• 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.

• 생명과학회지
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• 제21권1호
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• pp.36-43
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• 2011

Glycate화된 단백질이 혈관질환의 발생에 관여하는지 알아보기 위하여 glycated albumin (GA)이 혈관평활근 세포에서 인터루킨-6 발현에 영향을 주는지 조사하고 또한 그 기전을 구명하였다. GA에 노출된 혈관평활근세포에서 인터루킨-6 transcript가 증가하고, 인터루킨-6 단백질의 분비가 증가하고, 또한 인터루킨-6 유전자의 promoter가 활성화되었다. GA에 의한 인터루킨-6 유전자의 promoter 활성화는 dominant negative 형태의 Toll-like receptor (TLR)-4와 myeloid differentiation factor 88 (Myd88)에 의하여 크게 감소되었지만, dominant negative 형태의 TLR-2와 TIR-domain-containing adapter-inducing interferon-$\beta$ (TRIF)의 영향을 받지 않았다. 그리고 Extrcellular signal-related kinase (ERK) 억제 물질들은 GA에 의한 인터루킨-6의 분비 및 인터루킨-6 유전자 promoter 활성화를 억제하였다. 그리고 인터루킨-6 유전자의 promoter의 NF-${\kappa}B$-binding sequence에 변이는 GA에 의한 인터루킨-6 유전자의 promoter 활성화 억제하였다. 이러한 결과는 혈관평활근세포에서 GA에 의한 인터루킨-6 유전자 활성화에 TLR-4와 ERK 및 NF-${\kappa}B$가 관여함을 의미한다.

• Journal of Veterinary Science
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• 제24권1호
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• pp.2.1-2.14
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• 2023

Background: Hypothermia is a crucial environmental factor that elevates the risk of cardiovascular disease, but the underlying effect is unclear. Objectives: This study examined the role of cold stress (CS) in cardiac injury and its underlying mechanisms. Methods: In this study, a chronic CS-induced myocardial injury model was used; mice were subjected to chronic CS (4℃) for three hours per day for three weeks. Results: CS could result in myocardial injury by inducing the levels of heat shock proteins 70 (HSP70), enhancing the generation of creatine phosphokinase-isoenzyme (CKMB) and malondialdehyde (MDA), increasing the contents of tumor necrosis factor-α (TNF-α), high mobility group box 1 (HMGB1) interleukin1b (IL-1β), IL-18, IL-6, and triggering the depletion of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Multiple signaling pathways were activated by cold exposure, including pyroptosis-associated NOD-like receptor 3 (NLRP3)-regulated caspase-1-dependent/Gasdermin D (GSDMD), inflammation-related toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)-mediated nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK), as well as oxidative stressinvolved thioredoxin-1/thioredoxin-interacting protein (Txnip) signaling pathways, which play a pivotal role in myocardial injury resulting from hypothermia. Conclusions: These findings provide new insights into the increased risk of cardiovascular disease at extremely low temperatures.

• 한국식품영양과학회지
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• 제46권2호
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• pp.267-272
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• 2017

본 연구에서는 팔미틴산을 처리한 지방간질환 간세포 모델과 비만/당뇨 동물 모델인 KK/HlJ 마우스를 이용하여 피세아테놀과 레스베라트롤 투여가 염증조절에 주는 영향을 알아보고자 하였다. 4주간의 피세아테놀과 레스베라트롤 섭취는 공복혈당과 경구당부하 검사 2시간 후 AUC를 감소시켜 혈당 조절 개선 효과를 보였다. 또한, 팔미틴산을 처리한 지방간질환 간세포 모델에 피세아테놀과 레스베라트롤을 처리한 결과 염증조절 경로인자인 TLR4와 $NF-{\kappa}B$의 발현을 유의적으로 감소시켰다. 이를 in vivo 비만/당뇨 동물 모델인 KK/HlJ 마우스의 간 조직에서 확인한 결과 피세아테놀 섭취는 NLRP3와 $NF-{\kappa}B$의 간 조직에서의 발현을 유의적으로 감소시켰고, IL-1 발현을 감소시키는 경향을 보였다. 하지만 동량의 레스베라트롤 섭취는 이와 같은 항염증 효과를 보이지 않았다. 결론적으로 혈당 조절 개선 효과와 항염증 효과에 있어 피세아테놀이 레스베라트롤보다 우수한 효과를 가지고, 피세아테놀의 항염증 효과는 혈당 조절 개선 효과에 부분적으로 기여할 것으로 제안한다.

• The Korean Journal of Physiology and Pharmacology
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• 제25권3호
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• pp.217-225
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• 2021

Neuropathic pain (NP) that contributes to the comorbidity between pain and depression is a clinical dilemma. Neuroinflammatory responses are known to have potentially important roles in the initiation of NP and depressive mood. In this study, we aimed to investigate the effects of paeoniflorin (PF) on NP-induced depression-like behaviors by targeting the hippocampal neuroinflammation through the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. We used a murine model of NP caused by unilateral sciatic nerve cuffing (Cuff). PF was injected intraperitoneally once a day for a total of 14 days. Pain and depression-like behavior changes were evaluated via behavioral tests. Pathological changes in the hippocampus of mice were observed by H&E staining. The levels of proinflammatory cytokines in the hippocampus were detected using ELISA. Activated microglia were measured by immunohistochemical staining. The TLR4/NF-κB signaling pathway-associated protein expression in the hippocampus was detected by western blotting. We found that the PF could significantly alleviate Cuff-induced hyperalgesia and depressive behaviors, lessen the pathological damage to the hippocampal cell, reduce proinflammatory cytokines levels, and inhibit microglial over-activation. Furthermore, PF downregulated the expression levels of TLR4/NF-κB signaling pathway-related proteins in the hippocampus. These results indicate that PF is an effective drug for improving the comorbidity between NP and depression.

• Molecules and Cells
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• 제45권4호
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• pp.257-272
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• 2022

In addition to inducing apoptosis, caspase inhibition contributes to necroptosis and/or autophagy depending on the cell type and cellular context. In macrophages, necroptosis can be induced by co-treatment with Toll-like receptor (TLR) ligands (lipopolysaccharide [LPS] for TLR4 and polyinosinic-polycytidylic acid [poly I:C] for TLR3) and a cell-permeable pan-caspase inhibitor zVAD. Here, we elucidated the signaling pathways and molecular mechanisms of cell death. We showed that LPS/zVAD- and poly I:C/zVAD-induced cell death in bone marrow-derived macrophages (BMDMs) was inhibited by receptor-interacting protein kinase 1 (RIP1) inhibitor necrostatin-1 and autophagy inhibitor 3-methyladenine. Electron microscopic images displayed autophagosome/autolysosomes, and immunoblotting data revealed increased LC3II expression. Although zVAD did not affect LPS- or poly I:C-induced activation of IKK, JNK, and p38, it enhanced IRF3 and STAT1 activation as well as type I interferon (IFN) expression. In addition, zVAD inhibited ERK and Akt phosphorylation induced by LPS and poly I:C. Of note, zVAD-induced enhancement of the IRF3/IFN/STAT1 axis was abolished by necrostatin-1, while zVAD-induced inhibition of ERK and Akt was not. Our data further support the involvement of autocrine IFNs action in reactive oxygen species (ROS)-dependent necroptosis, LPS/zVAD-elicited ROS production was inhibited by necrostatin-1, neutralizing antibody of IFN receptor (IFNR) and JAK inhibitor AZD1480. Accordingly, both cell death and ROS production induced by TLR ligands plus zVAD were abrogated in STAT1 knockout macrophages. We conclude that enhanced TRIF-RIP1-dependent autocrine action of IFNβ, rather than inhibition of ERK or Akt, is involved in TLRs/zVAD-induced autophagic and necroptotic cell death via the JAK/STAT1/ROS pathway.

• Asian Pacific Journal of Cancer Prevention
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• 제15권15호
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• pp.6145-6150
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• 2014

Toll-like receptors (TLRs) are expressed in immune and tumor cells and recognize pathogen-associated molecular patterns. Cervical cancer (CC) is directly linked to a persistent infection with high risk human papillomaviruses (HR-HPVs) and could be associated with alteration of TLRs expression. TLR9 plays a key role in the recognition of DNA viruses and better understanding of this signaling pathway in CC could lead to the development of novel immunotherapeutic approaches. The present study was undertaken to determine the level of TLR9 expression in cervical neoplasias from Tunisian women with 53 formalin-fixed and paraffin-embedded specimens, including 22 samples of invasive cervical carcinoma (ICC), 18 of cervical intraepithelial neoplasia (CIN), 7 of condyloma and 6 normal cervical tissues as control cases. Quantification of TLR9 expression was based on scoring four degrees of extent and intensity of immunostaining in squamous epithelial cells. TLR9 expression gradually increased from CIN1 (80% weak intensity) to CIN2 (83.3% moderate), CIN3 (57.1% strong) and ICC (100% very strong). It was absent in normal cervical tissue and weak in 71.4% of condyloma. The mean scores of TLR9 expression were compared using the Kruskall-Wallis test and there was a statistical significance between normal tissue and condyloma as well as between condyloma, CINs and ICC. These results suggest that TLR9 may play a role in progression of cervical neoplasia in Tunisian patients and could represent a useful biomarker for malignant transformation of cervical squamous cells.

• Journal of Microbiology and Biotechnology
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• 제26권12호
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• pp.2214-2223
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• 2016

Toll-like receptors (TLRs) can recognize conserved molecular patterns and initiate a wide range of innate and adaptive immune responses against invading infectious agents. The aim of this study was to assess the transcript profile of mink TLRs (mTLRs) in mink peripheral blood mononuclear cells (PBMCs) and a range of tissues, and to explore the potential role of mTLRs in the antiviral immune response process. The results indicated that the mTLR partial nucleotide sequences had a high degree of nucleotide identity with ferret sequences (95-98%). Phylogenetic analysis showed that mammalian TLRs grouped into five TLR families, with a closer relationship of the mTLRs with those of ferret than the other mammalian sequences. Moreover, all the mTLRs were ubiquitously expressed in lymphoid organs (spleen and lymph nodes) and PBMCs. Interestingly, the mTLR expression patterns in lung, uterus, and heart showed quite a lot of similarity. Another remarkable observation was the wide expression of mTLR1-3 mRNAs in all tissues. Among the analyzed tissues, skeletal muscle was revealed to being the lowest repertoire of mTLR expression. Additionally, mink PBMCs exposed to the canine distemper virus revealed significant upregulation of mTLR2, mTLR4, mTLR7, and mTLR8 mRNAs, indicating that mTLRs have a role in innate immunity in the mink. Collectively, our results are the first to establish the basic expression patterns of mTLRs and the relationship between mTLRs and a virus, which will contribute to better understanding of the evolution and the functions of mTLRs in the innate immune system in minks.

• 농업과학연구
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• 제49권1호
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• pp.11-18
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• 2022

A disrupted immune system during pregnancy is involved in pregnancy complications, such as spontaneous abortion, preeclampsia, and recurrent pregnancy loss. This study examined the role of toll-like receptor (TLR) 4 and ASC (apoptosis-associated speck-like protein containing a CARD [c-terminal caspase recruitment domain]) in pregnancy complications using a lipopolysaccharide (LPS)-induced miscarriage mice model. Incidences of miscarriage and embryonic resorption were examined at 9.5 days of pregnancy in wild-type (WT), ASC knockout (KO), and TLR4 KO mice after injecting them with LPS. The fetuses and placenta were obtained after sacrifice at 15.5 days of pregnancy. A significantly lower frequency of fetus absorption was found in TLR4 KO mice, whereas corresponding absorption outcomes were strongly induced in the WT and ASC KO mice upon an LPS injection. As expected, TLR4 KO mice were resistant to LPS-induced abortion. A histological analysis of the miscarried placenta showed increasing levels of the eosin staining of spongiotrophoblast cells without any obvious difference between WT and ASC KO mice. These results suggest that TLR4 KO mice are resistant to LPS, which affects pregnancy persistence, whereas WT and ASC KO mice show high miscarriage rates due to LPS. Moreover, the ASC adaptor is not directly involved in LPS-induced miscarriages, and the NLRP3 inflammasome can be activated by other proteins in the absence of ASC.

• 한국균학회지
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• 제46권2호
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• pp.161-176
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• 2018

진균류 유래의 ${\beta}$-glucan은 pathogen-associated molecular patterns의 일종이기도 하며 면역촉진과 항암작용을 나타냄이 알려져 있지만 세포 내 신호전달에 관해서는 알려진 바가 많지 않다. 대식세포주인 RAW264.7 세포에 불로초에서 추출한 ${\beta}$-glucan을 처리하였을 때 세포막에서는 덱틴-1, toll-like receptor 2, 4, 6의 발현이 증가되었으며, 세포 내에서는 macrophage inflammatory protein (MIP)-1a, MIP-$1{\beta}$, MIP-$1{\gamma}$, IL-$1{\beta}$ 그리고 tumor necrosis factor (TNF)-${\alpha}$의 발현이 증가되었다. 또한 대식세포주에 불로초의 ${\beta}$-glucan과 PI3K 또는 MEK1/MEK2 억제제를 각각 처리하였을 때에 세포 내의 MIP-1a, MIP-$1{\beta}$, MIP-$1{\gamma}$, interleukin-$1{\beta}$, TNF-${\alpha}$의 발현이 감소되었다. 따라서 불로초의 ${\beta}$-glucan은 대식세포에서 MyD88의 경로인 PI3K/Akt를 경유할 뿐만 아니라 MEK 경로를 활성화시킴으로써 다양한 면역조절작용이 가능한 것으로 여겨진다.