• Molecules and Cells
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• 제37권8호
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• pp.598-604
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• 2014

Fatty acids, important components of a normal diet, have been reported to play a role in bone metabolism. Osteoclasts are bone-resorbing cells that are responsible for many bone-destructive diseases such as osteoporosis. In this study, we investigated the impact of a medium-chain fatty acid, capric acid, on the osteoclast differentiation, function, and survival induced by receptor activator of NF-${\kappa}B$ ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Capric acid inhibited RANKL-mediated osteoclastogenesis in bone marrow-derived macrophages and suppressed RANKL-induced $I{\kappa}B{\alpha}$ phosphorylation, p65 nuclear translocation, and NF-${\kappa}B$ transcriptional activity. Capric acid further blocked the RANKL-stimulated activation of ERK without affecting JNK or p38. The induction of NFATc1 in response to RANKL was also attenuated by capric acid. In addition, capric acid abrogated M-CSF and RANKL-mediated cytoskeleton reorganization, which is crucial for the efficient bone resorption of osteoclasts. Capric acid also increased apoptosis in mature osteoclasts through the induction of Bim expression and the suppression of ERK activation by M-CSF. Together, our results reveal that capric acid has inhibitory effects on osteoclast development. We therefore suggest that capric acid may have potential therapeutic implications for the treatment of bone resorption-associated disorders.

• Molecules and Cells
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• 제40권10호
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• pp.706-713
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• 2017

Osteoclasts are bone-resorbing cells that are derived from hematopoietic precursor cells and require macrophage-colony stimulating factor and receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL) for their survival, proliferation, differentiation, and activation. The binding of RANKL to its receptor RANK triggers osteoclast precursors to differentiate into osteoclasts. This process depends on RANKL-RANK signaling, which is temporally regulated by various adaptor proteins and kinases. Here we summarize the current understanding of the mechanisms that regulate RANK signaling during osteoclastogenesis. In the early stage, RANK signaling is mediated by recruiting adaptor molecules such as tumor necrosis factor receptorassociated factor 6 (TRAF6), which leads to the activation of mitogen-activated protein kinases (MAPKs), and the transcription factors nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and activator protein-1 (AP-1). Activated NF-${\kappa}B$ induces the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is the key osteoclastogenesis regulator. In the intermediate stage of signaling, the co-stimulatory signal induces $Ca^{2+}$ oscillation via activated phospholipase $C{\gamma}2$ ($PLC{\gamma}2$) together with c-Fos/AP-1, wherein $Ca^{2+}$ signaling facilitates the robust production of NFATc1. In the late stage of osteoclastogenesis, NFATc1 translocates into the nucleus where it induces numerous osteoclast-specific target genes that are responsible for cell fusion and function.

• Molecules and Cells
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• 제40권10호
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• pp.752-760
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• 2017

A2B adenosine receptor (A2BAR) is known to be the regulator of bone homeostasis, but its regulatory mechanisms in osteoclast formation are less well-defined. Here, we demonstrate the effect of A2BAR stimulation on osteoclast differentiation and activity by RANKL. A2BAR was expressed in bone marrow-derived monocyte/macrophage (BMM) and RANKL increased A2BAR expression during osteoclastogenesis. A2BAR stimulation with its specific agonist BAY 60-6583 was sufficient to inhibit the activation of ERK1/2, p38 MAP kinases and $NF-{\kappa}B$ by RANKL as well as it abrogated cell-cell fusion in the late stage of osteoclast differentiation. Stimulation of A2BAR suppressed the expression of osteoclast marker genes, such as c-Fos, TRAP, Cathepsin-K and NFATc1, induced by RANKL, and transcriptional activity of NFATc1 was also inhibited by stimulation of A2BAR. A2BAR stimulation caused a notable reduction in the expression of Atp6v0d2 and DC-STAMP related to cell-cell fusion of osteoclasts. Especially, a decrease in bone resorption activity through suppression of actin ring formation by A2BAR stimulation was observed. Taken together, these results suggest that A2BAR stimulation inhibits the activation of ERK1/2, p38 and $NF-{\kappa}B$ by RANKL, which suppresses the induction of osteoclast marker genes, thus contributing to the decrease in osteoclast cell-cell fusion and bone resorption activity.

• Journal of Periodontal and Implant Science
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• 제23권3호
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• pp.454-460
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• 1993

Abnormalities of the T cell subsets have been detected in the immunologically mediated disease sites such as periodontal lesions which are attributable to the regulatory effect of cell differentiation and specific chemokinetic effect of various cytokines. Macrophage Inflammatory protein$(MIP)-1{\alpha}$ and gammain terferon$({\gamma}-IFN)$ serve as important immunoregulatory molecules through which growth and differentiation of specific T cell subsets are known to be negatively regulated. Murine cytolytic T cell line CTLL-2 were used to perform the [$^3H$]-thymidine incorporation test, by which we obtained more comprehensive view in regulatory actions of cytokines on the T cell subset proliferation. 1. $rMIP-{\alpha}$(200ng/ml) and $r{\gamma}-IFN$(100U/ml) appreared to suppress the proliferation rate to CTLL-2 by 74 and 86% respectively, and the suppressive action of two cytokines were synergisic. 2. Culture supernatant of anti-CD3 mAb-stimulated mouse splenocyte enhanced the proliferation rate of CTLL-2 up to 10-fold with dose-dependent manner. However, culture supernatant of unstimulated splenocyte showed only 2-fold increase in the proliferation rate. 3. CTLL-2 cell proliferation was strictly IL-2 dependent.

• Journal of Ginseng Research
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• 제41권3호
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• pp.298-306
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• 2017

Background: Compound K (CK) is a bioactive derivative of ginsenoside Rb1 in Panax ginseng (Korean ginseng). Its biological and pharmacological activities have been studied in various disease conditions, although its immunomodulatory role in innate immunity mediated by monocytes/macrophages has been poorly understood. In this study, we aimed to elucidate the regulatory role of CK on cellular events mediated by monocytes and macrophages in innate immune responses. Methods: The immunomodulatory role of CK was explored by various immunoassays including cell-cell adhesion, fibronectin adhesion, cell migration, phagocytic uptake, costimulatory molecules, reactive oxygen species production, luciferase activity, and by the measurement of mRNA levels of proinflammatory genes. Results: Compound K induced cell cluster formation through cell-cell adhesion, cell migration, and phagocytic activity, but it suppressed cell-tissue interactions in U937 and RAW264.7 cells. Compound K also upregulated the surface expression of the cell adhesion molecule cluster of differentiation (CD) 43 (CD43) and costimulatory molecules CD69, CD80, and CD86, but it downregulated the expression of monocyte differentiation marker CD82 in RAW264.7 cells. Moreover, CK induced the release of reactive oxygen species and induced messenger RNA expression of proinflammatory genes, inducible nitric oxide synthase, and tumor necrosis factor-alpha by enhancing the nuclear translocation and transcriptional activities of nuclear factor kappa-B and activator protein-1. Conclusion: Our results suggest that CK has an immunomodulatory role in innate immune responses through regulating various cellular events mediated by monocytes and macrophages.

• Journal of Veterinary Science
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• 제23권4호
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• pp.47.1-47.11
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• 2022

Background: In lipopolysaccharide-induced RAW264.7 cells, Aster tataricus (AT) inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells and MAPKs pathways and critical pathways of osteoclast development and bone resorption. Objectives: This study examined how aster saponin A2 (AS-A2) isolated from AT affects the processes and function of osteoclastogenesis induced by receptor activator of nuclear factor kappa-B ligand (RANKL) in RAW264.7 cells and bone marrow macrophages (BMMs). Methods: The cell viability, tartrate-resistant acid phosphatase staining, pit formation assay, polymerase chain reaction, and western blot were carried out to determine the effects of AS-A2 on osteoclastogenesis. Results: In RAW264.7 and BMMs, AS-A2 decreased RANKL-initiated osteoclast differentiation in a concentration-dependent manner. In AS-A2-treated cells, the phosphorylation of ERK1/2, JNK, and p38 protein expression were reduced considerably compared to the control cells. In RAW264.7 cells, AS-A2 suppressed the RANKL-induced activation of osteoclast-related genes. During osteoclast differentiation, AS-A2 suppressed the transcriptional and translational expression of NFATc1 and c-Fos. AS-A2 inhibited osteoclast development, reducing the size of the bone resorption pit area. Conclusion: AS-A2 isolated from AT appears to be a viable therapeutic therapy for osteolytic illnesses, such as osteoporosis, Paget's disease, and osteogenesis imperfecta.

• Molecules and Cells
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• 제45권10호
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• pp.749-760
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• 2022

Osteoclast generation from monocyte/macrophage lineage precursor cells needs to be tightly regulated to maintain bone homeostasis and is frequently over-activated in inflammatory conditions. PARK2, a protein associated with Parkinson's disease, plays an important role in mitophagy via its ubiquitin ligase function. In this study, we investigated whether PARK2 is involved in osteoclastogenesis. PARK2 expression was found to be increased during the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. PARK2 gene silencing with siRNA significantly reduced osteoclastogenesis induced by RANKL, LPS (lipopolysaccharide), TNFα (tumor necrosis factor α), and IL-1β (interleukin-1β). On the other hand, overexpression of PARK2 promoted osteoclastogenesis. This regulation of osteoclastogenesis by PARK2 was mediated by IKK (inhibitory κB kinase) and NF-κB activation while MAPK (mitogen-activated protein kinases) activation was not involved. Additionally, administration of PARK2 siRNA significantly reduced osteoclastogenesis and bone loss in an in vivo model of inflammatory bone erosion. Taken together, this study establishes a novel role for PARK2 as a positive regulator in osteoclast differentiation and inflammatory bone destruction.

• IMMUNE NETWORK
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• 제24권2호
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• pp.14.1-14.26
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• 2024

The inflammatory response during cutaneous leishmaniasis (CL) involves immune and non-immune cell cooperation to contain and eliminate Leishmania parasites. The orchestration of these responses is coordinated primarily by CD4⁺ T cells; however, the disease outcome depends on the Th cell predominant phenotype. Although Th1 and Th2 phenotypes are the most addressed as steers for the resolution or perpetuation of the disease, Th17 cell activities, especially IL-17 release, are recognized to be vital during CL development. Th17 cells perform vital functions during both acute and chronic phases of CL. Overall, Th17 cells induce the migration of phagocytes (neutrophils, macrophages) to the infection site and CD8⁺ T cells and NK cell activation. They also provoke granzyme and perforin secretion from CD8⁺ T cells, macrophage differentiation towards an M2 phenotype, and expansion of B and Treg cells. Likewise, immune cells from the inflammatory infiltrate have modulatory activities over Th17 cells involving their differentiation from naive CD4⁺ T cells and further expansion by generating a microenvironment rich in optimal cytokines such as IL-1β, TGF-β, IL-6, and IL-21. Th17 cell activities and synergies are crucial for the resistance of the infection during the early and acute stages; however, if unchecked, Th17 cells might lead to a chronic stage. This review discusses the synergies between Th17 cells and the inflammatory infiltrate and how these interactions might destine the course of CL.

• 생명과학회지
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• 제33권3호
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• pp.295-303
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• 2023

면역 체계와 대사 체계는 항상성을 유지하는데 중요한 요소이다. 면역 반응과 대사 조절은 연관성이 높아, 정상적인 대사가 교란되면 대사 질환이 발생하며, 면역 반응에도 변화가 발생하였다. 마찬가지로, 비만은 면역 반응과 높은 관련이 있다. 에너지 대사의 불균형으로 발생하는 비만은 인슐린 저항성, 제2형 당뇨병, 지방간 질환, 동맥경화증, 고혈압 등의 대사 질환과 관련이 있다. 알려진 바로는, 비만은 낮은 수준의 염증이 만성화된 상태가 특징이다. 비만 환경에서, 면역세포의 미세 환경은 대식세포, 자연살해세포, T세포 같은 면역세포의 독특한 활성화 표현형에 의해 염증성이 되었다. 또한, 면역 세포는 세포 간의 기전, 사이토카인을 매개하는 기전을 통해 상호작용하여 비만으로 인한 염증 반응을 강화한다. 이러한 현상은 기존의 췌장 리파아제나 알파-아밀라아제 같은 체내 효소의 억제나 지방전구세포의 분화를 억제를 표적으로 하는 일반적인 비만의 약리학적 치료 외에 면역세포 활성화 조절을 표적으로 하는 비만의 약리학적 치료 전략을 시사한다. 본 논문에서는 대식세포, 자연살해세포, T세포의 활성화 표현형과 비만 환경 내이들의 양상에 대해 정리하였다. 또한, 본 논문에서는 현재까지 확인된 면역세포의 활성화 조절을 통한 비만을 완화하는 약리학적 물질에 대해서 정리하였다.

• Journal of Periodontal and Implant Science
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• 제40권3호
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• pp.119-124
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• 2010

Purpose: In addition to regulating body weight, leptin is also recognized for its role in the regulation of immune function and inflammation. The purpose of this study was to investigate the effect of leptin on Prevotella (P.) intermedia lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-$\alpha$ production in differentiated THP-1 cells, a human monocytic cell line. Methods: LPS from P. intermedia ATCC 25611 was prepared by the standard hot phenol-water method. THP-1 cells were incubated in the medium supplemented with phorbol myristate acetate to induce differentiation into macrophage-like cells. The amount of TNF-$\alpha$ and interleukin-8 secreted into the culture medium was determined by enzyme-linked immunosorbent assay (ELISA). TNF-$\alpha$ and Ob-R mRNA expression levels were determined by semi-quantitative reverse transcription-polymerase chain reaction analysis. Results: Leptin enhanced P. intermedia LPS-induced TNF-$\alpha$ production in a dose-dependent manner. Leptin modulated P. intermedia LPS-induced TNF-$\alpha$ expression predominantly at the transcriptional level. Effect of leptin on P. intermedia LPS-induced TNF-$\alpha$ production was not mediated by the leptin receptor. Conclusions: The ability of leptin to enhance P. intermedia LPS-induced TNF-$\alpha$ production may be important in the establishment of chronic lesion accompanied by osseous tissue destruction observed in inflammatory periodontal disease.