• BMB Reports
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• 제56권6호
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• pp.359-364
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• 2023

KAI1/CD82, a membrane tetraspanin protein, can prevent various cancers and retinal disorders through its anti-angiogenic and anti-metastatic capacity. However, little is known about its anti-inflammatory effect and molecular mechanism. Therefore, the present study aimed to inLPSvestigate effect of a recombinant protein of the large extracellular domain of human KAI1 (Gly 111-Leu 228, rhKAI1) on lipopolysaccharides (LPS)-stimulated RAW264.7 macrophage-like cells and mouse bone marrow-derived macrophages (BMDM) and to identify its underlying mechanism. Our data showed that rhKAI1 suppressed expression levels of classically macrophages (M1) phenotype-related surface markers F4/80+CD86+ in LPS-stimulated BMDM and RAW264.7 cells. In addition, LPS markedly increased mRNA expression and release levels of pro-inflammatory cytokines and mediators such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α, cyclooxygenase-2, nitric oxide and prostaglandin E2, whereas these increases were substantially down-regulated by rhKAI1. Furthermore, LPS strongly increased expression of NF-κB p65 in the nuclei and phosphorylation of ERK, JNK, and p38 MAPK. However, nuclear translocation of NF-κB p65 and phosphorylation of JNK were greatly reversed in the presence of rhKAI1. Especially, rhKAI1 markedly suppressed expression of toll-like receptor (TLR4) and prevented binding of LPS with TLR4 through molecular docking predict analysis. Importantly, Glu 214 of rhKAI1 residue strongly interacted with Lys 360 of TLR4 residue, with a binding distance of 2.9 Å. Taken together, these findings suggest that rhKAI1 has an anti-inflammatory effect on LPS-polarized macrophages by interacting with TLR4 and down-regulating the JNK/NF-κB signaling pathway.

• 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.

• 한국자원식물학회지
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• 제34권5호
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• pp.411-419
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• 2021

본 연구에서 금화규 뿌리 추출물(AMR)이 마우스 대식세포인 RAW264.7 세포의 활성화 유도를 통한 면역증진 활성과 마우스 지방전구세포인 3T3-L1 세포의 지질축적억제를 통한 항비만 활성을 평가하였다. 금화규 뿌리 추출물(AMR)은 전반적으로 RAW264.7 세포에서 TLR2/TLR4의 자극을 통해 p38과 JNK를 활성화시켜 NO, iNOS, IL-1𝛽, IL-6, TNF-𝛼와 같은 면역증진 인자의 발현을 증가시키는 것으로 판단된다. 그러나 IL-6의 경우, p38과 JNK 활성화에 의존하지 않는 것으로 확인되어 TLR2/4에 의한 다른 신호전달이 관여하는 것으로 사료되어 추가적인 연구가 필요하다. 또한, 금화규 뿌리 추출물(AMR)은 PPAR𝛾의 과대발현을 억제하여 지방전구세포의 성숙한 지방세포로의 분화를 억제하고, 성숙한 지방세포에서 CEBP𝛼, PPAR𝛾, perilipin-1, FABP4, adiponectin의 발현을 억제하여 지방세포 내 지질 형성 및 축적을 억제하는 것으로 판단된다. 본 연구를 통해 구명된 결과들은 금화규 뿌리 추출물(AMR)이 향후 면역증진 및 항비만을 위한 보조제 또는 건강 기능성 식품과 의약품으로의 개발 및 활용이 가능할 것으로 생각된다.

• Nutrition Research and Practice
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• 제9권4호
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• pp.364-369
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• 2015

BACKGROUND/OBJECTIVES: Inflammation is associated with various types of acute and chronic alcohol liver diseases. In this study, we examined whether umbelliferone (7-hydroxycoumarin, UF) ameliorates chronic alcohol-induced liver damage by modulating inflammatory response and the antioxidant system. METHODS: Rats were fed a Liber-Decarli liquid diet containing 5% alcohol with or without UF (0.05 g/L) for 8 weeks, while normal rats received an isocaloric carbohydrate liquid diet. RESULTS: Chronic alcohol intake significantly increased serum tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and interleukin 6 levels and decreased interleukin 10 level; however, UF supplementation reversed the cytokines related to liver damage. UF significantly suppressed hepatic lipopolysaccharide binding protein, toll-like receptor 4 (TLR4), nuclear factor kappa B, and TNF-${\alpha}$ gene expression increases in response to chronic alcohol intake. Masson's trichrome staining revealed that UF improved mild hepatic fibrosis caused by alcohol, and UF also significantly increased the mRNA expressions and activities of superoxide dismutase and catalase in liver, and thus, decreased lipid peroxide and mitochondrial hydrogen peroxide levels. CONCLUSIONS: The findings of this study indicate that UF protects against alcohol-induced liver damage by inhibiting the TLR4 signaling pathway and activating the antioxidant system.

• Journal of Ginseng Research
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• 제46권1호
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• pp.62-70
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• 2022

Background: Maternal Toxoplasma gondii (T. gondii) infection during pregnancy has been associated with various mental illnesses in the offspring. Ginsenoside Rh2 (GRh2) is a major bioactive compound obtained from ginseng that has an anti-T. gondii effect and attenuates microglial activation through toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. GRh2 also alleviated tumor-associated or lipopolysaccharide-induced depression. However, the effects and potential mechanisms of GRh2 on depression-like behavior in mouse offspring caused by maternal T. gondii infection during pregnancy have not been investigated. Methods: We examined GRh2 effects on the depression-like behavior in mouse offspring, caused by maternal T. gondii infection during pregnancy, by measuring depression-like behaviors and assaying parameters at the neuronal and molecular level. Results: We showed that GRh2 significantly improved behavioral measures: sucrose consumption, forced swim time and tail suspended immobility time of their offspring. These corresponded with increased tissue concentrations of 5-hydroxytryptamine and dopamine, and attenuated indoleamine 2,3-dioxygenase or enhanced tyrosine hydroxylase expression in the prefrontal cortex. GRh2 ameliorated neuronal damage in the prefrontal cortex. Molecular docking results revealed that GRh2 binds strongly to both TLR4 and high mobility group box 1 (HMGB1). Conclusion: This study demonstrated that GRh2 ameliorated the depression-like behavior in mouse offspring of maternal T. gondii infection during pregnancy by attenuating the excessive activation of microglia and neuroinflammation through the HMGB1/TLR4/NF-κB signaling pathway. It suggests that GRh2 could be considered a potential therapy in preventing and treating psychiatric disorders in the offspring mice of mothers with prenatal exposure to T. gondii infection.

• BMB Reports
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• 제47권2호
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• pp.115-120
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• 2014

In this study, we show that Mycobacterium avium subsp. paratuberculosis MAP1305 induces the maturation of bone marrow-derived dendritic cells (BMDCs), a representative antigen presenting cell (APC). MAP1305 protein induces DC maturation and the production of pro-inflammatory cytokines (Interleukin (IL)-6), tumor necrosis factor (TNF)-${\alpha}$, and IL-$1{\beta}$) through Toll like receptor-4 (TLR-4) signaling by directly binding with TLR4. MAP1305 activates the phosphorylation of MAPKs, such as ERK, p38MAPK, and JNK, which is essential for DC maturation. Furthermore, MAP1305-treated DCs transform naive T cells to polarized $CD4^+$ and $CD8^+$ T cells, thus indicating a key role for this protein in the Th1 polarization of the resulting immune response. Taken together, M. avium subsp. paratuberculosis MAP1305 is important for the regulation of innate immune response through DC-mediated proliferation of $CD4^+$ and $CD8^+$ T cells.

• BMB Reports
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• 제47권9호
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• pp.512-517
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• 2014

In this study, we showed that Mycobacterium abscessus MAB2560 induces the maturation of dendritic cells (DCs), which are representative antigen-presenting cells (APCs). M. abscessus MAB2560 stimulate the production of pro-inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor (TNF)-${\alpha}$, IL-$1{\beta}$, and IL-12p70] and reduce the endocytic capacity and maturation of DCs. Using $TLR4^{-/-}$ DCs, we found that MAB2560 mediated DC maturation via Toll-like receptor 4 (TLR4). MAB2560 also activated the MAPK signaling pathway, which was essential for DC maturation. Furthermore, MAB2560-treated DCs induced the transformation of $na\ddot{i}ve$ T cells to polarized $CD4^+$ and $CD8^+$ T cells, which would be crucial for Th1 polarization of the immune response. Taken together, our results indicate that MAB2560 could potentially regulate the host immune response to M. abscessus and may have critical implications for the manipulation of DC functions for developing DC-based immunotherapy.

• Nutrition Research and Practice
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• 제7권6호
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• pp.460-465
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• 2013

The hepatoprotective activity of Acanthopanax koreanum Nakai extract (AE) was investigated against D-Galactosamine/Lipopolysaccharide (D-GalN/LPS)-induced liver failure rats compared with that of acanthoic acid (AA) isolated from AE. Although D-GalN/LPS (250 mg/kg body weight/$10{\mu}g/kg$ body weight, i.p.) induced hepatic damage, pretreatments with AE (1 and 3% AE/g day) and AA (0.037% AA, equivalent to 3% AE/g day) alleviated the hepatic damage. This effect was the result of a significant decrease in the activity of alanine transaminase. Concomitantly, both the nitric oxide and IL-6 levels in the plasma were significantly decreased by high-dose AE (AE3) treatment compared to the GalN/LPS control (AE0). This response resulted from the regulation of pro-inflammatory signaling via a decrease in TLR4 and CD14 mRNA levels in the liver. While a high degree of necrosis and hemorrhage were observed in the AE0, pretreatment with AE3 and AA reduced the extent of hepatocyte degeneration, necrosis, hemorrhage and inflammatory cell infiltrates compared to the AE0. In conclusion, these results suggest that especially high-dose AE are capable of alleviating D-GalN/LPS-induced hepatic injury by decreasing hepatic toxicity, thereby mitigating the TLR 4-dependent cytokine release. The anti-inflammatory effect of AE could be contributing to that of AA and AE is better than AA.

• 대한한방소아과학회지
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• 제38권1호
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• pp.1-9
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• 2024

Objective The purpose of this study was to confirm the effects of Galgeunhwanggeumhwangryeon-tang (PSCG) extract on skin moisturizing, antibacterial, and tight junction recovery in atopic dermatitis-induced mice. Methods In this study, we used 4-week-old NC/Nga mice divided into four groups: control (Ctrl), lipid barrier elimination (LBE), dexamethasone (Dx) after lipid barrier elimination (DEX), and PSCG after lipid barrier elimination (PSC). Ten rats were assigned to each treatment group. Three days after drug administration following lipid barrier elimination, ceramide kinase, caspase 14, sodium hydrogen antiporter (NHE), cathelicidin, claudin, and toll-like receptor (TLR)-2 were observed to confirm the restoration of skin moisturizer production, antimicrobial barriers, and tight junctions in the skin barrier. Results Ceramide kinase and caspase 14 positive reaction were significantly higher in PSC than in LBE and DEX. Both NHE and cathelicidin showed higher positive reactions in PSC than in LBE and DEX. Claudin, and TLR-2 showed higher levels of positive staining in the PSC group than in the LBE and DEX groups. Conclusion It was confirmed that the PSCG extract can have the potential to restore the damaged skin barrier in atopic dermatitis.

• 대한본초학회지
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• 제21권3호
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• pp.103-109
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• 2006

Objectives : The purpose of this study was to investigate the TLR-4 mediated anti-inflammatory effects of extract from Xanthii Fructus(XF) on the peritoneal macrophage. Methods : To evaluate of TLR-4 mediated inflammatory of XF, we examined NO and cytokine production in TRL-4 ligand(LPS-lipopolysacchride) induced macrophages. Furthermore, we checked molecular mechanism using western blot. Results : l.Extract from XF reduced LPS-induced Nitric oxide (NO), tumor necrosis factor-a (TNF-a), interleukin (IL)-6 and IL-12 production in peritoneal macrophages 2.Extract from XF itself does not have any cytotoxic effect.XS inhibited degradation of IkBa in the TLR-4 mediated peritoneal macrophages Conclusion : XF down-regulated TLR4 ligand(LPS)-induced NO and cytokine productions.