• IMMUNE NETWORK
• /
• 제3권4호
• /
• pp.310-319
• /
• 2003

Inflammatory mediators has been recognized as an important role in the pathogenesis of rheumatoid arthritis (RA). IL-17 is increasingly recognized as an important regulator of immune and inflammatory responses, including induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence of the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. However, the signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in the regulation of IL-17 production in RA. PBMC were separated from RA (n=24) patients, and stimulated with various agents (anti CD3, anti CD28, PHA, ConA, IL-15). IL-17 levels were determined by sandwich ELISA and RT-PCR. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody, PHA, IL-15 or MCP-1 (P<0.05). ConA also strongly induced IL-17 production (P<0.001), whereas TNF-alpha, IL-1beta, IL-18 or TGF-beta did not. IL-17 was detected in the PBMC of patients with osteoarthritis (OA) but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K-Akt pathway and activation of the PI3K-Akt pathway resulted in a pronounced augmentation of nuclear factor kappaB ($NF-{\kappa}B$). IL-17 production by activated PBMC in RA is completely or partially blocked in the presence of $NF-{\kappa}B$ inhibitor PDTC and PI3K-Akt inhibitor, wortmannin and LY294002, respectively. Whereas the inhibition of AP-1 and extracellular signal-regulated kinase (ERK)1/2 did not affect IL-17 production. These results provide new insight into that PI3K/Akt and $NF-{\kappa}B$ dependent signal transduction pathway could be involved in the overproduction of key inflammatory cytokine, IL-17 in rheumatoid arthritis.

• 한국환경성돌연변이발암원학회지
• /
• 제22권2호
• /
• pp.112-124
• /
• 2002

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to exert detrimental toxicities on various organ systems including reproductive, cardiovascular, nervous, or dermal system. Immunomodulatory effects of TCDD is thymic atrophy, downregulation of cytotoxic T or B lymphocyte differentiation and activation, which were demonstrated using experimental animals, whereas immunotoxicity in human has not been investigated well. This study was proceeded to evaluate general immunologic spectrum of the Korean Vietnam War veterans exposed to TCDD during their operation, and compare with that of the non-exposed control subjects with similar age. Regarding composition and quantity, immune cells in peripheral blood collected from the TCDD-exposed was not much different from those of the control except decreased red blood cell, hemoglobin and hematocrit level. Furthermore, plasma IgG2, G3, and G4 isotype distribution was similar between two groups, but IgG1 level was significantly lowered in the TCDD-exposed, indicating a TCDD-mediated functional alteration of B cells. Significantly enhanced level of IgE in plasma, a hallmark of dermal or respiratory allergic response, was also observed in the TCDD-exposed compared with that of the control. Elevated generation of IL-4 and IL-10 was resulted from in vitro stimulation of T cells with PMA plus ionomycin or PHA, respectively, from the TCDD-exposed in comparison to those of the control, suggesting a skewed type-2 response. In addition, the level of IFN${\gamma}$, a multifunctional cytokine for T cell-mediated immunity, was lowered in the TCDD-exposed with upregulation of tumor necrosis factor $\alpha$. The present study suggests that TCDD exposure disturbs immunohomeostasis in humans observed as an aberrant plasma IgE and IgG1 levels and dysregulation of T cell activities.

• 생명과학회지
• /
• 제19권10호
• /
• pp.1444-1450
• /
• 2009

본 연구를 통해 BALB/c 마우스에서 quercetin의 경구투여가 PCL로 유도된 접촉성 피부 알레르기의 예방에 미치는 효과에 대해 알아보았다. Quercetin을 투여 농도에 따라 대조군(0 mg/kg), 저용량군(50 mg/kg), 고용량군(100 mg/kg)으로 나누고 8일에 걸쳐 총 8번 경구투여를 실시한 후 알레르기 유발물질인 PCL을 마우스의 양쪽 귀에 감작시켜 접촉성 피부 알레르기를 유발 시켰다. Quercetin의 투여 농도별 ear swelling 변화를 확인한 결과 quercetin을 투여하지 않은 대조군에 비해 quercetin을 투여한 군의 ear swelling 증가폭이 낮게 나타났고, 100 mg/kg (고용량군)에서 농도 유의적으로 ear swelling의 증가폭이 현저히 낮게 나타났다. Quercetin의 투여 농도에 따른 혈청 내 염증성 매개 물질의 농도 변화를 알아보기 위한 IgE 및 histamine level 측정 결과에서 quercetin을 투여하지 않은 대조군에 비해 quercetin을 투여한 50 mg/kg (저용량군), 100 mg/kg (고용량군)에서 낮은 수준의 IgE, histamine 수치가 나왔다. H&E염색과 Toluidine blue stain을 통한 조직병리학적 검사결과에서 quercetin을 투여한 고용량군의 귀 두께가 대조군에 비해 얇게 관찰되었고, 비만세포의 유무를 알아보기 위한 Toluidine blue stain의 결과 대조군에 비해 고용량군에서 적은 수의 비만세포들이 관찰되었다. 따라서 ear swelling과 IgE, histamine level, 조직병리학적 결과를 종합해 봤을 때 식물성 flavonoid 성분인 quercetin은 접촉성 피부 알레르기의 예방에 상당한 효과가 있다고 판단되며, 부작용이 발생하는 기존의 치료제를 대체할 수 있는 후보 물질로써 중요한 가치가 있다고 사료된다.

• BMB Reports
• /
• 제34권5호
• /
• pp.484-488
• /
• 2001

STATs are proteins with a dual function: signal transducers in the cytoplasm and transcriptional activators in the nucleus. Among the six known major STATs (STAT1-6), STAT3 has been implicated in the widest range of signaling pathways that regulate cell growth and differentiation. As a part of our on-going investigation on the pleiotropic functions of STAT proteins, we examined the role of STAT3 as a molecular adaptor that links diverse cell growth signaling pathways. We observed that STAT3 can be specifically activated by multiple cytokines, such as IL-3, in transformed fibroblasts and IL-4 or IFN-$\gamma$ in primary immune cells, respectively. The selective activation of STAT3 in H-ras-transformed NIH3T3 cells is associated with an increased expression of phosphoserioe STAT3 in these cells, compared to the parental cells. Notably phosphoresine-STAT3 interacts with oncogenic ras, shown by immunoprecipitation and Western blots. The results suggest the role of STAT3 in rasinduced cellular transformation as a molecular adaptor linking the Jak/STAT and Ras/MAPK pathways. In primary immune cells, IL-4 and IFN-$\gamma$ each induced (in addition to the characteristic STAT6 and STAT1 homodimers) the formation of STAT3-containing complexes that bind to GAS probes, which correspond to the $Fe{\varepsilon}$ Rll and $Fe{\gamma}$ RI promoter sequences, respectively. Since IL-4 and IFN-$\gamma$ are known to counter-regulate the expression of these genes, the ability of STAT3 to form heterodimeric complexes with STAT6 or STAT1 implies its role in the fine-tuned control of genes that are regulated by IL-4 and IFN-$\gamma$.

• Clinical and Experimental Pediatrics
• /
• 제56권11호
• /
• pp.482-489
• /
• 2013

Purpose: The aim of the present study was to investigate the differences in lower airway inflammatory immune responses, including cellular responses and responses in terms of inflammatory mediators in bronchoalveolar lavage fluid (BALF) and the airway, to rhinovirus (RV) infection on asthma exacerbation by comparing a control and a murine asthma model, with or without RV infection. Methods: BALB/c mice were intraperitoneally injected with a crude extract of Dermatophagoides farinae (Df ) or phosphate buffered saline (PBS) and were subsequently intranasally treated with a crude extract of Df or PBS. Airway responsiveness and cell infiltration, differential cell counts in BALF, and cytokine and chemokine concentrations in BALF were measured 24 hours after intranasal RV1B infection. Results: RV infection increased the enhanced pause (Penh) in both the Df sensitized and challenged mice (Df mice) and PBS-treated mice (PBS mice) (P<0.05). Airway eosinophil infiltration increased in Df mice after RV infection (P<0.05). The levels of interleukin (IL) 13, tumor necrosis factor alpha, and regulated on activation, normal T cells expressed and secreted (RANTES) increased in response to RV infection in Df mice, but not in PBS mice (P<0.05). The level of IL-10 significantly decreased following RV infection in Df mice (P<0.05). Conclusion: Our findings suggest that the augmented induction of proinflammatory cytokines, Th2 cytokines, and chemokines that mediate an eosinophil response and the decreased induction of regulatory cytokines after RV infection may be important manifestations leading to airway inflammation with eosinophil infiltration and changes in airway responsiveness in the asthma model.

• 한국가금학회지
• /
• 제34권1호
• /
• pp.31-36
• /
• 2007

비태인이 산란계의 면역 반응에 어떠한 영향을 미치는지 알아보기 위하여 in vitro와 in vivo 시험을 시행하였다. 처리구당 18수씩 총 72수를 공시하였고, 비태인 0, 300, 600, 1,200 ppm 수준으로 산란계 사료에 첨가 급여하였다. 시험결과, in vitro 시험에서 비장 림프구 증식은 비태인 만을 처리하였을 때에는 증식 반응은 일어나지 않았으나 Con A와 PWM을 처리하였을 때 증식 반응은 현저하게 증가하였다. 또한 Con A만을 처리했을 때보다 Con A와 비태인을 동시에 처리했을 때 반응성이 현저하게 증가하였다. 그러나 PWM과 비태인을 동시에 처리했을 때는 PWM만을 처리했을 때와 비교해서 차이를 보이지 않았다. 사료에 비태인을 첨가 급여한 in vivo시험에서 Con A의 자극에 대한 비장 림프구 증식반응은 비태인의 첨가 수준에 따라 증가하는 경향을 보였으나 1,200 ppm 급여구에서는 대조구에 비하여 감소하는 경향을 보였다. 이러한 경향은 Con A와 함께 비태인(0.1 mM)을 처리했을 때도 동일하게 나타났다. PWM의 자극에 대한 반응은 Con A에 비하여 약하게 나타났으며 비태인 급여 수준에 따른 차이도 적게 나타났다. 비태인을 급여한 산란계 비장의 무게에서 처리구간에 통계적인 차이는 없었다. 비태인 첨가구는 대조구에 비하여 전체적으로 증가하는 경향을 보였고, 비태인 300 ppm 첨가구가 가장 높은 수치를 나타내었다. 비태인을 수준별로 급여하여 SRBC 항체가를 조사한 결과에서도 처리구간 유의적인 차이는 나타나지 않았다. 따라서 본 시험의 결과, 비태인의 처리는 in vivo 상에서 Con A로 비장 림프구의 증식을 유도한 경우 유의하게 비장 림프구의 증식을 증가시켰다.

• 한국식품과학회지
• /
• 제49권5호
• /
• pp.559-566
• /
• 2017

본 연구는 자소엽 조다당 추출물(PCP)의 면역활성에 관하여 알아보기 위하여, 선천면역계의 대표적인 면역세포인 수지상세포 및 후천면역계의 대표적인 면역세포인 비장세포에 PCP를 처리하여 면역세포의 면역활성능에 관하여 측정하였다. 수지상세포에 PCP를 1, 5 및 $10{\mu}g/mL$의 농도를 처리한 결과, 세포생존율이 $103.4{\pm}3.8$, $108.8{\pm}2.1$, $117.8{\pm}3.3%$ (n =3)로 나타나 세포독성을 유발하지 않았으며, 주요 면역활성 인자인 산화질소의 분비능을 관찰한 결과, 각각 $2.7{\pm}0.2$, $4.5{\pm}0.2$, $7.3{\pm}0.3{\mu}M$ (n =3)로 농도 의존적으로 나타났다. 농도(1, 5 및 $10{\mu}g/mL$)별 PCP 처리구에서 사이토카인의 분비능을 관찰한 결과, TNF-${\alpha}$ ($372.3{\pm}0.32$, $604.8{\pm}0.54$ 및 $954.2{\pm}1.32pg/mL$), IL-6 ($508.4{\pm}0.39$, $761.5{\pm}1.34$ 및 $1038.5{\pm}1.67pg/mL$), IL-$1{\beta}$ ($314.5{\pm}1.04$, $524.8{\pm}1.89$ 및 $664.8{\pm}0.89pg/mL$), IL-12 ($321.4{\pm}0.94$, $832.5{\pm}0.85$ 및 $901.{\pm}0.94pg/mL$)가 유의적으로 증가되는 것으로 관찰되었다. 또한 후천면역에서 중요한 역할을 수행하는 면역 T 세포가 다량으로 분포하는 비장 조직으로부터 비장세포를 분리하여 PCP를 처리하였을 때, 세포 증식능이 유의적으로 증가하였으며, 면역활성을 유도하는 Th1 세포가 분비하는 사이토카인의 함량 또한 유의적으로 증가되는 것으로 나타났다. 이러한 결과로 미루어 볼 때 PCP의 처리는 선천면역뿐만 아니라 후천면역에 관여하는 다양한 면역세포의 활성화에 직간접적으로 관여하는 것으로 사료된다. 본 연구는 자소엽조다당 추출물의 면역활성 유도 효과에 관한 가능성을 제시하였고, 향후 자소엽 조다당 추출물을 분리 및 정제과정을 통하여 구조분석 및 정제된 조다당 추출물의 정확한 면역활성과 면역활성기전에 관한 면밀한 연구가 필요할 것으로 사료된다.

• Asian-Australasian Journal of Animal Sciences
• /
• 제31권8호
• /
• pp.1366-1372
• /
• 2018

Objective: A disintegrin and metallopeptidase with thrombospondin motifs type 8 (ADAMTS8) is crucial for diverse physiological processes, such as inflammation, tissue morphogenesis, and tumorigenesis. The chicken ADAMTS8 (chADAMTS8) gene was differentially expressed in the kidney following exposure to different calcium concentrations, suggesting a pathological role of this protein in metabolic diseases. We aimed to examine the molecular characteristics of chADAMTS8 and analyze the gene-expression differences in response to toll-like receptor 3 (TLR3) stimulation. Methods: The ADAMTS8 mRNA and amino acid sequences of various species (chicken, duck, cow, mouse, rat, human, chimpanzee, pig, and horse) were retrieved from the Ensembl database and subjected to bioinformatics analyses. Reverse-transcription polymerase chain reaction (RT-PCR) and quantitative PCR (qPCR) experiments were performed with various chicken tissues and the chicken fibroblast DF-1 cell line, which was stimulated with polyinosinic-polycytidylic acid (poly[I:C]; a TLR3 ligand). Results: The chADAMTS8 gene was predicted to contain three thrombospondin type 1 (TSP1) domains, whose amino acid sequences shared homology among the different species, whereas sequences outside the TSP1 domains (especially the amino-terminal region) were very dif­ferent. Phylogenetic analysis revealed that chADAMTS8 is evolutionarily clustered in the same clade with that of the duck. chADAMTS8 mRNA was broadly expressed in chicken tissues, and the expression was significantly up-regulated in the DF-1 cells in response to poly(I:C) stimulation (p<0.05). These results showed that chADAMTS8 may be a target gene for TLR3 signaling. Conclusion: In this report, the genetic information of chADAMTS8 gene, its expression in chicken tissues, and chicken DF-1 cells under the stimulation of TLR3 were shown. The result suggests that chADAMTS8 expression may be induced by viral infection and correlated with TLR3-mediated signaling pathway. Further study of the function of chADAMTS8 during TLR3-dependent inflammation (which represents RNA viral infection) is needed and it will also be important to examine the molecular mechanisms during different regulation, depending on innate immune receptor activation.

• Archives of Pharmacal Research
• /
• 제22권5호
• /
• pp.437-447
• /
• 1999

Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM) results from the destruction of insulin-producing pancreatic $\beta$ cells by a progressive $\beta$ cell-specific autoimmune process. The pathogenesis of autoimmune IDDM has been extensively studied for the past two decades using animal models such as the non-obese diabetic (NOD) mouse and the Bio-Breeding (BB) rat. However, the initial events that trigger the immune responses leading to the selective destruction of the $\beta$ cells are poorly understood. It is thought that $\beta$ cell auto-antigens are involved in the triggering of $\beta$ cell-specific autoimmunity. Among a dozen putative $\beta$ cell autoantigens, glutamic acid decarboxylase (GAD) has bee proposed as perhaps the strongest candidate in both humans and the NOD mouse. In the NOD mouse, GAD, as compared with other $\beta$ cell autoantigens, provokes the earliest T cell proliferative response. The suppression of GAD expression in the $\beta$ cells results in the prevention of autoimmune diabetes in NOD mice. In addition, the major populations of cells infiltrating the iselts during the early stage of insulitis in BB rats and NOD mice are macrophages and dendritic cells. The inactivation of macrophages in NOD mice results in the prevention of T cell mediated autoimmune diabetes. Macrophages are primary contributors to the creation of the immune environment conducive to the development and activation of $\beta$cell-specific Th1-type CD4+ T cells and CD8+ cytotoxic T cells that cause autoimmune diabetes in NOD mice. CD4+ and CD8+ T cells are both believed to be important for the destruction of $\beta$ cells. These cells, as final effectors, can kill the insulin-producing $\beta$ cells by the induction of apoptosis. In addition, CD8+ cytotoxic T cells release granzyme and cytolysin (perforin), which are also toxic to $\beta$ cells. In this way, macrophages, CD4+ T cells and CD8+ T cells act synergistically to kill the $\beta$ cells in conjunction with $\beta$ cell autoantigens and MHC class I and II antigens, resulting in the onset of autoimmune type I diabetes.

• 한국식품영양학회지
• /
• 제29권3호
• /
• pp.431-437
• /
• 2016

본 연구는 전통약재로 주로 사용되는 구절초에서 분리한 다당류(CZPS)가 선천 및 적응면역에서 중추적인 역할을 수행하는 대식세포의 활성화에 미치는 영향에 관하여 관찰하였다. 구절초에서 분리한 다당류를 마우스 유래 대식세포주인 RAW 264.7 cell에 처리하였을 때, iNOS의 발현을 조절하여 NO의 생성이 증가되었으며, 또한 면역활성 물질인 TNF-${\alpha}$, IL-$1{\beta}$ 및 IL-6 등의 cytokine의 분비능이 증가되었으며, 이러한 면역활성 매개자인 NO 및 cytokine의 증가의 원인에 관한 정확한 면역세포내 신호전달에 관하여 알아본 결과, CZPS 처리는 MAPKs(ERK, p38)의 인산화를 촉진시키며, 이로 인한 전사인자인 NF-${\kappa}B$의 인산화를 증가시켜, 대식세포의 활성화를 유도시키는 것으로 관찰되었다.