• IMMUNE NETWORK
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• 제13권5호
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• pp.194-198
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• 2013

Recent papers have shown that the initial event in the pathogenesis of autoimmune type 1 diabetes (T1D) comprises sensing of molecular patterns released from apoptotic ${\beta}$-cells by innate immune receptors such as toll-like receptor (TLR). We have reported that apoptotic ${\beta}$-cells undergoing secondary necrosis called 'late apoptotic' ${\beta}$-cells stimulate dendritic cells (DCs) and induce diabetogenic T cell priming through TLR2. The role of other innate immune receptors such as TLR7 or TLR9 in the initiation of T1D has also been suggested. We hypothesized that TLR2 blockade could inhibit T1D at the initial step of T1D. Indeed, when a TLR2 agonist, $Pam3CSK_4$ was administered chronically, the development of T1D in nonobese diabetic (NOD) mice was inhibited. Diabetogenic T cell priming by DCs was attenuated by chronic treatment with $Pam3CSK_4$, indicating DC tolerance. For the treatment of established T1D, immune tolerance alone is not enough because ${\beta}$-cell mass is critically reduced. We employed TLR2 tolerance in conjunction with islet transplantation, which led to reversal of newly established T1D. Dipeptidyl peptidase 4 (DPP4) inhibitors are a new class of anti-diabetic agents that have beneficial effects on ${\beta}$-cells. We investigated whether a combination of DPP4 inhibition and TLR2 tolerization could reverse newly established T1D without islet transplantation. We could achieve normoglycemia by TLR2 tolerization in combination with DPP4 inhibition but not by TLR2 tolerization or DPP4 inhibition alone. ${\beta}$-cell mass was significantly increased by combined treatment with TLR2 tolerization and DPP4 inhibition. These results suggest the possibility that a novel strategy of TLR tolerization will be available for the inhibition or treatment of established T1D when combined with measures increasing critically reduced ${\beta}$-cell mass of T1D patients such as DPP4 inhibition or stem cell technology.

• BMB Reports
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• 제45권9호
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• pp.538-543
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• 2012

We evaluated the expression of the costimulatory molecules CD80 and CD83 and major histocompatibility (MHC) class II induced by 2,4-dinitrofluorobenzene (DNFB) in the RAW 264.7 macrophage cell line. In contrast to the previously reported effect of DNFB on dendritic cells, CD86 expression did not change. Furthermore, we observed that the CD83 expression level transiently increased and then decreased. Induction of CD80 and MHC class II molecule expression and a decrease in CD83 expression by DNFB in vitro were also confirmed in splenocytes of BALB/c and NC/Nga mice. However, DNFB did not influence CD83 expression in peritoneal $CD11b^+$ cells from BALB/c or NC/Nga mice. Detailed in vivo experiments and further studies on the possible contribution of $CD11b^+$ cells to induce atopic dermatitis (AD) would be helpful to attain a better understanding of AD pathogenesis.

• BMB Reports
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• 제40권4호
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• pp.486-493
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• 2007

Atopic dermatitis (AD) is a chronic inflammatory skin disease and the pathogenesis of AD is associated with the release of various cytokines/chemokines due to activated $Th_2$ immune responses. Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG dinucleotide in the context of particular base sequence (CpG motifs) are known to have the immunostimulatory activities in mice and to convert from Th2 to Th1 immune responses in AD. We aimed to investigate that CpG ODN, especially phosphodiester form, can stimulate the protective immunity in NC/Nga mice with AD. We isolated BMDCs from NC/Nga mice and then, cultured with GM-CSF and IL-4 for 6 days, and treated for 2 days by either phosphorothioate ODN or phosphodiester ODN. CpG ODN-treated DCs resulted in more production of IL-12. When CpG ODN-treated DCs were intravenously injected into the NC/Nga mice, the NC/Nga mice with CpG ODN-treated DCs showed significant improvement of AD symptoms and decrease of IgE level. Histopathologically, the NC/Nga mice skin with CpG ODN-treated DCs showed the decreased IL-4 and TARC expression comparing with non-injected mice. These results may suggest that phosphodiester CpG ODN-treated DCs might function as a potent adjuvant for AD in a mouse model.

• BMB Reports
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• 제42권4호
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• pp.200-205
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• 2009

Thromboxane A2 (TBXA2) is a potent vasoconstrictor in cerebral circulation and is a known contributor to the pathogenesis of cerebral infarction. Thromboxane A2 synthase 1 (TBXAS1) and thromboxane A2 receptors (TBXA2R) are key components in TBXA2 function. We examined whether genetic variants in TBXA2R and TBXAS1 are risk factors for cerebral infarction by genotyping 453 Korean patients with noncardiogenic cerebral infarction and 260 controls. A few, specific polymorphisms in the TBXA2R (-3372G>C, +4710T>C and 4839T>C) and TBXAS1 (+16184G>T, +141931A>T and +177729G>A) genes were chosen and investigated. Logistic regression showed the frequencies of TBXAS1+16184G>T and TBXAS1-ht3 were significantly more frequent in cerebral infarction (P = 0.002, OR = 2.75 and P = 0.01, OR = 1.57, respectively), specifically in small-artery occlusion (SAO) type of cerebral infarction (P = 0.0003 and 0.005, respectively). These results suggest specific TBXAS1 gene polymorphisms may be a useful marker for development of cerebral infarction, especially SAO type in Korean population.

• 대한임상검사과학회지
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• 제47권4호
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• pp.168-174
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• 2015

류마티스 관절염은 주로 관절의 활막 세포의 증식, 병리학적 면역 반응과 관절의 진행성 파괴를 특징으로 하는 만성 염증성 질환이다. 이 질환은 중요한 사회적 건강 문제로 대두된다. 이 논문을 통해 분자수준에서 변화와 류마티스 관절염의 진단 또는 질병의 진행에 대한 발병 기전을 새로운 관점에서 발병기전을 제공한다. 또한 조기 진단과 류마티스 관절염의 예후에 도움이 될 것으로 보인다. 새로운 혈청학적 및 면역학적 바이오마커에 초점을 맞추고 있다. 따라서 넓게 질병 진행의 위험 환자를 식별하는 혈청학적, 생체 면역학적 요인 등을 규명하고 적용시키는 것을 도출할 수 있다. 진단 검사 의학을 기반으로 하는 증거는 환자에게 최선의 결과를 제공할 수 있다. 마지막으로. 최근의 연구 데이터는 이 접근을 통해서 치료를 최적화하기 위해 조기 진단 및 치료에 도움이 되는 새로운 접근 방식으로 궁극적인 유용성을 정립하는데 도움이 될 것으로 사료된다.

• BMB Reports
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• 제36권1호
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• pp.95-109
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• 2003

Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance. The sources of the increased oxidative stress in patients with chronic inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) derive from the increased burden of inhaled oxidants, and from the increased amounts of reactive oxygen species (ROS) generated by several inflammatory, immune and various structural cells of the airways. Increased levels of ROS produced in the airways is reflected by increased markers of oxidative stress in the airspaces, sputum, breath, lungs and blood in patients with lung diseases. ROS, either directly or via the formation of lipid peroxidation products such as 4-hydroxy-2-nonenal may play a role in enhancing the inflammation through the activation of stress kinases (JNK, MAPK, p38) and redox sensitive transcription factors such as NF-${\kappa}B$ and AP-1. Recent evidences have indicated that oxidative stress and pro-inflammatory mediators can alter nuclear histone acetylation/deacetylation allowing access for transcription factor DNA binding leading to enhanced pro-inflammatory gene expression in various lung cells. Understanding of the mechanisms of redox signaling, NF-${\kappa}B$/AP-1 regulation, the balance between histone acetylation and deacetylation and the release and expression of pro- and anti-inflammatory mediators may lead to the development of novel therapies based on the pharmacological manipulation of antioxidants in lung inflammation and injury. Antioxidants that have effective wide spectrum activity and good bioavailability, thiols or molecules which have dual antioxidant and anti-inflammatory activity, may be potential therapeutic agents which not only protect against the direct injurious effects of oxidants, but may fundamentally alter the underlying inflammatory processes which play an important role in the pathogenesis of chronic inflammatory lung diseases.

• BMB Reports
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• 제38권2호
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• pp.151-160
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• 2005

By a cDNA array representing 2308 signal transduction related genes, we studied the expression profiles of HeLa cells stably transfected by Hepatitis C virus nonstructural protein 4B (HCV-NS4B). The alterations of the expression of four genes were confirmed by real-time quantitative RT-PCR; and the aldo-keto reductase family 1, member C1 (AKR1C1) enzyme activity was detected in HCV-NS4B transiently transfected HeLa cells and Huh-7, a human hepatoma cell line. Of the 2,308 genes we examined, 34 were up-regulated and 56 were down-regulated. These 90 genes involved oncogenes, tumor suppressors, cell receptors, complements, adhesions, transcription and translation, cytoskeletion and cellular stress. The expression profiling suggested that multiple regulatory pathways were affected by HCV-NS4B directly or indirectly. And since these genes are related to carcinogenesis, host defense system and cell homeostatic mechanism, we can conclude that HCV-NS4B could play some important roles in the pathogenesis mechanism of HCV.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2005년도 춘계학술대회
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• pp.53-60
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• 2005

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting $1\%$ of the population above the age of 65 and is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta. Although the underlying cause of dopaminergic cell death or the mechanism by which these cells degenerate is still not clearly understood, oxidative stress, mitochondrial dysfunction, and protein misfolding are thought to play important roles in the dopaminergic degeneration in PD. Tetrahydrobiopterin (BH4) is synthesized exclusively in the monoaminergic, including dopaminergic, cells and serves as an endogenous and obligatory cofactor for syntheses of the potential oxidative stressors dopamine and nitric oxide. In addition to its contribution toward the syntheses of these two potentially toxic molecules, BH4 itself can directly generate oxidative stress. BH4 undergoes oxidation during the hydroxylation reaction as well as nonenzymatic autooxidation to produce hydrogen peroxide and superoxide radical. We have previously suggested BH4 as an endogenous molecule responsible for the dopaminergic neurodegeneration. BH4 exerts selective toxicity to dopamine-producing cells via generation of oxidative stress, mitochondrial dysfunction, and apoptosis. BH4 also induces morphological, biochemical, and behavioral characteristics associated with PD in vivo. BH4 as well as enzyme activity and gene expression of GTP cyclohydrolase I, the rate-limiting enzyme in BH4 synthesis pathway, are readily upregulated by cellular changes such as calcium influx and by various stimuli including stress situations. This points to the possibility that cellular availability of BH4 might be increased in aberrant conditions, leading to increased extracellular BH4 subsequent degeneration. The fact that BH4 is specifically and endogenously synthesized in dopaminergic cells, Is readily upregulated, and generates oxidative stress-related cell death provides physical relevance of this molecule as an attractive candidate with which to explain the mechanism of pathogenesis of PD.

• BMB Reports
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• 제44권2호
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• pp.135-139
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• 2011

Chronic alcohol consumption contributes to numerous diseases, including cancers, cardiovascular diseases, and liver cirrhosis. Epidemiological studies have shown that excessive alcohol consumption is a risk factor for dementia. Along this line, Alzheimer's disease (AD) is the most common form of dementia and is caused by the accumulation of amyloid-$\beta$ ($A{\beta}$ plaques in neurons. In this study, we hypothesized that chronic ethanol consumption is associated with pathological processing of APP in AD. To investigate the relationship between chronic alcohol consumption and $A{\beta}$ production, brain samples from rats fed an alcohol liquid diet for 5 weeks were analyzed. We show that the expression levels of APP, BACE1, and immature nicastrin were increased in the cerebellum, hippocampus, and striatum of the alcohol-fed group compared to the control group. Total nicastrin and PS1 levels were induced in the hippocampus of alcohol-fed rats. These data suggest that the altered expression of APP and $A{\beta}$-producing enzymes possibly contributes to the chronic alcohol consumption-mediated pathogenesis of AD.

• 대한한의학회지
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• 제21권3호
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• pp.57-67
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• 2000

Currently asthma is considered to be an inflammatory disease characterized by airway hyperresponsiveness and pulmonary eosinophilia, and mediated by Th lymphocytes expressing a Th 2 cytokine pattern. In many recent studies, molecular biological methods have been used to investigate the role of cytokines in pathogenesis and new therapeutic targets of asthma. Objectives: We aimed to identify the effect of Haepyoijin-tang on the transcriptional activities of cytokines involved in the asthma model. Materials and Methods: RBL-2H3 cell lines were used. Cells were stimulated with DNP-IgE or Calcium inophore+PMA for maximal gene expression. After 24 hours of Haepyoijin-tang-treatment, total cellular RNAs were collected using the Trizol solution method. Then the transcriptional activities of cytokines(IL-1, 4, 5, 10, 13, $TNF-{\alpha}$) were measured by RT-PCR with electrophoresis. Results: DNP-IgE and Calcium inophore+PMA induced IL-4/IL-5 production separately peaked at 3 hours after the stimulation, but the efficacy was better in the Calcium inophore+PMA group. In the IL-4 study, sample groups of 10%, 1 %, 0.01 % Haepyoijin-tang-treatment showed 83%, 98%, 96% of transcriptional activities compared to the control group. In the IL-5 study, sample groups of 10%, 1%, 0.1 %, 0.01 % Haepyoijin-tang showed 97%, 99%, 99%, 99% of transcriptional activities compared to the control group. In other studies any result was not obtained. Conclusions: This study shows that Haepyoijin-tang has an inhibitory effect on the transcription of IL-4 and IL-5 gene expression in RBL-2H3 cell lines. Advanced studies are required to investigate the mechanisms of inhibition by herbal medicine in the asthma model.