• Title/Summary/Keyword: NFAT2

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Beneficial effects of naringenin and morin on interleukin-5 and reactive oxygen species production in BALB/c mice with ovalbumin-induced asthma

  • Qi, Peng;Wei, Chunhua;Kou, Dianbo
    • The Korean Journal of Physiology and Pharmacology
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    • v.25 no.6
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    • pp.555-564
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    • 2021
  • We investigated the effects of naringenin and morin on IL-5 and ROS production in PMA+ionomycin-treated EL-4 cells with the corroboration of their antioxidant and anti-inflammatory properties using an asthma-induced mouse model. The EL-4 cell line was used to study the outcomes of naringenin or morin, followed by cell viability studies. Western blot analysis and ELISA test were used to determine Th2 mediated cytokines. In vivo studies were carried out on BALB/c mice to induce allergic asthma using ovalbumin administered intraperitoneally. Intracellular ROS was determined using 2',7'-dichlorodihydrofluorescein diacetate, followed by serum enzymatic (AST and ALT) estimations and inflammatory cell count in the bronchoalveolar lavage fluid (BALF) and lung tissues. Histopathological studies were conducted to examine lung tissue-stained architecture. Our findings suggested that naringenin and morin significantly suppressed IL-5 and ROS production via various pathways. Interestingly, by reducing NFAT activity, naringenin and morin stimulated HO-1 expression, thereby suppressing IL-5 secretion due to regulating the transcription factor Nrf2 via P13/Akt or ERK/JNK signalling pathways in EL-4 cells, demonstrating the involvement of HO-1 expression in inhibiting asthmatic inflammation. The increased inflammatory cells in the BALF were substantially decreased by both naringenin and morin, followed by inhibition in the elevated Th-2 cytokines levels. The TNF-α protein levels in an allergic asthma mouse model were significantly reduced by suppressing Akt phosphorylation and eosinophil formation. Recent findings confirmed that naringenin and morin possess the potential to control asthma-related immune responses through antioxidant and anti-inflammatory properties, indicating potential therapeutic agents or functional foods.

Effect of Co-administration of Aconiti Lateralis Preparata Radix and Cinnamomi Cortex on Osteoclast Differentiation (부자와 육계 병용투여 시 파골세포 분화 억제에 미치는 영향)

  • Jung, Gi-Eun;Kim, Jung Young;Kim, Ji-Hoon;Han, Sang-Yong;Kim, Yun-Kyung
    • The Korea Journal of Herbology
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    • v.29 no.2
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    • pp.61-67
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    • 2014
  • Objectives : Aconiti Lateralis Preparata Radix (Aconitum Carmichaeli, AC) and Cinnamomi Cortex (Cinnamomi Cortex, CC) have been treated to elderly for kidney yang enhancement in Korean traditional medicine. In this study, the effects of water extract of AC and CC on RANKL (Receptor Activator for Nuclear Factor ${\kappa}B$ Ligand)-induced osteoclast differentiation were evaluated in culture system. Methods : MTT assay was used to evaluate the potential cytotoxicity of AC and CC extracts in bone macrophage marrows (BMMs) stimulated with M-CSF. TRAP (tartrate-resistant acid phosphatase) staining and TRAP activity were performed to know the inhibitory effect on osteoclast differentiation. The protein expression levels of nuclear factors such as activated T cell(NFAT)c1, c-Fos, MAPKs and ${\beta}$-actin in cell lysates treated with AC and CC extracts were analysed by western blotting. Results : AC, CC extracts and their co-administration inhibited significantly RANKL-induced osteoclast differentiation in BMMs in a dose dependent manner without toxicity. Each AC and CC extracts inhibited the phosphorylation of p38. Also, AC and CC extracts, respectively, inhibited the protein expression of c-Fos and NFATc1 more than Co-administration of AC and CC even if all treatments did. It was observed that RANKL-induced degradation of I-${\kappa}B$ is significantly suppressed by all treatments. Conclusions : Taken together, It was concluded that AC and CC have beneficial effect on osteoporosis by inhibition of osteoclast differentiation. Thus, Atractylodis AC and CC could be a treatment option for osteoporosis.

Signaling Through the Murine T Cell Receptor Induces IL-17 Production in the Absence of Costimulation, IL-23 or Dendritic Cells

  • Liu, Xikui K.;Clements, James L.;Gaffen, Sarah L.
    • Molecules and Cells
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    • v.20 no.3
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    • pp.339-347
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    • 2005
  • IL-17 (IL-17A or CTLA-8) is the founding member of a novel family of inflammatory cytokines, and emerging evidence indicates that it plays a central role in inflammation and autoimmunity. IL-17 is made primarily, if not exclusively by T cells, but relatively little is known about how its expression is regulated. In the present study, we examined the requirements and mechanisms for IL-17 expression in primary mouse lymphocytes. Like many cytokines, IL-17 is induced rapidly in primary T cells after stimulation of the T cell receptor (TCR) through CD3 crossinking. Surprisingly, however, the pattern of regulation of IL-17 is different in mice than in humans, because "costimulation" of T cells through CD28 only mildly enhanced IL-17 expression, whereas levels of IL-2 were dramatically enhanced. Similarly, several other costimulatory molecules such as ICOS, 4-1BB and CD40L exerted only very weak enhancing effects on IL-17 production. In agreement with other reports, IL-23 enhanced CD3-induced IL-17 expression. However, IL-17 production can occur autonomously in T cells, as neither dendritic cells nor IL-23 were necessary for promoting short-term production of IL-17. Finally, to begin to characterize the TCR-mediated signaling pathway(s) required for IL-17 production, we showed that IL-17 expression is sensitive to cyclosporin-A and MAPK inhibitors, suggesting the involvement of the calcineurin/NFAT and MAPK signaling pathways.

Increase in Intracellular Calcium is Necessary for RANKL Induction by High Extracellular Calcium

  • Jun, Ji-Hae;Kim, Hyung-Keun;Woo, Kyung-Mi;Kim, Gwan-Shik;Baek, Jeong-Hwa
    • International Journal of Oral Biology
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    • v.30 no.1
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    • pp.9-15
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    • 2005
  • Recently, we reported that high extracellular calcium increased receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL) expression via p44/42 mitogen-activated protein kinase (p44/42 MAPK) activation in mouse osteoblasts. However, the mechanism for p44/42 MAPK activation by high extracellular calcium is unclear. In this study, we examined the role of intracellular calcium increase in high extracellular calcium-induced RANKL induction and p44/42 MAPK activation. Primary cultured mouse calvarial osteoblasts were used. RANKL expression was highly induced by 10 mM calcium treatment. Ionomycin, a calcium ionophore, also increased RANKL expression and activated p44/42 MAPK. U0126, an inhibitor of MEK1/2, an upstream activator of p44/42 MAPK, blocked the RANKL induction by both high extracellular calcium and ionomycin. High extracellular calcium increased the phosphorylation of proline-rich tyrosine kinase 2 (Pyk2), one of the known upstream regulators of p44/42 MAPK activation. Bisindolylmaleimide, an inhibitor of protein kinase C, did not block RANKL induction and p44/42 MAPK activation induced by high extracellular calcium. 2-Aminoethoxydiphenyl borate, an inhibitor of inositol 1,4,5-trisphosphate (IP3) receptor, blocked the RANKL induction by high extracellular calcium. It also partially suppressed the activation of Pyk2 and p44/42 MAPK. Cyclosporin A, an inhibitor of calcineurin, also inhibited high calcium-induced RANKL expression in dose dependent manner. However, cyclosporin A did not affect the activation of Pyk2 and p44/42 MAPK by high extracellular calcium treatment. These results suggest that 1) the increase in intracellular calcium via IP3-mediated calcium release is necessary for RANKL induction by high extracellular calcium treatment, 2) Pyk2 activation, but not protein kinase C, following the increase in intracellular calcium might be involved in p44/42 MAPK activation, and 3) calcineurin-NFAT activation by the increase in intracellular calcium is involved in RANKL induction by high extracellular calcium treatment.

Effects of Sulraphane on Osteoclastogenesis in RAW 264.7 (RAW 264.7 세포에서 sulforaphane의 파골세포형성 저해효과)

  • Hwang, Joon-Ho;Yi, Mi-Ran;Kang, Chang-Hee;Bu, Hee-Jung
    • Journal of agriculture & life science
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    • v.50 no.2
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    • pp.151-160
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    • 2016
  • Inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with osteoporosis. Sulforaphane, isolated from the Broccoli(Brassica oleracea var. italia) florets, inhibits the production of inflamatory cytokine. In the present study, we determined inhibitory effect of sulforaphane on Receptor activator of nuclear factor κB ligand(RANKL)-induced osteoclast formation. Sulforaphane inhibited the expression of osteoclast marker genes, such as tartrate-resistant acid phosphatase(TRAP), cathepsin K, matrix metalloproteinase 9(MMP-9), and calcitonin receptor in RANKL-induced RAW 264.7 macrophage. Also, sluforaphane inhibited the expression of osteoclast protein, such as TRAP, MMP-9, tumor necrosis factor receptor-associated factor 6(TRAF6) and transcription factor nuclease factor of activated T cells(NFAT)c1. Sulforaphane inhibited RANKL-induced activiation of nuclear factor kappaB(NF-kappaB) by suppression RANKL-mediated NF-kappaB transcriptional acitivation. We are confirmed that sulforaphane inhibits not only transcriptional activity of NF-kappaB but also expressions of the osteoclastogenesis factors(TRAP, cathepsin K, MMP-9, calcitonin, TRAF6) and trranscription factor NFATc1.

Effect of Water Extract of Cynanchi Wilfordii Radix in RANKL-induced Osteoclast Differentiation (백하수오(白何首烏) 물 추출물의 파골세포 분화에 미치는 영향)

  • Ahn, Yong-Hwan;Oh, Jae-Min;Lee, Myeung-Su;Jung, Jong-Hyuk;Chae, Soo-Uk;Moon, Seo-Young;Jeon, Byung-Hoon;Choi, Min-Kyu
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.26 no.2
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    • pp.160-165
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    • 2012
  • Osteoporotic fracture became a serious social problem, which related with mortality and morbidity in old age population. Osteoclast which is responsible for bone resorption is originated from hematopoietic cell line and plays a key role osteoporotic bone loss. Cynanchum wilfordii (Asclepiadaceae) roots have been used in Korean folk medicine for the treatment of diabetes mellitus and aging progression. Also, recent studies have shown that the extract and fractions of Cynanchi Wilfordii Radix have various pharmacological actions including scavenging free radicals, enhancing immunity, reducing high serum cholesterol, and anti-tumor activity. However, the effect of extract of Cynanchi Wilfordii Radix in osteoclast differentiation had not been reported. Thus, we evaluated the effect of Cynanchi Wilfordii Radix on receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL)-induced osteoclast differentiation. Through our study, we found that Cynanchi Wilfordii Radix significantly inhibited osteoclast differentiation induced by RANKL. Cynanchi Wilfordii Radix suppressed the activation of p38 pathway and $NF{\kappa}B$ in bone marrow macrophages (BMMs) treated with RANKL. Also, Cynanchi Wilfordii Radix significantly inhibited the mRNA expression of c-Fos, tartrate-resistant acid phosphatase (TRAP), osteoclast-associated receptor (OSCAR), nuclear factor of activated T cells (NFAT)c1 and cathepsin K in BMMs treated with RANKL. Particularly, Cynanchi Wilfordii Radix inhibited the protein expression of c-fos and NFATc1. Taken together, our results demonstrated that Cynanchi Wilfordii Radix may be useful treatment option of bone-related disease such as osteoporosis leads to fracture of bone and rheumatoid arthritis.

Understanding Contemporary Interstate Rivalries: Consensus Rivalries and Rivalry Termination (숙적관계 국가들에 대한 연구 - 숙적관계 종식에 영향을 미치는 주요 요인들을 중심으로 -)

  • Oh, Soon-Kun
    • Strategy21
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    • s.32
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    • pp.222-270
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    • 2013
  • 서구 근대 국제관계학의 태동은 "전쟁의 원인"을 밝혀내려고 했던 유럽 지식인들의 학문적 도전에서부터 비롯되었다고 할 수 있다. 1, 2차 세계대전의 잔혹함을 겪으면서 이들은 전쟁(특히 전쟁의 원인)에 대한 좀 더 과학적인 연구를 통해 어떻게 하면 국가들 간의 전쟁을 예방할 수 있을까에 집중해 왔다. 이러한 학문적 경향을 반영한 것이 잘 알려진 미국 미시간 대학의 "전쟁 상관성 연구 프로젝트(Correlates of War Project)"이다. 이는 나폴레옹 전쟁이 끝나고 비엔나체제가 시작된 1815년 이후 국가들 간 발생한 모든 전쟁 관련 자료를 데이터베이스화하여,국제관계학자들이 전쟁(Interstate War)이나 군사분쟁(Militarized Interstate Disputes)을 정량 또는 정성적으로 연구할 수 있도록 다양한 정보들을 제공하고 있다. 최근 Paul F. Diehl, William R. Thompson과 같은 학자들은 전쟁을 분석단위로 하는 전쟁의 원인(Causes of War)을 연구하는 학풍에서 벗어나, 국가들 간의 분쟁과 전쟁을 연구하기 위해 숙적관계(Rivalry)라는 새로운 분석의 단위를 제시하였다. 숙적관계는 국제관계에 있어서 지속적으로 분쟁 또는 전쟁을 일으키는, 즉 무력분쟁의 긴 역사를 가지고 있는, 두 국가를 일컫는다. 국가들 간의 숙적관계는 학자들에 따라 Interstate Rivalry, Enduring Rivalry, Strategic Rivalry 등 다양한 정의와 성격을 갖고 있다. 이러한 국가들의 사례로는 2차대전 이전까지 프랑스-독일 관계, 2차대전 이후 중동지역 이스라엘과 아랍국가들 간의 관계, 냉전기 미소관계, 인도-파키스탄 및 남북한 관계 등을 예로 들 수 있다. 이렇게 널리 알려진 숙적관계 외에도 남미의 칠레-아르헨티나, 에콰도르-페루와 아프리카의 소말리아-에티오피아 등 학자들에 따라 1815년 이후 약 200개의 숙적관계를 제시하고 있다. 숙적관계에 대한 연구는 기존의 전쟁의 원인 중심이었던 정량적 국제분쟁 연구에 두 국가의 분쟁역사를 포함시키는 정성적 연구를 접합시키고 있다. 본 연구는 1945년 이후 숙적관계 국가들의 관계종식과 관련하여, 거시론적이고 전체론적 접근방법(Macro - level Holistic Approach)을 제시하고 있다. 먼저 1945년 이후 발생한 국가들 간의 숙적관계 종식(Rivalry Termination)을 이해하기 위해, 거시적 관점에서 숙적관계를 발생시키게 된 역사적 원인을 살펴보고 있다. 특히 1945년 이후 숙적관계와 관련된 중요한 요인들 중에서 전쟁, 영토분쟁, 그리고 근대국가 형성에 대해 살펴보고 다음과 같은 두 가지 명제(proposition)를 제시한다. 첫째, 1945년 이후의 숙적관계 형성과 지속에는 2차대전 이후 독립국가 형성, 헌팅턴이 주장한 제3의 물결(민주화), 그리고 냉전기 미소경쟁 등의 역사적 배경이 영향을 주었다는 것이다. 둘째, 이러한 역사적 배경에 더하여 1945년 이후 숙적관계는 전쟁에 의해 시작된 숙적관계와 전쟁 없이 시작된 숙적관계 등 2가지로 나눌 수 있으며, 전쟁에 의해 시작되고 영토분쟁과 근대국가 형성 문제를 내포하고 있는 숙적관계가 그렇지 않은 숙적관계에 비해 오랫동안 지속되며 관계해결이 어렵다는 것이다. 앞서 제시된 2가지 명제들과 관련하여 본문에서는 다양한 학자들이 제시한 숙적관계 정의들에 일치하는 23개의 숙적관계(Consensus Rivalries)를 선정하여 이들에 대한 비교분석(Descriptive Analysis)을 실시하였다. 이들 사례들을 1945년 이전과 이후로 나누어, 숙적관계 형성과 종식에 있어 핵심요소인 국가들 간 힘의 차이(Power Relations), 분쟁의 주요 원인(Primary Conflict Issue), 숙적관계에 있어 다른 국가들과의 연계성(Rivalry Linkage), 전쟁의 횟수와 시기 등을 통해 비교하였다. 숙적관계의 종식과 관련하여 약소국 간의 숙적관계(Minor Dyad)가 오래 지속되고, 영토분쟁(Territorial Disputes)이 숙적관계를 지속시키는 주요인이며, 다른 숙적관계와의 연계성이 적은 숙적들이 오래 지속된다는 비교분석 결과가 나왔다. 또한 전쟁의 횟수는 숙적관계 종식에 큰 영향을 미치지 못하지만 전쟁으로 인해 시작된 숙적관계가 그렇지 않은 경우보다 더욱 오래 지속되는 것으로 확인되었다. 끝으로 2차대전 이전의 숙적관계는 대부분 전쟁을 통해 종식되었지만, 1945년 이후에는 전쟁 없이도 숙적관계가 종식된 경우가 많았음을 보여 주고 있다. 본 연구의 주목적은 "1945년 이후 형성된 숙적관계를 어떻게 종식시킬 수 있을 것인가?"라는 규범적 논제를 통해, 23개의 주요 숙적관계를 발굴하여 거시적, 역사적 관점에서 비교분석함에 있다. 이는 특히 우리나라가 처한 현실과 관련하여 중요한 시사점을 갖는다. 남북관계가 갖는 특수성보다는 1945년 이후 국제정치 역사속에서 발생한 숙적관계 현상이라는 일반성의 틀에서 남북관계를 이해하고자 했다. 남북관계를 베트남, 예멘, 독일 등 분단국가의 사례들과만 비교 연구하는 제한된 시각에서 벗어나, 인도-파키스탄, 그리스-터키, 에콰도르-페루 등 유사한 숙적들 간의 관계들과 비교하는 새로운 연구의 장을 제시하고자 한다. 따라서 앞으로 숙적관계 종식에 대한 더욱 다양화된 사례연구를 통해 한반도 분쟁해결에 필요한 새로운 교훈을 얻을 수 있을 것이다. 예를 들면 2차대전 이후 발생한 국경을 접하고 있는 비강대국들의 평화적인 숙적관계 종식에 대한 사례연구는 남북한이 앞으로 지향해야 할 방향을 제시해 줄 수 있을 것이다. 끝으로 본 연구는 특정한 정책적 함의를 도출하기 보다는 숙적관계와 관련된 하나의 거시적 이론를 제시하고, 주요 숙적관계 국가들에 대한 비교설명을 통해 현존하는 숙적관계 해결을 위한 하나의 분석의 틀을 제시하는 것으로 국제분쟁 연구에 기여하고자 하였다.

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