• Toxicological Research
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• 제23권2호
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• pp.97-105
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• 2007

Toll-like receptors (TLRs) playa crucial role in initiating and regulating innate and adaptive immune responses by detecting invading microbial pathogens. TLRs can also respond to non-microbial molecules derived from damaged tissue. Accumulating evidence suggests that deregulation of TLRs results in the dysfunction of immune system and ultimately increases the risk of many immune and inflammatory diseases including infectious diseases, allergy, and autoimmune diseases. Therefore, understanding how the immune system is controlled by TLRs will provide new insight to find the way to prevent or treat infectious diseases and immune disorders.

• Molecules and Cells
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• 제21권2호
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• pp.174-185
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• 2006

Toll-like receptors (TLRs) were evolved to detect invading pathogens and to induce innate immune responses in order to mount host defense mechanisms. It becomes apparent that the activation of certain TLRs is also modulated by endogenous molecules including lipid components, fatty acids. Results from epidemiological and animal studies demonstrated that saturated and polyunsaturated dietary fatty acids can differentially modify the risk of development of many chronic diseases. Inflammation is now recognized as an important underlying etiologic condition for the pathogenesis of many chronic diseases. Therefore, if the activation of TLRs and consequent inflammatory and immune responses are differentially modulated by types of lipids in vivo, this would suggest that the risk of the development of chronic inflammatory diseases and the host defense against microbial infection may be modified by the types of dietary fat consumed.

• Molecules and Cells
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• 제28권4호
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• pp.365-368
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• 2009

Toll-like receptors (TLRs) play an important role in host defense by sensing invading microbial pathogens and initiating innate immune responses. The stimulation of TLRs by microbial components triggers the activation of myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-${\beta}$ (TRIF)-dependent downstream signaling pathways. Isoliquiritigenin (ILG), an active ingredient of Licorice, has been used for centuries to treat many chronic diseases. ILG inhibits the MyD88-dependent pathway by inhibiting the activity of inhibitor-${\kappa}B$ kinase. However, it is not known whether ILG inhibits the TRIF-dependent pathway. To evaluate the therapeutic potential of ILG, we examined its effect on signal transduction via the TRIF-dependent pathway of TLRs induced by several agonists. ILG inhibited nuclear factor-${\kappa}B$ and interferon regulatory factor 3 activation induced by lipopolysaccharide or polyinosinic-polycytidylic acid. ILG inhibited the lipopolysaccharide-induced phosphorylation of interferon regulatory factor 3 as well as interferon-inducible genes such as interferon inducible protein-10, and regulated activation of normal T-cell expressed and secreted (RANTES). These results suggest that ILG can modulate TRIF-dependent signaling pathways of TLRs, leading to decreased inflammatory gene expression.

• 대한의생명과학회지
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• 제18권3호
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• pp.181-192
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• 2012

Toll-like receptors (TLRs) induce innate immune responses that are essential for host defense against invading microbial pathogens. In general, TLRs have two major downstream signaling pathways; myeloid differential factor 88 (MyD88) and Toll/IL-1R domain-containing adaptor inducing IFN-${\beta}$ (TRIF) leading to the activation of NF-${\kappa}B$ and IRF3. Numerous studies demonstrated that certain phytochemicals possessing anti-inflammatory effects inhibit NF-${\kappa}B$ activation induced by pro-inflammatory stimuli including lipopolysaccharide and tumor necrosis factor-${\alpha}$ ($TNF{\alpha}$). However, the direct molecular targets for such anti-inflammatory phytochemicals are not fully identified. In this paper, we will discuss about the molecular targets of phytochemicals in TLRs signaling pathways. These results present a novel anti-inflammatory mechanism of phytochemicals in TLRs signaling.

• Clinical and Experimental Pediatrics
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• 제53권12호
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• pp.985-988
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• 2010

The innate immune response is the first line of defense against microbial infections. Innate immunity is made up of the surface barrier, cellular immunity and humoral immunity. In newborn, immunologic function and demands are different to adults. Neonatal innate immunity specifically suppresses Th1-type immune responses, and not Th2-type immune responses, which are enhanced. And the impaired response of macrophages is associated with the defective innate immunity in newborn period. Toll-like receptors (TLRs) play a key roles in the detection of invading pathogens and in the induction of innate immune responses. In newborn, the expression of TLRs is age dependent, so preterm has low expression of TLRs. Also, there are defects in signaling pathways downstream of TLRs. As a consequence, the defects of TLRs activity cause the susceptibility to infection in the neonatal period.

• BMB Reports
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• 제44권7호
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• pp.468-472
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• 2011

Toll-like receptors (TLRs) are pattern recognition receptors that recognize molecular structures derived from microbes and initiate innate immunity. TLRs have two downstream signaling pathways, the MyD88- and TRIF-dependent pathways. Dysregulated activation of TLRs is closely linked to increased risk of many chronic diseases. Previously, we synthesized fumaryl pyrrolidinone, (E)-isopropyl 4-oxo-4-(2-oxopyrrolidin-1-yl)-2-butenoate (IPOP), which contains a fumaric acid isopropyl ester and pyrrolidinone, and demonstrated that it inhibits the activation of nuclear factor kappa B by inhibiting the MyD88-dependent pathway of TLRs. However, the effect of IPOP on the TRIF-dependent pathway remains unknown. Here, we report the effect of IPOP on signal transduction via the TRIF-dependent pathway of TLRs. IPOP inhibited lipopolysaccharide- or polyinosinic-polycytidylic acidinduced interferon regulatory factor 3 activation, as well as interferon-inducible genes such as interferon inducible protein-10. These results suggest that IPOP can modulate the TRIF-dependent signaling pathway of TLRs, leading to decreased inflammatory gene expression.

• Genomics & Informatics
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• 제10권3호
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• pp.153-166
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• 2012

A variety of ligands differ in their capacity to bind the receptor, elicit gene expression, and modulate physiological responses. Such receptors include Toll-like receptors (TLRs), which recognize various patterns of pathogens and lead to primary innate immune activation against invaders, and G-protein coupled receptors (GPCRs), whose interaction with their cognate ligands activates heterotrimeric G proteins and regulates specific downstream effectors, including immuno-stimulating molecules. Once TLRs are activated, they lead to the expression of hundreds of genes together and bridge the arm of innate and adaptive immune responses. We characterized the gene expression profile of Toll-like receptor 4 (TLR4) in RAW 264.7 cells when it bound with its ligand, 2-keto-3-deoxyoctonate (KDO), the active part of lipopolysaccharide. In addition, to determine the network communications among the TLR, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and GPCR, we tested RAW 264.7 cells with KDO, interferon-${\beta}$, or cAMP analog 8-Br. The ligands were also administered as a pair of double and triple combinations.

• Journal of Plant Biotechnology
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• 제32권4호
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• pp.269-273
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• 2005

Methylotrophic 효모 Pichia pastoris 발현시스템을 사용하여 인간 TLR9 단백질의 세포내 TIR 도메인을 발현하였다. TIR 단백질이 P. pastoris에서 발현되어 배지 속으로 분비되는 것을 SDS-PAGE로 확인하였고, 발현된 단백질을 western-blot, MALDI-TOF 질량분석으로 동정하였다. 이를 통하여 TIR 딘백질이 P. pastoris에서 안정적으로 발현됨을 알 수 있었다. 그리고 발현된 단백질을 니켈 친화, 양이온교환수지, 겔 투과 크로마토그라피를 사용하여 순수 분리 정제하였다. P. pastoris를 이용한 단백질의 발현과 정제방법은 대장균에서 잘 발현되지 않는 단백질의 발현에 응용될 수 있을 것이다.

• 한국식품과학회지
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• 제39권5호
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• pp.481-487
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• 2007

Toll-like receptors (TLRs) induce innate immune responses that are essential for host defenses against invading microbial pathogens, thus leading to the activation of adaptive immune responses. In general, TLRs have two major downstream signaling pathways: the MyD88- and TRIF-dependent pathways, which lead to the activation of $NF-{\kappa}B$ and IRF3. Numerous studies have demonstrated that certain phytochemicals possessing anti-inflammatory effects inhibit $NF-{\kappa}B$ activation induced by pro-inflammatory stimuli, including lipopolysaccharides and $TNF{\alpha}$. However, the direct molecular targets for such anti-inflammatory phytochemicals have not been fully identified. Identifying the direct targets of phytochemicals within the TLR pathways is important because the activation of TLRs by pro-inflammatory stimuli can induce inflammatory responses that are the key etiological conditions in the development of many chronic inflammatory diseases. In this paper we discuss the molecular targets of resveratrol, (-)-epigallocatechin-3-gallate (EGCG), and curcumin in the TLR signaling pathways. Resveratrol specifically inhibited the TRIF pathway in TLR3 and TLR4 signaling, by targetting TBK1 and RIP1 in the TRIF complex. Furthermore, EGCG suppressed the activation of IRF3 by targetting TBK1 in the TRIF-dependent signaling pathways. In contrast, the molecular target of curcumin within the TLR signaling pathways is the receptor itself, in addition to $IKK{\beta}$. Together, certain dietary phytochemicals can modulate TLR-derived signaling and inflammatory target gene expression, and in turn, alter susceptibility to microbial infection and chronic inflammatory diseases.

• 대한의생명과학회지
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• 제16권1호
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• pp.39-45
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• 2010

Toll-like receptors (TLRs), which are pattern recognition receptors (PRRs), recognize pathogen-associated molecular patterns (PAMPs) and regulate the activation of innate immunity. All TLR signaling pathways culminate in the activation of NF-${\kappa}B$, leading to the induction of inflammatory gene products such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Parthenolide, a sesquiterpene lactone isolated from the herb feverfew (Tanacetum parthenium), has been used as folk remedies to treat many chronic diseases for many years. In the present report, we present biochemical evidence that parthenolide inhibits the NF-${\kappa}B$ activation induced by TLR agonists and the overexpression of downstream signaling components of TLRs, MyD88, $IKK{\beta}$, and p65. Parthenolide also inhibits TLR agonists-induced COX-2 and iNOS expression. These results suggest that parthenolide can modulate the immune responses regulated by TLR signaling pathways.