• Title/Summary/Keyword: IL-10$IFN-{\gamma}$

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Skin Barrier Recovery by Protease-Activated Receptor-2 Antagonist Lobaric Acid

  • Joo, Yeon Ah;Chung, Hyunjin;Yoon, Sohyun;Park, Jong Il;Lee, Ji Eun;Myung, Cheol Hwan;Hwang, Jae Sung
    • Biomolecules & Therapeutics
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    • v.24 no.5
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    • pp.529-535
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    • 2016
  • Atopic dermatitis (AD) results from gene and environment interactions that lead to a range of immunological abnormalities and breakdown of the skin barrier. Protease-activated receptor 2 (PAR2) belongs to a family of G-protein coupled receptors and is expressed in suprabasal layers of the epidermis. PAR2 is activated by both trypsin and a specific agonist peptide, SLIGKV-$NH_2$ and is involved in both epidermal permeability barrier homeostasis and epithelial inflammation. In this study, we investigated the effect of lobaric acid on inflammation, keratinocyte differentiation, and recovery of the skin barrier in hairless mice. Lobaric acid blocked trypsin-induced and SLIGKV-$NH_2$-induced PAR2 activation resulting in decreased mobilization of intracellular $Ca^{2+}$ in HaCaT keratinocytes. Lobaric acid reduced expression of interleukin-8 induced by SLIGKV-$NH_2$ and thymus and activation regulated chemokine (TARC) induced by tumor necrosis factor-a (TNF-${\alpha}$) and IFN-${\gamma}$ in HaCaT keratinocytes. Lobaric acid also blocked SLIGKV-$NH_2$-induced activation of ERK, which is a downstream signal of PAR2 in normal human keratinocytes (NHEKs). Treatment with SLIGKV-$NH_2$ downregulated expression of involucrin, a differentiation marker protein in HaCaT keratinocytes, and upregulated expression of involucrin, transglutamase1 and filaggrin in NHEKs. However, lobaric acid antagonized the effect of SLIGKV-$NH_2$ in HaCaT keratinocytes and NHEKs. Topical application of lobaric acid accelerated barrier recovery kinetics in a SKH-1 hairless mouse model. These results suggested that lobaric acid is a PAR2 antagonist and could be a possible therapeutic agent for atopic dermatitis.

The Role of Uteroglobin in the Immunomodulation of Nonsmall Cell Lung Cancer Cells (비소세포 폐암세포에서 Uteroglobin의 면역 조절 기능에 대한 연구)

  • Yoon, Jung Min;Lim, Jae-Jun;Yoo, Chul-Gyu;Lee, Choon-Taek;Han, Sung Koo;Shim, Young-Soo;Kim, Young Whan
    • Tuberculosis and Respiratory Diseases
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    • v.57 no.4
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    • pp.336-344
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    • 2004
  • Background : Immunotherapy for cancer has not been successful because of several obstacles in tumor and its environment. Inappropriate secretions of cytokines and growth factors by tumors cause substantial changes in the immune responses against tumors, affording the tumors some degree of protection from immune attack. Uteroglobin (UG, Clara cell secretory protein) has been known to have anti-inflammatory, immunomodulatory and anti-cancer activities. However, in lung cancer cells, UG expression is decreased. This study investigated the role of UG in the immunomodulation of lung cancer. Methods : The UG protein was overexpressed by Adenovirus(Ad)-UG transduction in non-small cell lung cancer cell lines. The concentration of Prostaglandin $E_2$ ($PGE_2$) was measured by Enzyme Immunoassay (EIA). Peripheral blood mononuclear cells (PBMC) from whole blood were prepared with Ficoll. PBMC were cultured in RPMI 1640, supernatant of A549, or A549 with UG or NS-398. Concentration of Th 1 type and Th 2 type cytokines from PBMC were measured by ELISA. Results : UG suppressed $PGE_2$, Cyclooxygenase-2 (COX-2) product. Both Th1 type such as Interleukin-2 (IL-2), Interferon-${\gamma}$ (IFN-${\gamma}$) and Tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and Th2 type cytokines such as IL-10 and Tumor growth factor-${\beta}$ (TGF-${\beta}$) were increased when PBMC were cultured with supernatant of non small lung cancer cells. UG and COX-2 inhibitor, NS-398 induced normal immune response of PBMC. Although Th 1 type cytokines were increased, Th 2 type cytokines were reduced by UG. Conclusion : UG suppressed PGE2, COX-2 product. Supernatant of NSCLC induced imbalance of immune response of PBMC. However, UG reversed this imbalance. These results suggest that UG may be used in the development of immunotherapy for lung cancer.

Medicinal Herb Extracts Attenuate 1-Chloro-2,4dinitrobenzene-induced Development of Atopic Dermatitis-like Skin Lesions (한약재 단일 추출물 및 복합 추출물을 이용한 아토피성 피부염 억제 효과)

  • Lee, Moon Hee;Han, Min Ho;Yoon, Jung Jeh;Song, Myung Kyu;Kim, Min Ju;Hong, Su Hyun;Choi, Byung Tae;Kim, Byung Woo;Hwang, Hye Jin;Choi, Yung Hyun
    • Journal of Life Science
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    • v.24 no.8
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    • pp.851-859
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    • 2014
  • The present study was designed to investigate whether ethanol extracts of Sophora flavescens (GS), Glycyrrhiza uralensis (GC), Dictamnus dasycarpus (BSP), and their mixtures (GGB-1, -2, -3, and -4) inhibit 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD) in a mouse model. DNCB was topically applied on the dorsal surface of Balb/c mice to induce AD-like skin lesions. The pathological phenotypes of AD, such as erythema, ear thickness, edema, scabs, and discharge, were significantly decreased in the GGB (DNCB + GS:GC:BSP = 3:1:1 mixture)-1-treated groups compared with the other treated groups. The weight of the spleen in immune organs was significantly decreased in the GGB-1-treated groups, whereas the weight of the liver in a control group was similar to that of the groups treated with the samples. Furthermore, toluidine blue staining analysis, a method used to specifically identify mast cells, showed that master cell infiltration into the dermis of the GGB-1-treated group was significantly decreased. The immunoglobulin E concentration was lower in the GGB-1-treated group. In addition, the levels of inflammatory cytokines (interferon-${\gamma}$, interleukin-1, 4, 5, 6, and 13, $1{\beta}$, and tumor necrosis factor-${\alpha}$) were also significantly reduced in the GGB-1-treated group. Taken together, these results suggest that a mixture of GS, GC, and BSP in a proportion of 3:1:1 (GGB-1) may contribute to the relief of AD symptoms and may be considered an excellent candidate for an AD therapeutic drug.

Comparative study on efficacies and ingredient contents of different solvent extracts of Insampaedok-san (인삼패독산의 추출용매에 따른 성분함량 및 효능연구)

  • Lim, Hye-Sun;Ha, Hyekyung;Seo, Chang-Seob;Jin, Seong Eun;Kim, Yeji;Jeon, Woo-Young;Yoo, Sae-Room;Shin, In-Sik;Kim, Jung-Hoon;Kim, Seong-Sil;Shin, Na Ra;Lee, Mee-Young;Jeong, Soo-Jin;Kim, Ohn Soon;Shin, Hyeun-Kyoo
    • The Korea Journal of Herbology
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    • v.27 no.6
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    • pp.115-122
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    • 2012
  • Objectives : This study evaluated activities and ingredient contents concerning extracts according to extraction solvents of Insampaedok-san (IS, Renshen bai du-san). Methods : The herbal constituents of IS were extracted with water and 70% ethanol at $100^{\circ}C$ for 2 hr. Using the HPLC system, the six ingredient contents of different solvent extracts of IS were analyzed. The nitric oxide (NO), prostaglandin $E_2$ ($PGE_2$) production and proinflammatory cytokines were measured in RAW264.7 cells stimulated with lipopolysaccharide (LPS). The macrophage-derived chemokine (MDC/CCL22) and regulated on activation normal T-cell expression and secreted (RANTES/CCL5) production were measured in HaCaT and BEAS-2B cells stimulated tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and interferon-${\gamma}$ (IFN-${\gamma}$). The activities of glycerol-3-phosphate dehydrogenase (GPDH) and leptin level were measured in 3T3-L1 cells. Results : The calibration curves showed good linearity ($r^2$=1.0000) for different concentration ranges. The contents of liquiritin, naringin, hesperidin, neohesperirin and glycyrrizin in 70% ethanol extracts of IS were relatively higher than that of water extract, however the content of ferulic acid in 70% ethanol and water extract of IS were similar. The extraction solvents of water and 70% ethanol were evaluated inhibitory effect on the production of NO, $PGE_2$, TNF-${\alpha}$ and IL-6 in RAW 264.7 cells. Their extractions were inhibitory effect on production of MDC/CCL22 and RANTES/CCL5 in HaCaT cell and BEAS-2B cell, respectively. In addition, evaluated reduced on GPDH activity and leptin level in 3T3-L1 preadipocyte cell. Conclusions : Our results suggest that IS extracts were inhibitory effects of disease such as inflammation, allergies and obesity.

Effect of High Purity β-1.3/1.6-Glucan on Macrophages, Natural Killer Cells, and T Cell-Mediated Factors (고순도 β-1.3/1.6-Glucan이 대식세포 및 자연살해세포와 T 세포면역계에 미치는 영향)

  • Kwon, Hanol;Lee, Minhee;Park, Soo-Jeung;Lee, Dasom;Kim, Hyesook;Lee, Jeongmin
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.45 no.11
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    • pp.1564-1570
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    • 2016
  • The present study investigated the immunomodulatory effects of high-purity ${\beta}$-1.3/1.6-glucan on macrophages, natural killer (NK) cells, and T cell-mediated factors. Effect of high-purity ${\beta}$-1.3/1.6-glucan on cytotoxicity in macrophages was investigated. Using macrophages, cytotoxicity of high-purity ${\beta}$-1.3/1.6-glucan was evaluated by MTT assay. We treated high-purity ${\beta}$-1.3/1.6-glucan at concentrations of 10, 50, 100, 150, 200, and $250{\mu}g/mL$ in macrophages. High-purity ${\beta}$-1.3/1.6-glucan did not affect macrophage viability. Phagocytic activity was assessed using zymosan. Activity of high-purity ${\beta}$-1.3/1.6-glucan on macrophages significantly increased as compared with zymosan. We treated high-purity ${\beta}$-1.3/1.6-glucan to murine NK cells co-incubated with YAC-1 cells. High-purity ${\beta}$-1.3/1.6-glucan resulted in significantly increased activity of NK cells as compared with the control. In addition, treatment of macrophages with high-purity ${\beta}$-1.3/1.6-glucan resulted in significantly increased activity of T cell-mediated cytokine (IL-2, IL-12, $IFN-{\gamma}$, and $TNF-{\alpha}$) levels and CD4+/CD8+ T cells as compared with the control. In conclusion, high-purity ${\beta}$-1.3/1.6-glucan could enhance the immune response through activation of macrophages, NK cells, and T cell-mediated factors.

The Role of Lymphocyte Compartment and Cytokine in Coal Workers Pneumoconiosis (진폐증환자에서의 임파구 분획 및 싸이토카인의 역할)

  • Lee, Jung-Yeon;Yoo, Kwang-Ha;Ahn, Hae-Ryon;Kim, Sung-Ryul;Lee, Hae-Woon;Ahn, Cheol-Min;Kim, Hyung-Joong
    • Tuberculosis and Respiratory Diseases
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    • v.52 no.3
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    • pp.241-250
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    • 2002
  • Background : Coal-worker's pneumoconiosis(CWP) is characterized by a chronic inflammatory lung reaction associated with macrophage accumulation in the alveolar spaces. CWP is usually divided into two stage : simple pneumoconiosis(SP) where there are a limited number of fibrotic lesions remain limited, with radiological opacities smaller than 1cm and progressive massive fibrosis(PMF), which is characterized by the development of a perifocal extensive fibrotic response of the lung and severe alterations in pulmonary function. In this study, the lymphocyte compartment and cytokine were evaluated by measuring the serum levels in the control, SP and PMF groups. Materials and Methods : The coal workers selected for this study were employees(patients?) of the Tae-Baek and Dong-Hae hospital. All were men, 45-76 years old and the mean duration of their exposure to coal dust was 23.2 years in the lymphocyte compartment and 24.3 years in the cytokine checked group. According to X-ray examination results, the patients were classified into either one of the SP, PMF categories. The normal controls examined were 26-70 years old men. The serum cytokine levels were estimated by using an end point enzyme immunoassay technique. Results : T lymphocyte, helper and suppressor T cells were highly related to pneumoconiosis in this study. A statistically significant decrease in the number of suppressor T lymphocytes was observed in the simple pneumoconiosis patients and at the same time, there was an increase in the lymphocyte index. Howevere, there was no statistically difference in the serum cytokines levels among the SP, PMF and control groups. Conclusion : T lymphocyte, helper T, and suppressor T cells may be highly related to the development of CWP compared to the control group particularly in the early stage of pneumoconiosis. The changes observed in the immunological system in patients with pneumoconiosis may lie at the bottom of the pathogenesis of fibrosis. Further study is needed to evaluate the lymphocyte compartment as a marker for pneumoconiosis development in the early stage.

The Effects of Bee Venom and Melittin Solution on PGE2, COX-2, and NF-kB Dependent Luciferase Activity in RAW 264.7 Cells (봉약침액(蜂藥鍼液)과 Melittin 약침액(藥鍼液)이 RAW 264.7 세포의 PGE2, COX-2 및 NF-kB에 미치는 영향(影響))

  • Jeong, Il-kook;Song, Ho-sueb
    • Journal of Acupuncture Research
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    • v.21 no.6
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    • pp.19-36
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    • 2004
  • Objective : The purpose of this study was to investigate the effect of Bee Venom and Melittin Solution on the lipopolysaccharide(LPS) and sodium nitroprusside(SNP)-induced expression of prostaglandin $E_2(PGE_2)$, cyclooxygenase-2(COX-2), nuclear factor kappa B($NF-{\kappa}B$) and nuclear factor kappa B($NF-{\kappa}B$) dependent luciferase activity in RAW 264.7 cells, a murine macrophage cell line. Methods : The expression of PGE2 was determined by determination of $PEG_2$, COX-2 was by western blotting with corresponding antibodies, $NF-{\kappa}B$ was by gel mobility shift assay method and $NF-{\kappa}B$ dependent luciferase activity was investigated by luciferase assay in RAW 264.7 cells. Results : 1. LPS and SNP-induced expression of $PEG_2$ was significant after 24hour. 2. The 0.5, 1 and $5{\mu}g/mL$ of bee venom and the 5 and $10{\mu}g/mL$ of melittin solution inhibited significantly LPS-induced expression of $PEG_2$ and, the $5{\mu}g/mL$ of bee venom and the 5 and $10{\mu}g/mL$ of melittin solution inhibited significantly SNP-induced expression of $PEG_2$ compared with control, respectively. The 0.5 and $1{\mu}g/mL$ of bee venom could not significantly inhibit SNP-induced expression of $PEG_2$ compared with control. 3. The $5{\mu}g/mL$ of bee venom and the 5 and $10{\mu}g/mL$ of melittin solution inhibited significantly LPS and SNP-induced expression of COX-2 compared with control, respectively. The 0.5 and $1{\mu}g/mL$ of bee venom inclined to decrease LPS and SNP-induced expression of COX-2 compared with control. 4. The 0.5, 1 and $5{\mu}g/mL$ of bee venom and the 5 and $10{\mu}g/mL$ of melittin solution inhibited significantly LPS and SNP-induced expression of $NF-{\kappa}B$ compared with control, respectively. 5. The 0.5, 1 and $5{\mu}g/mL$ of bee venom and the 5 and $10{\mu}g/mL$ of melittin solution inhibited significantly LPS-induced expression of $NF-{\kappa}B$ dependent luciferase activity and the 1 and $5{\mu}g/mL$ of bee venom and the 5 and $10{\mu}g/mL$ of melittin solution inhibited significantly SNP-induced expression of $NF-{\kappa}B$ dependent luciferase activity compared with control, respectively. The $NF-{\kappa}B$ inhibitor also inhibited significantly LPS and SNP-induced expression of $NF-{\kappa}B$ dependent luciferase activity compared with control. 6. The 0.5, 1 and $5{\mu}g/mL$ of bee venom and the 5 and $10{\mu}g/mL$ of melittin solution inhibited significantly LPS + IFN-${\gamma}$, TNF-${\alpha}$ and LPS + TNF-${\alpha}$-induced expression of $NF-{\kappa}B$ dependent luciferase activity compared with control, respectively. The $NF-{\kappa}B$ inhibitor also inhibited significantly LPS and SNP-induced expression of $NF-{\kappa}B$ dependent luciferase activity compared with control. Conclusions : These results suggest the inhibitory action of bee venom and melittin solution on the inflammatory mediators such as $PEG_2$, COX-2 and $NF-{\kappa}B$.

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홍삼 유래 성분들의 면역조절 효능

  • Jo, Jae-Yeol
    • Food preservation and processing industry
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    • v.8 no.2
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    • pp.6-12
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    • 2009
  • 면역반응은 외부 감염원으로부터 신체를 보호하고 외부감염원을 제거하고자 하는 주요항상성 유지기전의 하나이다. 이들 반응은 골수에서 생성되고 비장, 흉선 및 임파절 등에서 성숙되는 면역세포들에 의해 매개된다. 보통 태어나면서부터 얻어진 선천성 면역반응을 매개하는 대식세포, 수지상 세포 등과, 오랜기간 동안 감염된 다양한 면역원에 대한 경험을 토대로 얻어진 획득성 면역을 담당하는 T 임파구 등이 대표적인 면역세포로 알려져 있다. 다양한 면역질환이 최근 주요 사망률의 원인이 되고 있다. 최근, 암, 당뇨 및 뇌혈관질환 등이 생체에서 발생되는 급 만성염증에 의해 발생된다고 보고됨에 따라 면역세포 매개성 염증질환에 대한 치료제 개발을 서두르고 있다. 또한 암환자의 급격한 증가는 암발생의 주요 방어기전인 면역력 증강에 대한 요구들을 가중시키고 있다. 예로부터 사용되어 오던 고려인삼과 홍삼은 기를 보호하고 원기를 회복하는 명약으로 알려진 대표적인 우리나라 천연생약이다. 특별히, 홍삼은 단백질과 핵산의 합성을 촉진시키고, 조혈작용, 간기능 회복, 혈당강하, 운동수행 능력증대, 기억력 개선, 항피로작용 및 면역력 증대에 매우 효과가 좋은 것으로 보고되고 있다. 홍삼에 관한 많은 연구에 비해, 현재까지 홍삼이 면역력 증강에 미치는 효과에 대한 분자적 수준에서의 연구는 매우 미미한 것으로 확인되어져 있다. 홍삼의 투여는 NK 세포나 대식세포의 활성이 증가하고 항암제의 암세포 사멸을 증가시키는 것으로 확인되어졌다. 현재까지 알려진 주요 면역증강 성분은 산성다당류로 보고되었다. 또 한편으로 일부 진세노사이드류에서 항염증 효능이 확인되어졌으며, 이를 통해 피부염증 반응과 관절염에 대한 치료 효과가 있는 것으로 추측되고 있다 [본 연구는 KT&G 연구출연금 (2009-2010) 지원을 받아 이루어졌기에 이에 감사드린다]. 면역반응은 외부 감염물질의 침입으로 유도된 질병환경을 제거하고 수복하는 중요한 생체적 방어작용의 하나이다. 이들 과정은 체내로 유입된 미생물이나 미세화학물질들과 같은 독성물질을 소거하거나 파괴하는 것을 주요 역할로 한다. 외부로 부터 인체에 들어온 이물질에 대한 방어기전은 현재 두 가지 종류의 면역반응으로 구분해서 설명한다. 즉, 선천성 면역 반응 (innate immunity)과 후천성 면역 반응 (adaptive immunity)이 그것이다. 선천성 면역반응은 1) 피부나 점막의 표면과 같은 해부학적인 보호벽 구조와 2) 체온과 낮은 pH 및 chemical mediator (리소자임, collectin류) 등과 같은 생리적 방어구조, 3) phagocyte류 (대식세포, 수지상세포 및 호중구 등)에 의한 phagocytic/endocytic 방어, 그리고 4) 마지막으로 염증반응을 통한 감염에 저항하는 면역반응 등으로 구분된다. 후천성 면역반응은 획득성면역이라고도 불리고 특이성, 다양성, 기억 및 자기/비자기의 인식이라는 네 가지의 특징을 가지고 있으며, 외부 유입물질을 제거하는 반응에 따라 체액성 면역 반응 (humoral immune response)과 세포성 면역반응 (cell-mediated immune response)으로 구분된다. 체액성 면역은 침입한 항원의 구조 특이적으로 생성된 B cell 유래 항체와의 반응과 간이나 대식세포 등에서 합성되어 분비된 혈청내 보체 등에 의해 매개되는 반응으로 구성되어 있다. 세포성 면역반응은 T helper cell (CD4+), cytotoxic T cell (CD8+), B cell 및antigen presenting cell 중개를 통한 세포간 상호 작용에 의해 발생되는 면역반응이다. 선천성 면역반응의 하나인 염증은 우리 몸에서 가장 빈번히 발생되고 있는 방어작용의 하나이다. 예를 들면 감기에 걸렸을 경우, 환자의 편도선내 대식세포나 수지상세포류는 감염된 바이러스 단독 혹은 동시에 감염된 박테리아를 상대로 다양한 염증성 반응을 유도하게 된다. 또한, 상처가 생겼을 경우에도 감염원을 통해 유입된 병원성 세균과 주위조직내 선천성 면역담당 세포들 간의 면역학적 전투가 발생되게 된다. 이들 과정을 통해, 주위 세포나 조직이 손상되면, 즉각적으로 이들 면역세포들 (주로 phagocytes류)은 신속하게 손상을 극소화하고 더 나가서 손상된 부위를 원상으로 회복시키려는 일련의 염증반응을 유도하게 된다. 이들 반응은 우리가 흔히 알고 있는 발적 (redness), 부종 (swelling), 발열 (heat), 통증 (pain) 등의 증상으로 나타나게 된다. 즉, 손상된 부위 주변에 존재하는 모세혈관에 흐르는 혈류의 양이 증가하면서 혈관의 직경이 늘어나게 되고, 이로 인한 조직의 홍반과, 부어 오른 혈관에 의해 발열과 부종이 초래되는 것이다. 확장된 모세혈관의 투과성 증가는 체액과 세포들이 혈관에서 조직으로 이동하게 하는 원동력이 되고, 이를 통해 축적된 삼출물들은 단백질의 농도를 높여, 최종적으로 혈관에 존재하는 체액들이 조직으로 더 많이 이동되도록 유도하여 부종을 형성시킨다. 마지막으로 혈관 내 존재하는 면역세포들은 혈판 내벽에 점착되고 (margination), 혈관벽의 간극을 넓히는 역할을 하는 히스타민 (histamine)이나 일산화질소(nitric oxide : NO), 프로스타그린딘 (prostagladins : PGE2) 및 류코트리엔 (leukotriens) 등과 같은 chemical mediator의 도움으로 인해 혈관벽 사이로 삼출하게 되어 (extravasation), 손상된 부위로 이동하여 직접적인 외부 침입 물질의 파괴나 다른 면역세포들을 모으기 위한 cytokine (tumor necrosis factor [TNF]-$\alpha$, interleukin [IL]-1, IL-6 등) 혹은 chemokine (MIP-l, IL-8, MCP-l등)의 분비 등을 수행함으로써 염증반응을 매개하게 된다. 염증과정시 발생되는 여러 mediator 중 PGE2나 NO 및 TNF-$\alpha$ 등은 실험적 평가가 용이하여 이들 mediator 자체나 생성관련효소 (cyclooxygenase [COX] 및 nitric oxide synthase [NOS] 등)들은 현재항염증 치료제의 개발 연구시 주요 표적으로 연구되고 있다. 염증 반응은 지속기간에 따라 크게 급성염증과 만성염증으로 나뉘며, 삼출물의 종류에 따라서는 장액성, 섬유소성, 화농성 및 출혈성 염증 등으로 구분된다. 급성 염증 (acute inflammation)반응은 수일 내지 수주간 지속되는 일반적인 염증반응이라고 볼 수 있다. 국소반응은 기본징후인 발열과 발적, 부종, 통증 및 기능 상실이 특징적이며, 현미경적 소견으로는 혈관성 변화와 삼출물 형성이 주 작용이므로 일명 삼출성 염증이라고 한다. 만성 염증 (chronic inflammation)은, 급성 염증으로부터 이행되거나 만성으로 시작된다. 염증지속 기간은 보통 4주 이상 장기화 된다. 보통 염증의 경우에는 염증 생성 cytokine인 Th1 cytokine (IL-2, interferone [IFN]-$\gamma$ 및 TNF-$\alpha$ 등)의 생성 후, 거의 즉각적으로 항 염증성 cytokine인 Th2 cytokine(IL-4, IL-6, IL-10 및 transforming growth factor [TGF]-$\beta$ 등)이 생성되어 정상반응으로 회복된다. 그러나, 어떤 원인에서든 면역세포에 의한 염증원 제거 반응이 문제가 되면, 만성염증으로 진행된다. 이 반응에 주로 작용을 하는 염증세포로는 단핵구와 대식세포, 림프구, 형질세포 등이 있다. 암은 전세계적으로 사망률 1위의 원인이 되는 면역질환의 하나이다. 산화적 스트레스나 자외선 조사 혹은 암유발 물질들에 의해 염색체내 protooncogene, tumor-suppressor gene 혹은 DNA repairing gene의 일부 DNA의 돌연변이 혹은 결손 등이 발행되면 정상세포는 암화과정을 시작하게 된다. 양성세포 수준에서 약 5에서 10여년 후 악성수준의 암세포가 생성되게 되면 이들 세포는 새로운 환경을 찾아 전이하게 되는데 이를 통해 암환자들은 다양한 장기에 동인 오리진의 암세포들이 생성한 종양들을 가지게 된다. 이들 종양세포는 정상 장기의 기능을 손상시켜며 결국 생명을 잃게 만든다. 이들 염색체 수준에서의 돌연변이 유래 암세포는 거의 대부분이 체내 면역시스템에 의해 사멸되는 것으로 알려져 있다. 그러나 계속되는 스트레스나 암유발 물질의 노출은 체내 면역체계를 파괴하면서 최후의 방어선을 무너뜨리면서 암발생에 무방비 상태를 만들게 된다. 이런 이유로 체내 면역시스템의 정상적 가동 및 증강을 유도하게 하는 전략이 암예방시 매우 중요한 표적으로 인식되면서 다양한 형태의 면역증강 물질 개발을 시도하고 있다. 인삼은 두릅나무과의 여러해살이 풀로써, 오랜동안 한방 및 민간에서 원기를 회복시키고, 각종 질병을 치료할 수단으로 사용되고 있는 대표적인 전통생약이다. 예로부터 불로(不老), 장생(長生), 익기(益氣), 경신(經身)의 명약으로 구전되어졌는데, 이는 약 2천년 전 중국의 신농본초경(神農本草經)에서 "인삼은 오장(五腸)을 보하고, 정신을 안정시키고, 혼백을 고정하며 경계를 멈추게 하고, 외부로부터 침입하는 병사를 제거하여주며, 눈을 밝게 하고 마음을 열어 더욱 지혜롭게 하고 오랫동안 복용하면 몸이 가벼워지고 장수한다" 라고 기술되어있는 데에서 유래한 것이다. 다양한 연구를 통해 우리나라에서 생산되는 고려인삼 (Panax ginseng)이 효능 면에서 가장 탁월한 것으로 알려져 있으며 특별이 고려인삼으로부터 제조된 고려홍삼은 전세계적으로도 그 효능이 우수한 것으로 보고되어 있다. 대부분의 홍삼 약효는 dammarane계열의 triterpenoid인 ginsenosides라고 불리는 인삼 saponin에 의해 기인된 것으로 알려져 있다. 이들 화합물군의 기본 골격에 따라, protopanaxadiol (PD)계 (22종) 및 protopanaxatriol (PT)계 (10종)으로 구분되고 있다 (표 1). 실험적 접근을 통해 인삼의 약리작용 이해를 위한 다양한 노력들이 경주되고 있으나, 여전히 많은 부분에서 충분히 이해되고 있지 않다. 그러나, 현재까지 연구된 인삼의 약리작용 관련 연구들은 심혈관, 당뇨, 항암 및 항스트레스 등과 같은 분야에서 인삼효능이 우수한 것으로 보고하고 있다. 그러나 면역조절 및 염증현상과 관련된 최근 연구결과들은 많지 않으나, 향후 다양하게 연구될 효능부분으로 인식되고 있다.

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A Co-inhibitory Molecule, B7-H4, Synergistically Potentiates Oral Tolerance by Inducing CD4+CD25+FoxP3+ T Cells

  • Wen, Lanying;Yang, Sung-Yeun;Choi, Jae-Kyoung;Kim, Young-Hee;Kwon, Eun-Hee;Lee, Hyun-Ji;Jeoung, Hae-Young;Hwang, Du-Hyeon;Hwang, Dong-Jin;Choi, In-Hak
    • IMMUNE NETWORK
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    • v.8 no.1
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    • pp.21-28
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    • 2008
  • Background: A co-inhibitory molecule, B7-H4, is believed to negatively regulate T cell immunity by suppressing T cell proliferation and inhibiting cytokine production. However, the mechanism behind B7-H4-mediated tolerance remains unclear. Methods: Balb/c $(H-2^d)$ mice were fed with dendritic cell line, DC2.4 $(H-2^d)$ every day for 10 days. Meantime, mice were hydrodynamically injected with recombinant plasmid expressing B7-H4 fusion protein (B7-H4.hFc) or hFc via tail vein. One day after last feeding, mice were immunized with allogeneic B6 spleen cells. 14 days following immunization, mice were challenged with B6 spleen cells to ear back and the ear swelling was determined the next day. Subsequently, a mixed lymphocyte reaction (MLR) was also performed and cytokines profiles from the reaction were examined by sandwich ELISA. Frequency of immunosuppressive cell population was assayed with flow cytometry and mRNA for FoxP3 was determined by RT-PCR. Results: Tolerant mice given plasmid expressing B7-H4.hFc showed a significant reduction in ear swelling compared to control mice. In addition, T cells from mice given B7-H4.hFc plasmid revealed a significant hyporesponsiveness of T cells against allogeneic spleen cells and showed a significant decrease in Th1 and Th2 cytokines such as IFN-${\gamma}$, IL-5, and TNF-${\alpha}$. Interestingly, flow cytometric analysis showed that the frequency of CD4+CD25+FoxP3+ Tregs in spleen was increased in tolerant mice given recombinant B7-H4.hFc plasmid compared to control group. Conclusion: Our results demonstrate that B7-H4 synergistically potentiates oral tolerance induced by allogeneic cells by increasing the frequency of FoxP3+ CD4+CD25+ Treg and reducing Th1 and Th2 cytokine production.

Chemoprevention of Helicobacter pylori-associated Gastric Carcinogenesis in a Mouse Model; Is It Possible?

  • Hahm, Ki-Baik;Song, Young-Joon;Oh, Tae-Young;Lee, Jeong-Sang;Surh, Young-Joon;Kim, Young-Bae;Yoo, Byung-Moo;Kim, Jin-Hong;Ha, Sang-Uk;Nahm, Ki-Taik;Kim, Myung-Wook;Kim, Dae-Yong;Cho, Sung-Won
    • BMB Reports
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    • v.36 no.1
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    • pp.82-94
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    • 2003
  • Although debates still exist whether Helicobacter pylori infection is really class I carcinogen or not, H. pylori has been known to provoke precancerous lesions like gastric adenoma and chronic atrophic gastritis with intestinal metaplasia as well as gastric cancer. Chronic persistent, uncontrolled gastric inflammations are possible basis for ensuing gastric carcinogenesis and H. pylori infection increased COX-2 expressions, which might be the one of the mechanisms leading to gastric cancer. To know the implication of long-term treatment of antiinflammatory drugs, rebamipide or nimesulide, on H. pylori-associated gastric carcinogenesis, we infected C57BL/6 mice with H. pylori, especially after MNU administration to promote carcinogenesis and the effects of the long-term administration of rebamipide or nimesulide were evaluated. C57BL/6 mice were sacrificed 50 weeks after H. pylori infection. Colonization rates of H. pylori, degree of gastric inflammation and other pathological changes including atrophic gastritis and metaplasia, serum levels and mRNA transcripts of various mouse cytokines and chemokines, and NF-${\kappa}B$ binding activities, and finally the presence of gastric adenocarcinoma were compared between H. pylori infected group (HP), and H. pylori infected group administered with long-term rebamipide containing pellet diets (HPR) or nimesulide mixed pellets (HPN). Gastric mucosal expressions of ICAM-1, HCAM, MMP, and transcriptional regulations of NF-${\kappa}B$ binding were all significantly decreased in HPR group than in HP group. Multi-probe RNase protection assay showed the significantly decreased mRNA levels of apoptosis related genes and various cytokines genes like IFN-$\gamma$, RANTES, TNF-$\alpha$, TNFR p75, IL-$1{\beta}$ in HPR group. In the experiment designed to provoke gastric cancer through MNU treatment with H. pylori infection, the incidence of gastric carcinoma was not changed between HP and HPR group, but significantly decreased in HPN group, suggesting the chemoprevention of H. pylori-associated gastric carcinogenesis by COX-2 inhibition. Long-term administration of antiinflammatory drugs should be considered in the treatment of H. pylori since they showed the molecular and biologic advantages with possible chemopreventive effect against H. pylori-associated gastric carcinogenesis. If the final concrete proof showing the causal relationship between H. pylori infection and gastric carcinogenesis could be obtained, that will shed new light on chemoprevention of gastric cancer, that is, that gastric/cancer could be prevented through either the eradication of H. pylori or lessening the inflammation provoked by H. pylori infection in high risk group.