Publications by authors named "Seung Hyo Lee"

44 Publications

Soluble Fas ligand drives autoantibody-induced arthritis by binding to DR5/TRAIL-R2.

Elife 2021 07 5;10. Epub 2021 Jul 5.

Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.

To date, no study has demonstrated that soluble Fas ligand (sFasL)-mediated inflammation is regulated via interaction with Fas in vivo. We found that FasL interacts specifically with tumor necrosis factor receptor superfamily (TNFRSF)10B, also known as death receptor (DR)5. Autoantibody-induced arthritis (AIA) was attenuated in FasL ()- and soluble FasL ()-deficient mice, but not in Fas ( and )- or membrane FasL ()-deficient mice, suggesting sFasL promotes inflammation by binding to a Fas-independent receptor. Affinity purification mass spectrometry analysis using human (h) fibroblast-like synovial cells (FLSCs) identified DR5 as one of several proteins that could be the elusive Fas-independent FasL receptor. Subsequent cellular and biochemical analyses revealed that DR5 interacted specifically with recombinant FasL-Fc protein, although the strength of this interaction was approximately 60-fold lower than the affinity between TRAIL and DR5. A microarray assay using joint tissues from mice with arthritis implied that the chemokine CX3CL1 may play an important downstream role of the interaction. The interaction enhanced transcription and increased sCX3CL1 production in FLSCs, possibly in an NF-κB-dependent manner. Moreover, the sFasL-DR5 interaction-mediated CX3CL1-CX3CR1 axis initiated and amplified inflammation by enhancing inflammatory cell influx and aggravating inflammation via secondary chemokine production. Blockade of FasL or CX3CR1 attenuated AIA. Therefore, the sFasL-DR5 interaction promotes inflammation and is a potential therapeutic target.
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http://dx.doi.org/10.7554/eLife.48840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257255PMC
July 2021

Type of bystander and rate of cardiopulmonary resuscitation in nursing home patients suffering out-of-hospital cardiac arrest.

Am J Emerg Med 2021 09 15;47:17-23. Epub 2021 Mar 15.

Department of Emergency Medicine, Seoul National University Hospital, Seoul, South Korea; Laboratory of Emergency Medical Services, Seoul National University Hospital Biomedical Research Institute, Seoul, South Korea.

Aim: We investigated bystander cardiopulmonary resuscitation (CPR) provision rate and survival outcomes of out-of-hospital cardiac arrest (OHCA) patients in nursing homes by bystander type.

Methods: A population-based observational study was conducted for nursing home OHCAs during 2013-2018. The exposure was the bystander type: medical staff, non-medical staff, or family. The primary outcome was bystander CPR provision rate; the secondary outcomes were prehospital return of spontaneous circulation (ROSC) and survival to discharge. Multivariable logistic regression analysis which corrected for various demographic and clinical characteristics evaluated bystander type impact on study outcomes. Bystander CPR rate trend was investigated by bystander type.

Results: Of 8281 eligible OHCA patients, 26.0%, 70.8%, and 3.2% cases were detected by medical staff, non-medical staff, and family, respectively. Provision rate of bystander CPR was 69.9% and rate of bystander defibrillation was 0.4% in total. Bystander CPR was provided by medical staff, non-medical staff, and families in 74.8%, 68.9%, and 52.1% respectively. Total survival rate was 2.2%, out of which, 3.3% was for medical staff, 3.2% for non-medical staff, and 0.6% for family. Compared to the results of detection by medical staff, the adjusted odds ratios (95% CIs) for provision of bystander CPR were 0.56 (0.49-0.63) for detection by non-medical staff and 0.33 (0.25-0.44) for detection by family. The bystander CPR rates of all three groups increased over time, and among them, the medical staff group increased the most. For prehospital ROSC and survival to discharge, no significant differences were observed according to bystander type.

Conclusion: Although OHCA was detected more often by non-medical staff, they provided bystander CPR less frequently than the medical staff did. To improve survival outcome of nursing home OHCA, bundle interventions including increasing the usage of automated external defibrillators and expanding CPR training for non-medical staff in nursing home are needed.
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http://dx.doi.org/10.1016/j.ajem.2021.03.021DOI Listing
September 2021

Genome-wide RNA interference screening reveals a COPI-MAP2K3 pathway required for YAP regulation.

Proc Natl Acad Sci U S A 2020 08 3;117(33):19994-20003. Epub 2020 Aug 3.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 34141 Daejeon, Korea;

The transcriptional regulator YAP, which plays important roles in the development, regeneration, and tumorigenesis, is activated when released from inhibition by the Hippo kinase cascade. The regulatory mechanism of YAP in Hippo-low contexts is poorly understood. Here, we performed a genome-wide RNA interference screen to identify genes whose loss of function in a Hippo-null background affects YAP activity. We discovered that the coatomer protein complex I (COPI) is required for YAP nuclear enrichment and that COPI dependency of YAP confers an intrinsic vulnerability to COPI disruption in YAP-driven cancer cells. We identified MAP2K3 as a YAP regulator involved in inhibitory YAP phosphorylation induced by COPI subunit depletion. The endoplasmic reticulum stress response pathway activated by COPI malfunction appears to connect COPI and MAP2K3. In addition, we provide evidence that YAP inhibition by COPI disruption may contribute to transcriptional up-regulation of PTGS2 and proinflammatory cytokines. Our study offers a resource for investigating Hippo-independent YAP regulation as a therapeutic target for cancers and suggests a link between YAP and COPI-associated inflammatory diseases.
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http://dx.doi.org/10.1073/pnas.1915387117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443978PMC
August 2020

Placental growth factor regulates the generation of T17 cells to link angiogenesis with autoimmunity.

Nat Immunol 2019 10 12;20(10):1348-1359. Epub 2019 Aug 12.

Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, Korea.

Helper T cells actively communicate with adjacent cells by secreting soluble mediators, yet crosstalk between helper T cells and endothelial cells remains poorly understood. Here we found that placental growth factor (PlGF), a homolog of the vascular endothelial growth factor that enhances an angiogenic switch in disease, was selectively secreted by the T17 subset of helper T cells and promoted angiogenesis. Interestingly, the 'angio-lymphokine' PlGF, in turn, specifically induced the differentiation of pathogenic T17 cells by activating the transcription factor STAT3 via binding to its receptors and replaced the activity of interleukin-6 in the production of interleukin-17, whereas it suppressed the generation of regulatory T cells. Moreover, T cell-derived PlGF was required for the progression of autoimmune diseases associated with T17 differentiation, including experimental autoimmune encephalomyelitis and collagen-induced arthritis, in mice. Collectively, our findings provide insights into the PlGF-dictated links among angiogenesis, T17 cell development and autoimmunity.
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http://dx.doi.org/10.1038/s41590-019-0456-4DOI Listing
October 2019

Profiling of protein-protein interactions via single-molecule techniques predicts the dependence of cancers on growth-factor receptors.

Nat Biomed Eng 2018 04 2;2(4):239-253. Epub 2018 Apr 2.

School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul, South Korea.

The accumulation of genetic and epigenetic alterations in cancer cells rewires cellular signalling pathways through changes in the patterns of protein-protein interactions (PPIs). Understanding these patterns may facilitate the design of tailored cancer therapies. Here, we show that single-molecule pull-down and co-immunoprecipitation techniques can be used to characterize signalling complexes of the human epidermal growth-factor receptor (HER) family in specific cancers. By analysing cancer-specific signalling phenotypes, including post-translational modifications and PPIs with downstream interactions, we found that activating mutations of the epidermal growth-factor receptor (EGFR) gene led to the formation of large protein complexes surrounding mutant EGFR proteins and to a reduction in the dependency of mutant EGFR signalling on phosphotyrosine residues, and that the strength of HER-family PPIs is correlated with the strength of the dependence of breast and lung adenocarcinoma cells on HER-family signalling pathways. Furthermore, using co-immunoprecipitation profiling to screen for EGFR-dependent cancers, we identified non-small-cell lung cancers that respond to an EGFR-targeted inhibitor. Our approach might help predict responses to targeted cancer therapies, particularly for cancers that lack actionable genomic mutations.
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http://dx.doi.org/10.1038/s41551-018-0212-3DOI Listing
April 2018

Endothelial Sox17 promotes allergic airway inflammation.

J Allergy Clin Immunol 2019 08 28;144(2):561-573.e6. Epub 2019 Mar 28.

Division of Allergy and Clinical Immunology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Electronic address:

Background: IL-33, levels of which are known to be increased in patients with eosinophilic asthma and which is suggested as a therapeutic target for it, activates endothelial cells in which Sry-related high-mobility-group box (Sox) 17, an endothelium-specific transcription factor, was upregulated.

Objective: We investigated the relationship between Sox17 and IL-33 and the possible role of Sox17 in the pathogenesis of asthma using a mouse model of airway inflammation.

Methods: We used ovalbumin (OVA) to induce airway inflammation in endothelium-specific Sox17 null mutant mice and used IL-33 neutralizing antibody to evaluate the interplay between IL-33 and Sox17. We evaluated airway inflammation and measured levels of various cytokines, chemokines, and adhesion molecules. We also carried out loss- or gain-of-function experiments for Sox17 in human endothelial cells.

Results: Levels of IL-33 and Sox17 were significantly increased in the lungs of OVA-challenged mice. Anti-IL-33 neutralizing antibody treatment attenuated not only OVA-induced airway inflammation but also Sox17 expression in pulmonary endothelial cells. Importantly, endothelium-specific deletion of Sox17 resulted in significant alleviation of various clinical features of asthma, including airway inflammation, immune cell infiltration, cytokine/chemokine production, and airway hyperresponsiveness. Sox17 deletion also resulted in decreased densities of Ly6c monocytes and inflammatory dendritic cells in the lungs. In IL-33-stimulated human endothelial cells, Sox17 showed positive correlation with CCL2 and intercellular adhesion molecule 1 levels. Lastly, Sox17 promoted monocyte adhesion to endothelial cells and upregulated the extracellular signal-regulated kinase-signal transducer and activator of transcription 3 pathway.

Conclusion: Sox17 was regulated by IL-33, and its genetic ablation in endothelial cells resulted in alleviation of asthma-related pathophysiologic features. Sox17 might be a potential target for asthma management.
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http://dx.doi.org/10.1016/j.jaci.2019.02.034DOI Listing
August 2019

Neutrophils disturb pulmonary microcirculation in sepsis-induced acute lung injury.

Eur Respir J 2019 03 28;53(3). Epub 2019 Mar 28.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

The lung is highly vulnerable during sepsis, yet its functional deterioration accompanied by disturbances in the pulmonary microcirculation is poorly understood. This study aimed to investigate how the pulmonary microcirculation is distorted in sepsis-induced acute lung injury (ALI) and reveal the underlying cellular pathophysiologic mechanism.Using a custom-made intravital lung microscopic imaging system in a murine model of sepsis-induced ALI, we achieved direct real-time visualisation of the pulmonary microcirculation and circulating cells We derived the functional capillary ratio (FCR) as a quantitative parameter for assessing the fraction of functional microvasculature in the pulmonary microcirculation and dead space.We identified that the FCR rapidly decreases in the early stage of sepsis-induced ALI. The intravital imaging revealed that this decrease resulted from the generation of dead space, which was induced by prolonged neutrophil entrapment within the capillaries. We further showed that the neutrophils had an extended sequestration time and an arrest-like dynamic behaviour, both of which triggered neutrophil aggregates inside the capillaries and arterioles. Finally, we found that Mac-1 (CD11b/CD18) was upregulated in the sequestered neutrophils and that a Mac-1 inhibitor restored the FCR and improved hypoxaemia.Using the intravital lung imaging system, we observed that Mac-1-upregulated neutrophil aggregates led to the generation of dead space in the pulmonary microcirculation that was recovered by a Mac-1 inhibitor in sepsis-induced ALI.
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http://dx.doi.org/10.1183/13993003.00786-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437604PMC
March 2019

TGF-β/SMAD4 mediated UCP2 downregulation contributes to Aspergillus protease-induced inflammation in primary bronchial epithelial cells.

Redox Biol 2018 09 5;18:104-113. Epub 2018 Jul 5.

Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea. Electronic address:

Elevated levels of mitochondrial reactive oxygen species (ROS) can lead to the development of airway inflammation. In this study, we investigated the role of Aspergillus proteases-which contribute to the pathogenesis of Aspergillus-induced diseases such as allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, and atopic asthma-and their mechanisms of action in airway inflammation using primary human bronchial epithelial cells, and evaluated the inflammatory responses mediated by mitochondrial ROS. We found that Aspergillus proteases regulated the expression of multifunctional inflammatory cytokines such as interleukin (IL)- 1β, - 6, and - 8, and transforming growth factor (TGF)-β, which stimulated cytokine production and chemokines involved in leukocyte migration and activated an inflammatory cascade. Expression of these factors and activator protein (AP)- 1 were decreased by treatment with the mitochondrial ROS scavenger Mito-TEMPO, suggesting that mitochondria are important sources of ROS in the context of inflammatory response by Aspergillus protease. The regulation of mitochondrial ROS influenced the production of proinflammatory mediators by preventing mitochondrial ROS-induced AP-1 activation in airway epithelial cells. In addition, Aspergillus protease-mediated mitochondrial ROS production was associated with downregulation of uncoupling protein (UCP)- 2 expression by TGF-β-SMAD4 signaling, which may play a regulatory role in mitochondrial ROS formation during fungal protease-mediated epithelial inflammation. This improved understanding of the allergenic fungal protease-induced inflammatory mechanism in the bronchial epithelium will help in developing intervention strategies for the regulation of inflammatory response in allergic airway diseases.
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http://dx.doi.org/10.1016/j.redox.2018.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067066PMC
September 2018

Effects of 18-Glycyrrhetinic Acid on Fungal Protease-Induced Airway Inflammatory Responses.

Mediators Inflamm 2018 15;2018:6461032. Epub 2018 May 15.

Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.

Airway epithelial cells secrete diverse inflammatory mediators in response to various stimuli. Thus, early regulation of immune responses in the airway epithelium is likely critical for the control of chronic inflammatory diseases. The purpose of the present study was to evaluate the effects of 18-glycyrrhetinic acid (GA) on inflammatory responses generated in response to a fungal protease allergen that induces epithelial damage. To understand the underlying mechanisms, we also investigated the inhibitory effects of GA on the production of mitochondrial reactive oxygen species (ROS) in the human bronchial epithelial cell line BEAS2B. In this study, GA treatment reduced cytokine production and the human neutrophil cell line HL60 migration through decreased mitochondrial ROS production. In addition, GA significantly reduced inflammatory cell infiltration and cytokine levels in the bronchoalveolar lavage (BAL) fluid of fungal allergen-administered mice. Inhibitory effects of GA are dependent on the mitochondrial ROS/MAPK axis. Moreover, the effect of GA on the regulation of mitochondrial ROS depends on the expression of uncoupling protein-2 (UCP-2). Taken together, GA might represent a potential therapeutic agent for blocking inflammatory responses in airways.
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http://dx.doi.org/10.1155/2018/6461032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976916PMC
October 2018

IL4 Receptor-Targeted Proapoptotic Peptide Blocks Tumor Growth and Metastasis by Enhancing Antitumor Immunity.

Mol Cancer Ther 2017 Dec 6;16(12):2803-2816. Epub 2017 Sep 6.

Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Korea.

Cellular cross-talk between tumors and M2-polarized tumor-associated macrophages (TAM) favors tumor progression. Upregulation of IL4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted proapoptotic peptide could inhibit tumor progression. The IL4R-binding peptide (IL4RPep-1) preferentially bound to IL4R-expressing tumor cells and M2-polarized macrophages both and in 4T1 breast tumors To selectively kill IL4R-expressing cells, we designed an IL4R-targeted proapoptotic peptide, IL4RPep-1-K, by adding the proapoptotic peptide (KLAKLAK) to the end of IL4RPep-1. IL4RPep-1-K exerted selective cytotoxicity against diverse IL4R-expressing tumor cells and M2-polarized macrophages. Systemic administration of IL4RPep-1-K inhibited tumor growth and metastasis in 4T1 breast tumor-bearing mice. Interestingly, IL4RPep-1-K treatment increased the number of activated cytotoxic CD8 T cells while reducing the numbers of immunosuppressive regulatory T cells and M2-polarized TAMs. No significant systemic side effects were observed. These results suggest that IL4R-targeted proapoptotic peptide has potential for treating diverse IL4R-expressing cancers. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0339DOI Listing
December 2017

Prediction of drug-induced immune-mediated hepatotoxicity using hepatocyte-like cells derived from human embryonic stem cells.

Toxicology 2017 07 20;387:1-9. Epub 2017 Jun 20.

Biomedical Science and Engineering Interdisciplinary Program, Daejeon, 34141, South Korea; Graduate School of Medical Science and Engineering, Biomedical Research Center, Daejeon, 34141, South Korea. Electronic address:

Drug-induced liver injury (DILI) is a leading cause of liver disease and a key safety factor during drug development. In addition to the initiation events of drug-specific hepatotoxicity, dysregulated immune responses have been proposed as major pathological events of DILI. Thus, there is a need for a reliable cell culture model with which to assess drug-induced immune reactions to predict hepatotoxicity for drug development. To this end, stem cell-derived hepatocytes have shown great potentials. Here we report that hepatocyte-like cells derived from human embryonic stem cells (hES-HLCs) can be used to evaluate drug-induced hepatotoxic immunological events. Treatment with acetaminophen significantly elevated the levels of inflammatory cytokines by hES-HLCs. Moreover, three human immune cell lines, Jurkat, THP-1, and NK92MI, were activated when cultured in conditioned medium obtained from acetaminophen-treated hES-HLCs. To further validate, we tested thiazolidinedione (TZD) class, antidiabetic drugs, including troglitazone withdrawn from the market because of severe idiosyncratic drug hepatotoxicity. We found that TZD drug treatment to hES-HLCs resulted in the production of pro-inflammatory cytokines and eventually associated immune cell activation. In summary, our study demonstrates for the first time the potential of hES-HLCs as an in vitro model system for assessment of drug-induced as well as immune-mediated hepatotoxicity.
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http://dx.doi.org/10.1016/j.tox.2017.06.005DOI Listing
July 2017

Bilirubin nanoparticles ameliorate allergic lung inflammation in a mouse model of asthma.

Biomaterials 2017 Sep 12;140:37-44. Epub 2017 Jun 12.

Biomedical Science and Engineering Interdisciplinary Program, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea; Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, South Korea. Electronic address:

Although asthma, a chronic inflammatory airway disease, is relatively well-managed by inhaled corticosteroids, the side effects associated with the long-term use of these agents precipitate the need for alternative therapeutic options based on differing modes of action. Bilirubin, a potent endogenous antioxidant, and anti-inflammatory molecule have been shown to ameliorate asthmatic symptoms; however, its clinical translation has been limited owing to its water insolubility and associated potential toxicity. Here we report the first application of bilirubin-based nanoparticles (BRNPs) as a nanomedicine for the treatment of allergic lung inflammatory disease. BRNPs were prepared directly from self-assembly of PEGylated bilirubin in aqueous solution and had a hydrodynamic diameter of ∼100 nm. Because allergen-specific type 2 T-helper (Th2) cells play a key role in the pathogenesis and progression of allergic asthma, the effects of BRNPs on Th2 immune responses were investigated both in vivo and in vitro. BRNPs after intravenous injection (i.v.) showed much higher serum concentration and a longer circulation time of bilirubin than the intraperitoneal injection (i.p.) of BRNPs or unconjugated bilirubin (UCB). The anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Compared with UCB, treatment with BRNPs suppressed the symptoms of experimental allergic asthma and dramatically ameliorated Th2-related allergic lung inflammation. Consistent with these results, BRNPs caused a reduction of Th2 cell populations and the expression of related cytokines by antibody-stimulated CD4 T cells in vitro. Therefore, our results establish BRNPs as an important immunomodulatory agent that may be useful as a therapeutic for allergic lung inflammatory disease and other immune-mediated disorders.
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http://dx.doi.org/10.1016/j.biomaterials.2017.06.014DOI Listing
September 2017

Inositol polyphosphate multikinase promotes Toll-like receptor-induced inflammation by stabilizing TRAF6.

Sci Adv 2017 Apr 21;3(4):e1602296. Epub 2017 Apr 21.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.

Toll-like receptor (TLR) signaling is tightly controlled to protect hosts from microorganisms while simultaneously preventing uncontrolled immune responses. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a critical mediator of TLR signaling, but the precise mechanism of how TRAF6 protein stability is strictly controlled still remains obscure. We show that myeloid-specific deletion of inositol polyphosphate multikinase (IPMK), which has both inositol polyphosphate kinase activities and noncatalytic signaling functions, protects mice against polymicrobial sepsis and lipopolysaccharide-induced systemic inflammation. IPMK depletion in macrophages results in decreased levels of TRAF6 protein, thereby dampening TLR-induced signaling and proinflammatory cytokine production. Mechanistically, the regulatory role of IPMK is independent of its catalytic function, instead reflecting its direct binding to TRAF6. This interaction stabilizes TRAF6 by blocking its K48-linked ubiquitination and subsequent degradation by the proteasome. Thus, these findings identify IPMK as a key determinant of TRAF6 stability and elucidate the physiological function of IPMK in TLR-induced innate immunity.
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http://dx.doi.org/10.1126/sciadv.1602296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400429PMC
April 2017

Basophil-derived IL-6 regulates T17 cell differentiation and CD4 T cell immunity.

Sci Rep 2017 01 30;7:41744. Epub 2017 Jan 30.

Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.

Basophils are rare, circulating granulocytes proposed to be involved in T helper (T) type 2 immunity, mainly through secretion of interleukin (IL)-4. In addition to IL-4, basophils produce IL-6 and tumor necrosis factor (TNF)-α in response to immunoglobulin E (IgE) crosslinking. Differentiation of T17 cells requires IL-6 and transforming growth factor (TGF)-β, but whether basophils play a significant role in T17 induction is unknown. Here we show a role for basophils in T17 cell development by using in vitro T cell differentiation and in vivo T17-mediated inflammation models. Bone marrow derived-basophils (BMBs) and splenic basophils produce significant amounts of IL-6 as well as IL-4 following stimulation with IgE crosslink or cholera toxin (CT). In addition, through IL-6 secretion, BMBs cooperate with dendritic cells to promote T17 cell differentiation. In the T17 lung inflammation model, basophils are recruited to the inflamed lungs following CT challenge, and T17 responses are significantly reduced in the absence of basophils or IL-6. Furthermore, reconstitution with wild-type, but not IL-6-deficient, basophils restored CT-mediated lung inflammation. Lastly, basophil-deficient mice showed reduced phenotypes of T17-dependent experimental autoimmune encephalomyelitis. Therefore, our results indicate that basophils are an important inducer of T17 cell differentiation, which is dependent on IL-6 secretion.
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http://dx.doi.org/10.1038/srep41744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278410PMC
January 2017

Mitochondrial reactive oxygen species regulate fungal protease-induced inflammatory responses.

Toxicology 2017 03 10;378:86-94. Epub 2017 Jan 10.

Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea. Electronic address:

Epidemiological studies have shown that fungal infections are a main cause of respiratory tract diseases, such as asthma, bronchopneumonia, intoxication, and invasive fungal disease. Fungi such as Aspergillus and Candida species have become increasingly important pathogens as the global climate changes. Accordingly, in this study, we evaluated the toxicological potential of Aspergillus protease in the lower respiratory tract. Exposure of Aspergillus protease to A549 cells induced upregulation of tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, and intercellular adhesion molecule (ICAM)-1 mRNAs and increased production of interleukin (IL)-8 and MCP-1 protein through enhanced mitochondrial reactive oxygen species (ROS) generation and activation of mitogen-activated protein kinase (MAPK) and activator protein (AP)-1. Furthermore, the mitochondrial ROS scavenger Mito-TEMPO, which inhibited MAPK and AP-1, significantly reduced MCP-1 and IL-1β mRNA expression and reduced HL-60 cell migration through the suppression of MCP-1 and IL-8 protein secretion. Thus, our results demonstrated that mitochondria were an important source of Aspergillus protease-stimulated ROS and that regulation of mitochondrial ROS modulated inflammatory responses by preventing activation of MAPK and AP-1 in A549 cells.
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http://dx.doi.org/10.1016/j.tox.2017.01.008DOI Listing
March 2017

GM-CSF and IL-4 produced by NKT cells inversely regulate IL-1β production by macrophages.

Immunol Lett 2017 02 4;182:50-56. Epub 2017 Jan 4.

Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Ischemic/Hypoxia Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Natural Killer T (NKT) cells are distinct T cell subset that link innate and adaptive immune responses. IL-1β, produced by various immune cells, plays a key role in the regulation of innate immunity in vivo. However, it is unclear whether NKT cells regulate IL-1β production by macrophages. To address this, we co-cultured NKT cells and peritoneal macrophages in the presence of TCR stimulation and inflammasome activators. Among cytokines secreted from NKT cells, GM-CSF enhanced IL-1β production by macrophages via regulating LPS-mediated pro-IL-1β expression and NLRP3-dependent inflammasome activation, whereas IL-4 enhanced M2-differentiation of macrophages and decreased IL-1β production. Together, our findings suggest the NKT cells have double-sided effects on IL-1β-mediated innate immune responses by producing IL-4 and GM-CSF. These findings may be helpful for a comprehensive understanding of NKT cell-mediated regulatory mechanisms of the pro-inflammatory effects of IL-1β in inflammatory diseases in vivo.
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http://dx.doi.org/10.1016/j.imlet.2017.01.003DOI Listing
February 2017

Natural killer cells regulate eosinophilic inflammation in chronic rhinosinusitis.

Sci Rep 2016 06 8;6:27615. Epub 2016 Jun 8.

Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.

Eosinophils play a major pathologic role in the pathogenesis of diverse inflammatory diseases including chronic rhinosinusitis (CRS). Dysregulated production of prostaglandin (PG), particularly PGD2, is considered to be an important contributing factor to eosinophilic inflammation in CRS primarily through proinflammatory and chemotactic effects on eosinophils. Here, we provide evidence that PGD2 can promote eosinophilic inflammation through a suppression of Natural killer (NK) cell effector function and NK cell-mediated eosinophil regulation. Eosinophil apoptosis mediated by NK cells was significantly decreased in CRS patients compared with healthy controls. This decrease was associated with NK cell dysfunction and eosinophilic inflammation. Tissue eosinophils were positively correlated with blood eosinophils in CRS patients. In a murine model of CRS, NK cell depletion caused an exacerbation of blood eosinophilia and eosinophilic inflammation in the sinonasal tissue. PGD2 and its metabolite, but not PGE2 and a panel of cytokines including TGF-β, were increased in CRS patients compared with controls. Effector functions of NK cells were potently suppressed by PGD2-dependent, rather than PGE2-dependent, pathway in controls and CRS patients. Thus, our results suggest decreased NK cell-mediated eosinophil regulation, possibly through an increased level of PGD2, as a previously unrecognized link between PG dysregulation and eosinophilic inflammation in CRS.
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http://dx.doi.org/10.1038/srep27615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897886PMC
June 2016

Circulating Anti-Elastin Antibody Levels and Arterial Disease Characteristics: Associations with Arterial Stiffness and Atherosclerosis.

Yonsei Med J 2015 Nov;56(6):1545-51

Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Purpose: Elastin is a major arterial structural protein, and elastin-derived peptides are related to arterial change. We previously reported on a novel assay developed using aortic elastin peptides; however, its clinical implications remain unclear. In this study, we assessed whether anti-elastin antibody titers reflect the risk of coronary artery disease (CAD) or its characteristics.

Materials And Methods: We included 174 CAD patients and 171 age- and sex-matched controls. Anti-elastin antibody titers were quantified by enzyme-linked immunosorbent assay. Parameters of arterial stiffness, including the augmentation index (AI) and heart-to-femoral pulse wave velocity (hfPWV), were measured non-invasively. The clinical and angiographic characteristics of CAD patients were also evaluated. Associations between anti-elastin levels and vascular characteristics were examined by linear regression analysis.

Results: The median blood level of anti-elastin was significantly lower in the CAD group than in the controls [197 arbitrary unit (a.u.) vs. 63 a.u., p<0.001]. Levels of anti-elastin were significantly lower in men and in subjects with hypertension, diabetes mellitus, hyperlipidemia, or high hfPWV. Nevertheless, anti-elastin levels were not dependent on atherothrombotic events or the angiographic severity of CAD. In a multivariate analysis, male sex (β=-0.38, p<0.001), diabetes mellitus (β=-0.62, p<0.001), hyperlipidemia (β=-0.29, p<0.001), and AI (β=-0.006, p=0.02) were ultimately identified as determinants of anti-elastin levels.

Conclusion: Lower levels of anti-elastin are related to CAD. The association between antibody titers and CAD is linked to arterial stiffness rather than the advancement of atherosclerosis.
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http://dx.doi.org/10.3349/ymj.2015.56.6.1545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630041PMC
November 2015

TH2 cells and their cytokines regulate formation and function of lymphatic vessels.

Nat Commun 2015 Feb 4;6:6196. Epub 2015 Feb 4.

Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.

Lymphatic vessels (LVs) are critical for immune surveillance and involved in the pathogenesis of diverse diseases. LV density is increased during inflammation; however, little is known about how the resolution of LVs is controlled in different inflammatory conditions. Here we show the negative effects of T helper type 2 (TH2) cells and their cytokines on LV formation. IL-4 and IL-13 downregulate essential transcription factors of lymphatic endothelial cells (LECs) and inhibit tube formation. Co-culture of LECs with TH2 cells also inhibits tube formation, but this effect is fully reversed by interleukin (IL)-4 and/or IL-13 neutralization. Furthermore, the in vivo blockade of IL-4 and/or IL-13 in an asthma model not only increases the density but also enhances the function of lung LVs. These results demonstrate an anti-lymphangiogenic function of TH2 cells and their cytokines, suggesting a potential usefulness of IL-4 and/or IL-13 antagonist as therapeutic agents for allergic asthma through expanding LV mediated-enhanced antigen clearance from the inflammatory sites.
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http://dx.doi.org/10.1038/ncomms7196DOI Listing
February 2015

Non-transcriptional regulation of NLRP3 inflammasome signaling by IL-4.

Immunol Cell Biol 2015 Jul 20;93(6):591-9. Epub 2015 Jan 20.

Department of Microbiology, Brain Korea 21 PLUS Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.

Th2 cytokine IL-4 has been previously shown to suppress the production of proinflammatory cytokines in monocytes. However, the underlying molecular mechanism by which IL-4 signaling antagonizes proinflammatory responses is poorly characterized. In particular, whether IL-4 can modulate inflammasome signaling remains unknown. Here, we provide evidence that IL-4 suppresses NLRP3-dependent caspase-1 activation and the subsequent IL-1β secretion but does not inhibit absent in melanoma 2 (AIM2)- or NLRC4 (NOD-like receptor family, CARD domain-containing 4)-dependent caspase-1 activation in THP-1 and mouse bone marrow-derived macrophages. Upon lipopolysaccharide (LPS) or LPS/ATP stimulation, IL-4 markedly inhibited the assembly of NLRP3 inflammasome, including NLRP3-dependent ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) oligomerization, NLRP3-ASC interaction and NLRP3 speck-like oligomeric structure formation. The negative regulation of NLRP3 inflammasome by IL-4 was not due to the impaired mRNA or protein production of NLRP3 and proinflammatory cytokines. Supporting this observation, IL-4 attenuated NLRP3 inflammasome activation even in reconstituted NLRP3-expressing macrophages in which NLRP3 expression is not transcriptionally regulated by TLR-NF-κB signaling. Furthermore, the IL-4-mediated suppression of NLRP3 inflammasome was independent of STAT6-dependent transcription and mitochondrial reactive oxygen species (ROS). Instead, IL-4 inhibited subcellular redistribution of NLRP3 into mitochondria and microtubule polymerization upon NLRP3-activating stimulation. Our results collectively suggest that IL-4 could suppress NLRP3 inflammasome activation in a transcription-independent manner, thus providing an endogenous regulatory machinery to prevent excessive inflammasome activation.
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http://dx.doi.org/10.1038/icb.2014.125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496256PMC
July 2015

Interplay between Inflammatory Responses and Lymphatic Vessels.

Immune Netw 2014 Aug 22;14(4):182-6. Epub 2014 Aug 22.

Graduate School of Medical Science and Engineering, and Biomedical Research Center, and KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.

Lymphatic vessels are routes for leukocyte migration and fluid drainage. In addition to their passive roles in migration of leukocytes, increasing evidence indicates their active roles in immune regulation. Tissue inflammation rapidly induces lymphatic endothelial cell proliferation and chemokine production, thereby resulting in lymphangiogenesis. Furthermore, lymphatic endothelial cells induce T cell tolerance through various mechanisms. In this review, we focus on the current knowledge on how inflammatory cytokines affect lymphangiogenesis and the roles of lymphatic vessels in modulating immune responses.
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http://dx.doi.org/10.4110/in.2014.14.4.182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148488PMC
August 2014

Leukotriene enhanced allergic lung inflammation through induction of chemokine production.

Clin Exp Med 2015 Aug 13;15(3):233-44. Epub 2014 Jun 13.

Cellular Immunology Laboratory, Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.

The leukotrienes (LTs) enhance allergen- and interleukin (IL)-13-dependent allergic lung inflammatory disease. However, the precise requirement of LTs and the mechanism by which they elicit allergic lung responses remain uncertain. To clarify the involvement of LTs in respiratory allergen- and IL-13-induced experimental asthma and elucidate the underlying mechanisms of LTs-mediated enhanced allergic asthma, we investigated the role of LTs in two models of allergic inflammation: intranasal Aspergillus protease allergen and recombinant IL-13-induced T helper type 2 (Th2) cell-mediated inflammation, and also examined Th2-related chemokines downstream of LTs signaling. 5-Lipoxygenase (5-LO)-deficient mice exposed to short-term intranasal Aspergillus protease allergen showed attenuated airway inflammation, decreased airway hyper-responsiveness and reduced bronchoalveolar eosinophilia when compared to wild-type mice. However, this phenotype was less apparent using long exposure to the same allergen. 5-LO-deficient mice exposed to intranasal rIL-13 also showed attenuated phenotypes of allergic asthma via significant reduction in Th2-specific chemokines, CCL7 and CCL17 production and decreased Th2 cells recruitment to the lungs. Addition of leukotriene B4 (LTB4) and LTC4 to the airways of 5-LO-deficient mice resulted in the rescue of rIL-13-induced experimental asthma. Furthermore, LTs addition to rIL-13 synergistically enhanced the production of Th2-specific chemokines in the lung and inflammatory responses. Therefore, our findings suggest that LTs complement allergens and their downstream cytokine (e.g., IL-13) induced Th2 inflammation by enhancing the induction of Th2 chemokines.
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http://dx.doi.org/10.1007/s10238-014-0292-7DOI Listing
August 2015

Role of citrullinated fibrinogen peptides in the activation of CD4 T cells from patients with rheumatoid arthritis.

Immune Netw 2013 Aug 26;13(4):116-22. Epub 2013 Aug 26.

Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.

This study was conducted to determine whether CD4 T cell responses to citrullinated fibrinogen occur in patients with rheumatoid arthritis (RA), especially in HLA-DR4-positive subjects. Whole peripheral blood mononuclear cells (PBMCs) of RA patients and control subjects were stimulated with citrullinated fibrinogen peptides, and T-cell production of proliferation and proinflammatory cytokines, such as interferon-γ(IFN-γ) and interleukin-17A (IL-17A), were measured. In addition, CD4 T cells from RA patients were stimulated with the citrullinated fibrinogen peptide, Fib-α R84Cit, identified as a DRB1(*)0401-restricted T cell epitope in HLA-DR4 transgenic mice, and the degree of T cell activation was examined similarly. No proliferative responses to the citrullinated fibrinogen peptides were observed in whole PBMCs or CD4 T cells from RA patients. Furthermore, no increased production of IFN-γ or IL-17A was found in whole PBMCs or CD4 T cells stimulated with the citrullinated fibrinogen peptides, although these cells responded to recall antigen, a mixture of tetanus toxoid, purified protein derivative (PPD) from Mycobacterium tuberculosis, and Candida albicans. The results of this study indicate that anti-citrulline immunity in RA patients may be mediated by fibrinogen because there is no evidence of CD4 T cell-mediated immune responses to citrullinated fibrinogen peptides.
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http://dx.doi.org/10.4110/in.2013.13.4.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759708PMC
August 2013

Designed nanocage displaying ligand-specific Peptide bunches for high affinity and biological activity.

ACS Nano 2013 Sep 13;7(9):7462-71. Epub 2013 Aug 13.

Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University , Daegu 700-422, Republic of Korea.

Protein-cage nanoparticles are promising multifunctional platforms for targeted delivery of imaging and therapeutic agents owing to their biocompatibility, biodegradability, and low toxicity. The major advantage of protein-cage nanoparticles is the ability to decorate their surfaces with multiple functionalities through genetic and chemical modification to achieve desired properties for therapeutic and/or diagnostic purposes. Specific peptides identified by phage display can be genetically fused onto the surface of cage proteins to promote the association of nanoparticles with a particular cell type or tissue. Upon symmetrical assembly of the cage, peptides are clustered on the surface of the cage protein in bunches. The resulting PBNC (peptide bunches on nanocage) offers the potential of synergistically increasing the avidity of the peptide ligands, thereby enhancing their blocking ability for therapeutic purposes. Here, we demonstrated a proof-of-principle of PBNCs, fusing the interleukin-4 receptor (IL-4R)-targeting peptide, AP-1, identified previously by phage display, with ferritin-L-chain (FTL), which undergoes 24-subunit assembly to form highly stable AP-1-containing nanocage proteins (AP1-PBNCs). AP1-PBNCs bound specifically to the IL-4R-expressing cell line, A549, and their binding and internalization were specifically blocked by anti-IL-4R antibody. AP1-PBNCs exhibited dramatically enhanced binding avidity to IL-4R compared with AP-1 peptide, measured by surface plasmon resonance spectroscopy. Furthermore, treatment with AP1-PBNCs in a murine model of experimental asthma diminished airway hyper-responsiveness and eosinophilic airway inflammation along with decreased mucus hyperproduction. These findings hold great promise for the application of various PBNCs with ligand-specific peptides in therapeutics for different diseases, such as cancer.
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http://dx.doi.org/10.1021/nn403184uDOI Listing
September 2013

Innate type 2 immunity is associated with eosinophilic pleural effusion in primary spontaneous pneumothorax.

Am J Respir Crit Care Med 2013 Sep;188(5):577-85

Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Daejeon, Korea.

Rationale: Eosinophilic pleural effusion (EPE) is characterized by greater than 10% eosinophilia and is frequently associated with air and/or blood in the pleural cavity. Primary spontaneous pneumothorax (PSP), defined as the spontaneous presence of air in the pleural space, is one of the most common causes of EPE. Recent studies have shown that type 2 immune responses play important roles in eosinophilic airway inflammation resulting in pleural pathology.

Objectives: To determine the predominant immune responses associated with PSP in humans, and to examine whether IL-33, thymic stromal lymphopoietin (TSLP), or type 2 innate lymphoid cell (ILC2)-mediated immune responses are associated factors.

Methods: Eosinophil-associated cytokines were measured in the pleural fluid of patients with PSP and control subjects. Th2 cell and ILC2 responses in the pleural cavity and peripheral blood were also evaluated by in vitro restimulation and intracellular cytokine staining of T cells and ILC2s in patients with PSP (n = 62) and control subjects (n = 33). IL-33-mediated IL-5 production by ILC2s was also evaluated.

Measurements And Main Results: Significantly higher concentrations of IL-5 and eotaxin-3 were detected in the pleural fluid of patients with PSP, in addition to significantly higher concentrations of IL-33 and TSLP. Although IL-5 production was induced by IL-33 treatment of ILC2s, other Th2 cell-mediated immune responses were not detected.

Conclusions: Our results indicate that innate immune responses characterized by the production of IL-33, TSLP, and IL-5 are associated with the development of EPE in PSP by an ILC2-dependent and Th2-independent mechanism.
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http://dx.doi.org/10.1164/rccm.201302-0295OCDOI Listing
September 2013

CD11a polymorphisms regulate TH2 cell homing and TH2-related disease.

J Allergy Clin Immunol 2014 Jan 29;133(1):189-97.e1-8. Epub 2013 May 29.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, Tex; Department of Medicine, Baylor College of Medicine, Houston, Tex. Electronic address:

Background: TH2-dependent diseases vary in severity according to genotype, but relevant gene polymorphisms remain largely unknown. The integrin CD11a is a critical determinant of allergic responses, and allelic variants of this gene might influence allergic phenotypes.

Objective: We sought to determine major CD11a allelic variants in mice and human subjects and their importance to allergic disease expression.

Methods: We sequenced mouse CD11a alleles from C57BL/6 and BALB/c strains to identify major polymorphisms; human CD11a single nucleotide polymorphisms were compared with allergic disease phenotypes as part of the international HapMap project. Mice on a BALB/c or C57BL/6 background and congenic for the other strain's CD11a allele were created to determine the importance of mouse CD11a polymorphisms in vivo and in vitro.

Results: Compared with the C57BL/6 allele, the BALB/c CD11a allele contained a nonsynonymous change from asparagine to aspartic acid within the metal ion binding domain. In general, the BALB/c CD11a allele enhanced and the C57BL/6 CD11a allele suppressed TH2 cell-dependent disease caused by the parasite Leishmania major and allergic lung disease caused by the fungus Aspergillus niger. Relative to the C57BL/6 CD11a allele, the BALB/c CD11a allele conferred both greater T-cell adhesion to CD54 in vitro and enhanced TH2 cell homing to lungs in vivo. We further identified a human CD11a polymorphism that significantly associated with atopic disease and relevant allergic indices.

Conclusions: Polymorphisms in CD11a critically influence TH2 cell homing and diverse TH2-dependent immunopathologic states in mice and potentially influence the expression of human allergic disease.
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http://dx.doi.org/10.1016/j.jaci.2013.03.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842370PMC
January 2014

Apocynin regulates cytokine production of CD8(+) T cells.

Clin Exp Med 2014 Aug 23;14(3):261-8. Epub 2013 May 23.

Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Daejeon, 305-701, Korea.

Apocynin is known to suppress the production of reactive oxygen species (ROS) by inhibiting NADPH oxidases, specifically phagocytic NADPH oxidase (PHOX or NOX2). Given the pro-inflammatory effects of ROS, apocynin has been studied extensively for its use as a therapeutic agent in various disease models. While the effects of apocynin on neutrophils and monocytes have been investigated, it remains to be elucidated whether apocynin modulates the effector function of T cells. In the present study, we examined the effect of apocynin on CD8(+) T cells and further investigated its mechanism of action. We found that apocynin directly inhibited the production of pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-2 in anti-CD3/anti-CD28-stimulated CD8(+) T cells. The action of apocynin was upstream of the protein kinase C and calcium signaling in the T cell receptor signaling pathway because apocynin did not inhibit cytokine production in phorbol 12-myristate 13-acetate/ionomycin-stimulated CD8(+) T cells. Electrophoretic mobility shift assays revealed that apocynin attenuated anti-CD3/anti-CD28-induced NF-κB activation in CD8(+) T cells. In the experiments with NOX2-deficient mice, we demonstrated that apocynin inhibited TNF-α production of CD8(+) T cells in a NOX2-independent manner. Taken together, we demonstrated that apocynin, a well-known NOX2 inhibitor, suppressed the cytokine production of CD8(+) T cells. We also showed the NOX2-independent action of apocynin in the inhibition of TNF-α production in CD8(+) T cells.
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http://dx.doi.org/10.1007/s10238-013-0241-xDOI Listing
August 2014

Macelignan attenuated allergic lung inflammation and airway hyper-responsiveness in murine experimental asthma.

Life Sci 2013 Jun 30;92(22):1093-9. Epub 2013 Apr 30.

Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.

Aims: Macelignan isolated from Myristica fragrans Houtt. is widely used for spice and flavoring for foods, and has been reported to have anti-inflammatory activity. The aim of this study was to investigate the effects of macelignan on allergic lung inflammation with a murine model of experimental asthma.

Main Methods: Fungal protease mixed with chicken egg ovalbumin allergen was used as a challenge to induce murine experimental asthma. To determine its effects on allergy and inflammation, macelignan was administered orally during allergen challenge, and the symptoms of allergic asthma and its underlined mechanisms were examined.

Key Findings: Treatment with macelignan attenuated eosinophilic airway inflammation and airway hyper-responsiveness. With the administration of macelignan, interleukin-4 (IL-4) producing cells, but not interferon-γ (IFN-γ) or IL-17 producing cells, were diminished in the lungs. Additionally, activation of the T helper type 2 (Th2) cell-specific master transcription factor, GATA3 was decreased with macelignan treatment. Finally, production of IL-4 but not IFN-γ or IL-17, by CD4(+) T cells was reduced with stimulation when combined with the administration of macelignan.

Significance: Our data show that macelignan has anti-inflammatory effects on Th2 cell-mediated allergic lung inflammation and could potentially provide a novel preventative and/or therapy for the treatment of allergic diseases.
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http://dx.doi.org/10.1016/j.lfs.2013.04.010DOI Listing
June 2013

CD53, a suppressor of inflammatory cytokine production, is associated with population asthma risk via the functional promoter polymorphism -1560 C>T.

Biochim Biophys Acta 2013 Apr 10;1830(4):3011-8. Epub 2013 Jan 10.

Department of Microbiology, Chung-Ang University College of Medicine, Seoul, Republic of Korea.

Background: In this study, the association of asthma with CD53, a member of the tetraspanin family, was assessed for the first time in a mechanism-based study.

Methods: Genetic polymorphisms of CD53 were analyzed in 591 subjects and confirmed in a replication study of 1001 subjects. CD53 mRNA and protein levels were measured in peripheral blood leukocytes, and the effects of the promoter polymorphisms on nuclear factor binding were examined by electrophoretic mobility shift assay. Cellular functional studies were conducted by siRNA transfections.

Results: Among tagging SNPs of CD53, the -1560 C>T in the promoter region was significantly associated with asthma risk. Compared with the CC genotype, the CT and TT genotypes were associated with a higher asthma risk, with odd ratios of 1.74 (P=0.009) and 2.03 (P=0.004), respectively. These findings were confirmed in the replication study with odd ratios of 1.355 (P=0.047) and 1.495 (P=0.039), respectively. The -1560 C>T promoter SNP had functional effects on nuclear protein binding as well as mRNA and protein expression levels in peripheral blood leukocytes. When CD53 was knocked down by siRNA in THP-1 human monocytic cells stimulated with house dust mite, the production of inflammatory cytokines as well as NFκB activity was significantly over-activated, suggesting that CD53 suppresses over-activation of inflammatory responses.

Conclusions: The -1560 C>T SNP is a functional promoter polymorphism that is significantly associated with population asthma risk, and is thought to act by directly modulating nuclear protein binding, thereby altering the expression of CD53, a suppressor of inflammatory cytokine production.
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http://dx.doi.org/10.1016/j.bbagen.2012.12.030DOI Listing
April 2013

Serum elastin-derived peptides and anti-elastin antibody in patients with systemic sclerosis.

J Korean Med Sci 2012 May 25;27(5):484-8. Epub 2012 Apr 25.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

The elastin metabolism in systemic sclerosis (SSc) has been known to be abnormal. The authors investigated relationship between the clinical manifestations of systemic sclerosis (SSc) and serum levels of soluble elastin-derived peptide (S-EDP) and anti-elastin antibodies. Serum samples were obtained from 79 patients with SSc and 79 age- and sex-matched healthy controls. Concentrations of serum S-EDP and anti-elastin antibodies were measured by ELISA. The serum concentrations of S-EDP in SSc patients were significantly higher than in healthy controls (median, 144.44 ng/mL vs 79.59 ng/mL, P < 0.001). Serum EDP concentrations were found to be correlated with disease duration in SSc (P = 0.002) and particularly in diffuse cutaneous SSc (P = 0.005). Levels of anti-elastin antibodies were found to be more elevated in SSc patients than in healthy controls (median, 0.222 U vs 0.191 U, P = 0.049), more increased in diffuse cutaneous SSc than limited cutaneous SSc (median, 0.368 U vs 0.204 U, P = 0.031). In addition, levels of anti-elastin antibodies were also found to be negatively associated with presence of anti-centromere antibody (P = 0.023). The S-EDP levels were not found to be correlated with levels of anti-elastin antibodies. The increased S-EDP and anti-elastin antibody levels and association with clinical and laboratory characteristics may reflect the abnormal metabolism in SSc.
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http://dx.doi.org/10.3346/jkms.2012.27.5.484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342537PMC
May 2012
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