolved to recognize conserved products unique to microbial metabolism. These include lipopolysaccharide (LPS), lipotechoic acids, and peptidoglycans (PGN). We show here that TLRs, including TLR2, are expressed on the THP-1 human leukemia cell line. Activation of TLR2 signaling in THP-1 by PGN induces the synthesis of various soluble factors and proteins including interleukin-$1{\beta}$, interleukin-8 and TNF-${\alpha}$ and apoptosis of THP-1 with PGN dose and time dependence. Moreover, in this study we show that PGN induces apoptosis of THP-1 cells in a TNF-${\alpha}$-dependent manner. These findings indicate that TLR2 signaling results in a cascade leading to tumor apoptosis and differentiation, which may suggest new clinical prospects using TLR2 agonists as cytotoxic agents in certain cancers.

• Asian Pacific Journal of Cancer Prevention
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• 제17권7호
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• pp.3391-3394
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• 2016

Background: Helicobacter pylori is now recognized as a causative factor of chronic gastritis, gastroduodenal ulcers, gastric cancer and mucosa-associated lymphatic tissue lymphoma. Toll-like receptors are important bacterial receptors in gastric epithelial cell signaling transduction and play critical roles in gastric carcinogenesis. Materials and Methods: A total of 400 patients undergoing esophagogastroduodenoscopy for investigation of chronic abdominal pain were genotyped for single-nucleotide polymorphisms (SNPs) in TLR1 (rs4833095) using TagMan SNPs genotyping assay by real-time PCR hybridization. Relationships with susceptibility to H. pylori infection and pre-malignant gastric mucosa morphological patterns, classified by magnifying NBI endoscopy, were investigated. Results: The percentages of TLR1 rs4833095, CC homozygous, CT heterozygous and TT homozygous cases were 34, 46.5 and 19%, respectively. CC showed statistical differences between H. pylori positive and negative cases (P<0.001). CT and TT correlated with type 1 and type 2 gastric mucosal morphological patterns (P <0.01) whereas CC correlated with types 3 and 4 (P<0.01). Conclusions: This study demonstrated good correlation of TLR1 rs4833095 genotype with severity of inflammation in H. pylori infected gastric mucosa according to gastric mucosal morphologic patterns with magnifying NBI endoscopy.

• 대한의생명과학회지
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• 제19권2호
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• pp.168-172
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• 2013

Toll-like receptors (TLRs) play an important role for host defense against invading pathogens. TLR4 has been identified as the receptor for lipopolysaccharide (LPS), which is a cell wall component of gram-negative bacteria. The activation of TLR4 signaling by LPS leads to the activation of NF-${\kappa}B$ and the expression of pro-inflammatory gene products such as cytokines, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). To evaluate the therapeutic potential of (E)-1-(2-(2-nitrovinyl)phenyl)pyrrolidine (NVPP), previously synthesized in our laboratory, NF-${\kappa}B$ activation and iNOS and COX-2 expression induced by LPS were examined. NVPP inhibited the activation of NF-${\kappa}B$ induced by LPS. NVPP also suppressed the iNOS expression induced by LPS but it did not suppress COX-2 expression induced by LPS. These results suggest that NVPP has the specific mechanism for anti-inflammatory responses.

• 대한의생명과학회지
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• 제24권2호
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• pp.102-107
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• 2018

Toll-like receptors (TLRs) play an important role for host defense against invading pathogens. The activation of TLRs signaling leads to the activation of $NF-{\kappa}B$ and the expression of pro-inflammatory gene products such as cytokines and inducible nitric oxide synthase (iNOS). To evaluate the therapeutic potential of cardamonin, which is a naturally occurring chalcone from Alpinia species (zingiberaceous plant species), $NF-{\kappa}B$ activation and iNOS expression induced by MALP-2 (TLR2 and TLR6 agonist) or LPS (TLR4 agonist) were examined. Cardamonin inhibited the activation of $NF-{\kappa}B$ induced by MALP-2 or LPS. Cardamonin also suppressed the iNOS expression induced by MALP-2 or LPS. These results suggest that cardamonin has the specific mechanism for anti-inflammatory responses by regulating of TLRs signaling pathway.

• BMB Reports
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• 제50권2호
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• pp.55-57
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• 2017

Toll-like receptor 4 (TLR4) together with MD2, one of the key pattern recognition receptors for a pathogen-associated molecular pattern, activates innate immunity by recognizing lipopolysaccharide (LPS) of Gram-negative bacteria. Although LBP and CD14 catalyze LPS transfer to the TLR4/MD2 complex, the detail mechanisms underlying this dynamic LPS transfer remain elusive. Using negative-stain electron microscopy, we visualized the dynamic intermediate complexes during LPS transfer-LBP/LPS micelles and ternary CD14/LBP/LPS micelle complexes. We also reconstituted the entire cascade of LPS transfer to TLR4/MD2 in a total internal reflection fluorescence (TIRF) microscope for a single molecule fluorescence analysis. These analyses reveal longitudinal LBP binding to the surface of LPS micelles and multi-round binding/unbinding of CD14 to single LBP/LPS micelles via key charged residues on LBP and CD14. Finally, we reveal that a single LPS molecule bound to CD14 is transferred to TLR4/MD2 in a TLR4-dependent manner. These discoveries, which clarify the molecular mechanism of dynamic LPS transfer to TLR4/MD2 via LBP and CD14, provide novel insights into the initiation of innate immune responses.

• IMMUNE NETWORK
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• 제14권5호
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• pp.249-254
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• 2014

Allergic asthma is a chronic pulmonary inflammatory disease characterized by reversible airway obstruction, hyperresponsiveness and eosinophils infiltration. Toll-like receptors (TLRs) signaling are closely associated with asthma and have emerged as a novel therapeutic target in allergic disease. The functions of TLR3 and TLR4 in allergic airway inflammation have been studied; however, the precise role of TIR-domain-containing adapter-inducing interferon-${\beta}$ (TRIF), the adaptor molecule for both TLR3 and TLR4, is not yet fully understood. To investigate this, we developed a mouse model of OVA-induced allergic airway inflammation and compared the severity of allergic airway inflammation in WT and $TRIF^-/^-$ mice. Histopathological assessment revealed that the severity of inflammation in airway inflammation in TRIF-deficient mice was comparable to that in WT mice. The total number of cells recovered from bronchoalveolar lavage fluid did not differ between WT and TRIF-deficient mice. Moreover, TRIF deficiency did not affect Th1 and Th2 cytokine production in lung tissue nor the level of serum OVA-specific IgE, $IgG_1$ and $IgG_{2c}$. These findings suggest that TRIF-mediated signaling may not be critical for the development of allergic airway inflammation.

• Molecules and Cells
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• 제44권12호
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• pp.861-878
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• 2021

The human genome contains many retroviral elements called human endogenous retroviruses (HERVs), resulting from the integration of retroviruses throughout evolution. HERVs once were considered inactive junk because they are not replication-competent, primarily localized in the heterochromatin, and silenced by methylation. But HERVs are now clearly shown to actively regulate gene expression in various physiological and pathological conditions such as developmental processes, immune regulation, cancers, autoimmune diseases, and neurological disorders. Recent studies report that HERVs are activated in patients suffering from coronavirus disease 2019 (COVID-19), the current pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. In this review, we describe internal and external factors that influence HERV activities. We also present evidence showing the gene regulatory activity of HERV LTRs (long terminal repeats) in model organisms such as mice, rats, zebrafish, and invertebrate models of worms and flies. Finally, we discuss several molecular and cellular pathways involving various transcription factors and receptors, through which HERVs affect downstream cellular and physiological events such as epigenetic modifications, calcium influx, protein phosphorylation, and cytokine release. Understanding how HERVs participate in various physiological and pathological processes will help develop a strategy to generate effective therapeutic approaches targeting HERVs.

• IMMUNE NETWORK
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• 제20권3호
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• pp.21.1-21.10
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• 2020

TLRs are pattern recognition receptors (PRRs) whose cytoplasmic signalling domain is similar to that of IL-1. The extracellular domain of TLRs serve as the binding site of pathogen associated molecular patterns. TLRs are found on both plasma and endosomal membranes and they mainly exert their function by activating genes which lead to production of inflammatory factors. The latest TLR to be discovered, TLR10 is a unique TLR which exhibit anti-inflammatory properties. TLR10 is found on the plasma membrane with other TLRs namely TLR1, TLR2, TLR4, TLR5 and TLR6. Studies have revealed that TLR10 is found on the same gene cluster with TLR1 and TLR6 and is also a coreceptor of TLR2. Up to date, TLR10 is the only TLR which exhibit anti-inflammatory property. Previously, TLR10 was thought to be an "orphan receptor" but much recent studies have identified ligands for TLR10. Currently there is no review article on TLR10 that has been published. In this narrative review, we are going to give an account of TLR10, its functions mainly as an anti-inflammatory PRR and its possible applications as a target in therapeutics.

• Journal of Applied Biological Chemistry
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• 제54권4호
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• pp.279-283
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• 2011

염증의 중요한 분자학적 기전에는 cyclooxygenase-2 (COX-2)에 의한 prostaglandins (PGs) 생성과 inducible nitric oxide synthase (iNOS)에 의한 nitric oxide (NO) 생성이 있다. 많은 종류의 박테리아나 바이러스가 전사요소인 nuclear factor-${\kappa}$B(NF-${\kappa}$B)를 활성화시켜 여러 타깃 유전자의 발현을 조절해 PGs나 NO와 같은 염증물질을 유도하게 된다. 우리는 이번 실험을 통하여 phenethyl isothiocyanate (PEITC)가 toll-like receptor(TLR) agonists에 의해 유도된 NF-${\kappa}$B활성과 COX-2, iNOS 발현에 어떠한 영향을 미치는지 알아 보았다. PEITC는 lipopolysaccharide (LPS)와 polyinosinic-polycytidylic acid (poly[I:C])에 의해 유도된 NF-${\kappa}$B활성을 억제시켰다. 또한 PEITC는 LPS와 Poly[I:C]에 의해 유도된 iNOS의 발현도 억제시켰다. 하지만 PEITC는 TLR agonists들인 LPS, Poly[I:C], 2 kDa macrophage-activating lipopeptide (MALP-2), oligodeoxynucleotide 1668 (ODN1668)에 의한 COX-2 발현은 억제시키지 못하였다. 즉 PEITC가 TRIF-dependent 신호전달체계만을 조절하여 TRIF-dependent 신호전달체계에 의해 조절되는 iNOS는 억제하지만 MyD88-dependent 신호전달 체계에 의해 조절되는 COX-2는 억제하지 못한다는 것을 설명해준다. 이러한 결과는 iNOS와 COX-2가 서로 다른 메커니즘에 의해 조절된다는 것을 암시하며, PEITC가 여러 병원균들로부터 유도되는 염증반응이나 만성적인 질병들을 조절할 수 있음을 제시하는 중요한 결과이다.

• Journal of Ginseng Research
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• 제31권4호
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• pp.181-190
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• 2007

본 연구에서는 고려홍삼으로부터 새로 분리한 CK 함유분획을 이용하여 마우스 대식세포에 대한 선천면역반응 조절에 미치는 영향을 조사하였다. 본 연구에서 사용된 농도의 CK 함유분획에서는 세포독성 효과가 관찰되지 않았으며 CK함유 분획의 전처리에 의하여 그람음성세균의 LPS, 또는 CpG-ODN에 의해 유도되는 NF-${\kappa}B$와 MAPK 활성 및 전염증성 사이토카인, NO의 분비가 TLR4 및 TLR9 특이적으로 억제되었다. 이와 같은 결과는 CK 함유분획이 TLR4을 매개로하는 염증반응뿐만 아니라 TLR9을 통한 염증반응에도 영향을 미치는 것으로 해석된다. 따라서 앞으로 CK 함유 분획에 포함된 개별 사포닌 등 시료 성분에 대한 면밀한 분석, 그리고 이들 개별 물질이 각각의 신호전달 체계에 미치는 영향과 그 기작에 대한 연구가 더욱 필요할 것으로 사료되며 염증억제제로서의 개발 가능성을 탐구하기 위한 생체 내에서의 효능 및 작용기전 분석이 요구된다.