• 한국식품영양학회지
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• 제34권5호
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• pp.441-448
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• 2021

This study was designed to investigate the intracellular signaling pathways and immunoenhancing effect of macrophage activation by crude polysaccharides (CPP) extracted from citrus peels. CPP did not affect the cytotoxicity of RAW264.7 cells, but showed dose-dependent effects on cell viability. Also, CPP showed high production of chemokine (nitric oxide (NO)) and cytokines (interleukin (IL)-6 and tumor necrosis factor (TNF)-α). CPP increased IL-6, TNF-α, and inducible nitric oxide synthase (iNOS) mRNA expression dose-dependently. CPP also strongly induced the phosphorylation of the ERK, p38, and IκBα pathways in RAW 264.7 cells. In anti-pattern recognition receptors (PRRs) experiments, the effect of CPP on NO production was strongly suppressed by neutralizing toll-like receptor (TLR)2, TLR4, and Dectin1 antibodies, whereas IL-6 and TNF-α production by CPP was mainly suppressed by mannose receptor (MR). Therefore, these results suggest that CPP treatment-induced NO production was regulated by the ERK, p38, and NF-κB pathways through TLR2, TLR4, and Dectin1 receptors, whereas IL-6 and TNF-α production was primarily regulated by the ERK, p38, and NF-κB pathways through MR receptors.

• Journal of Microbiology and Biotechnology
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• 제24권8호
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• pp.1051-1058
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• 2014

Platelet-activating factor receptor (PAFR) plays an important role in bacterial infection and inflammation. We examined the effect of the bacterial cell wall components lipopolysaccharide (LPS) and lipoteichoic acid (LTA) from Lactobacillus plantarum (pLTA) and Staphylococcus aureus (aLTA) on PAFR expression in THP-1, a monocyte-like cell line. LPS and aLTA, but not pLTA, significantly increased PAFR expression, whereas priming with pLTA inhibited LPS-mediated or aLTA-mediated PAFR expression. Expression of Toll-like receptor (TLR) 2 and 4, and CD14 increased with LPS and aLTA treatments, but was inhibited by pLTA pretreatment. Neutralizing antibodies against TLR2, TLR4, and CD14 showed that these receptors were important in LPS-mediated or aLTA-mediated PAFR expression. PAFR expression is mainly regulated by the nuclear factor kappa B signaling pathway. Blocking PAF binding to PAFR using a PAFR inhibitor indicated that LPS-mediated or aLTA-mediated PAF expression affected TNF-${\alpha}$ production. In the mouse small intestine, pLTA inhibited PAFR, TLR2, and TLR4 expression that was induced by heat-labile toxin. Our data suggested that pLTA has an anti-inflammatory effect by inhibiting the expression of PAFR that was induced by pathogenic ligands.

• BMB Reports
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• 제46권7호
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• pp.376-381
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• 2013

It is unknown how soluble pattern-recognition receptors in blood, such as mannose-binding lectin (MBL) and ficolins, modulate mast cell-mediated inflammatory responses. We investigate how mouse MBL-A or ficolin-A regulate mouse bone marrow-derived mast cells (mBMMCs)-derived inflammatory response against bacterial lipopolysaccharide (LPS) stimulation. LPS-mediated pro-inflammatory cytokine productions on mBMMCs obtained from Toll-like receptor4 (TLR4)-deficient mice, TLR2-defficient mice, and their wildtype, were specifically attenuated by the addition of either mouse MBL-A or ficolin-A in a dose-dependent manner. However, the inhibitory effects by mouse MBL-A or ficolin-A were restored by the addition of mannose or N-acetylglucosamine, respectively. These results suggest that mouse MBL-A and ficolin-A bind to LPS via its carbohydrate-recognition domain and fibrinogen-like domain, respectively, whereby cytokine production by LPS-mediated TLR4 in mBMMCs appears to be down-regulated, indicating that mouse MBL and ficolin may have an inhibitory function toward mouse TLR4-mediated excessive inflammation on the mast cells.

• Molecules and Cells
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• 제27권1호
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• pp.5-14
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• 2009

The availability of effective vaccines has had the most profound positive effect on improving the quality of public health by preventing infectious diseases. Despite many successful vaccines, there are still old and new emerging pathogens against which there is no vaccine available. A better understanding of how vaccines work for providing protection will help to improve current vaccines as well as to develop effective vaccines against pathogens for which we do not have a proper means to control. Recent studies have focused on innate immunity as the first line of host defense and its role in inducing adaptive immunity; such studies have been an intense area of research, which will reveal the immunological mechanisms how vaccines work for protection. Toll-like receptors (TLRs), a family of receptors for pathogen-associated molecular patterns on cells of the innate immune system, play a critical role in detecting and responding to microbial infections. Importantly, the innate immune system modulates the quantity and quality of long-term T and B cell memory and protective immune responses to pathogens. Limited studies suggest that vaccines which mimic natural infection and/or the structure of pathogens seem to be effective in inducing long-term protective immunity. A better understanding of the similarities and differences of the molecular and cellular events in host responses to vaccination and pathogen infection would enable the rationale for design of novel preventive measures against many challenging pathogens.

• 대한의생명과학회지
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• 제19권3호
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• pp.173-179
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• 2013

Since the identification and characterization of toll-like receptors (TLR) in Drosophila, numerous scientific studies have examined the role of TLRs in host innate immunity. Recent studies have suggested a convergence of the nuclear factor kappa B (NF-${\kappa}B$) signaling and cytokine production regulated by the cytosolic elicitor known as NLRs (nucleotide-binding domain and leucine-rich repeat containing domain receptors) as a key modulator in inflammatory diseases. Among the NLRs, NOD1 and NOD2 have been intensively investigated for its role in inflammatory bowel disease (IBD). On the other hand, NLRs such as NLRP3, NLRP1, and NLRC4 (also known as IPAF) have been identified to form the inflammasome to activate downstream signaling molecules in response to pathogenic microbes. There is evidence to suggest that substantial crosstalk exists for the TLR and NLR signaling pathway in response to pathogen associated molecular pattern (PAMP). However, the substrate and the mechanistic role of NLRs are largely unknown in innate immune response. Understanding the signaling mechanisms by which NLRs recognize PAMP and other danger signals will shed light on elucidating the pathogenesis of various human inflammatory diseases such as IBD.

• The Korean Journal of Pain
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• 제22권1호
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• pp.1-15
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• 2009

Neuropathic pain is often refractory to intervention because of the complex etiology and an incomplete understanding of the mechanisms behind this type of pain. Glial cells, specifically microglia and astrocytes, are powerful modulators of pain and new targets of drug development for neuropathic pain. Glial activation could be the driving force behind chronic pain, maintaining the noxious signal transmission even after the original injury has healed. Glia express chemokine, purinergic, toll-like, glutaminergic and other receptors that enable them to respond to neural signals, and they can modulate neuronal synaptic function and neuronal excitability. Nerve injury upregulates multiple receptors in spinal microglia and astrocytes. Microglia influence neuronal communication by producing inflammatory products at the synapse, as do astrocytes because they completely encapsulate synapses and are in close contact with neuronal somas through gap junctions. Glia are the main source of inflammatory mediators in the central nervous system. New therapeutic strategies for neuropathic pain are emerging such as targeting the glial cells, novel pharmacologic approaches and gene therapy. Drugs targeting microglia and astrocytes, cytokine production, and neural structures including dorsal root ganglion are now under study, as is gene therapy. Isoform-specific inhibition will minimize the side effects produced by blocking all glia with a general inhibitor. Enhancing the anti-inflammatory cytokines could prove more beneficial than administering proinflammatory cytokine antagonists that block glial activation systemically. Research on therapeutic gene transfer to the central nervous system is underway, although obstacles prevent immediate clinical application.

• 대한의생명과학회지
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• 제25권1호
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• pp.60-65
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• 2019

Toll-like receptors (TLRs) are one of the families of pattern recognition receptors (PRR) operating in the innate immunity. TLRs have the ability to recognize relatively conserved microbial components, which are generally referred to as pathogen-associated molecular patterns (PAMPs). 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 pristimerin, which is a naturally occurring triterpenoid compound from Celastraceae plants, iNOS expression induced by MALP-2 (TLR2 and TLR6 agonist), Poly[I:C] (TLR3 agonist), or LPS (TLR4 agonist) were examined. Pristimerin suppressed the iNOS expression induced by MALP-2, Poly[I:C], or LPS. These results suggest that pristimerin can modulate TLRs signaling pathways leading to decreased inflammatory gene expression.

• 대한의생명과학회지
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• 제25권3호
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• pp.267-274
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• 2019

Toll-like receptors (TLRs) are one of the families of pattern recognition receptors (PRR) to recognize pathogen-associated molecular patterns (PAMPs). PAMPs stimulate TLRs to initiate specific immunoactivity. The activation of TLRs signaling leads to the expression of pro-inflammatory gene products such as cytokines and inducible nitric oxide synthase (iNOS). To evaluate the therapeutic potential of dehydrocostus lactone (DHL), which is a natural sesquiterpene lactone derived from various medicinal plants, iNOS expression induced by LPS (TLR4 agonist), MALP-2 (TLR2 and TLR6 agonist), or Poly[I:C] (TLR3 agonist) were examined. DHL suppressed the iNOS expression induced by LPS, MALP-2, or Poly[I:C]. DHL also inhibited nitrite production induced by LPS, MALP-2, or Poly[I:C]. These results suggest that DHL can modulate TLRs signaling pathways resulting in anti-inflammatory effect.

• The Korean Journal of Physiology and Pharmacology
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• 제8권5호
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• pp.253-257
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• 2004

Schwann cells play an important role in peripheral nerve regeneration. Upon neuronal injury, activated Schwann cells clean up the myelin debris by phagocytosis, and promote neuronal survival and axon outgrowth by secreting various neurotrophic factors. However, it is unclear how the nerve injury induces Schwann cell activation. Recently, it was reported that certain cytoplasmic molecules, which are secreted by cells undergoing necrotic cell death, induce immune cell activation via the toll-like receptors (TLRs). This suggests that the TLRs expressed on Schwann cells may recognize nerve damage by binding to the endogenous ligands secreted by the damaged nerve, thereby inducing Schwann cell activation. Accordingly, this study was undertaken to examine the expression and the function of the TLRs on primary Schwann cells and iSC, a rat Schwann cell line. The transcripts of TLR2, 3, 4, and 9 were detected on the primary Schwann cells as well as on iSC. The stimulation of iSC with poly (I : C), a synthetic ligand for the TLR3, induced the expression of $TNF-{\alpha}$ and RANTES. In addition, poly (I : C) stimulation induced the iNOS expression and nitric oxide secretion in iSC. These results suggest that the TLRs may be involved in the inflammatory activation of Schwann cells, which is observed during Wallerian degeneration after a peripheral nerve injury.

• International Journal of Oral Biology
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• 제31권3호
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• pp.87-92
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• 2006

Schwann cells play an important role in peripheral nerve regeneration. Upon nerve injury, Schwann cells are activated and produce various proinflammatory mediators including IL-6, LIF and MCP-1, which result in the recruitment of macrophages and phagocytosis of myelin debris. However, it is unclear how the nerve injury induces Schwann cell activation. Recently, it was reported that necrotic cells induce immune cell activation via toll-like receptors (TLRs). This suggests that the TLRs expressed on Schwann cells may recognize nerve damage by binding to the endogenous ligands secreted by the damaged nerve, thereby inducing Schwann cell activation. To explore the possibility, we stimulated iSC, a rat Schwann cell line, with damaged neuronal cell extracts (DNCE). The stimulation of iSC with DNCE induced the expression of various inflammatory mediators including IL-6, LIF, MCP-1 and iNOS. Studies on the signaling pathway indicate that $NF-{\kappa}B$, p38 and JNK activation are required for the DNCE-induced inflammatory gene expression. Furthermore, treatment of either anti-TLR3 neutralizing antibody or ribonuclease inhibited the DNCE-induced proinflammatory gene expression in iSC. In summary, these results suggest that damaged neuronal cells induce inflammatory Schwann cell activation via TLR3, which might be involved in the Wallerian degeneration after a peripheral nerve injury.