Ki-Young Lee

Sungkyunkwan University, Sŏul, Seoul, South Korea

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Publications (45)208.06 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: ECSIT (evolutionarily conserved signaling intermediate in Toll pathways) is known as a multifunctional regulator in different signals, including TLRs, TGF-beta, and BMP. Here, we report a new regulatory role of ECSIT in TLR4-mediated signal. By LPS stimulation, ECSIT endogenously formed a high mass signaling complex including TRAF6 and TAK1, in which ECSIT interacted with each protein and regulated TAK1 activity, leading to the activation of NF-κB. ECSIT-knockdown THP-1 (ECSITKD THP-1) cells exhibited severe impairments in NF-κB activity, cytokine productions, and NF-κB-dependent gene expressions, whereas those were dramatically restored by re-introduction of wild type (wt) ECSIT gene. Interestingly, ECSIT mutants, in which lack a specific interacting domain for either TAK1 or TRAF6, could not restore these activities. Moreover, no significant changes in both NF-κB activity and cytokine productions induced by TLR4 could be seen in TAK1KD or TRAF6KD THP-1 cells transduced by wt ECSIT, strongly suggesting the essential requirement of TAK1-ECSIT-TRAF6 complex in TLR4 signaling. Taken together, our data demonstrate that the ECSIT complex, including TAK1 and TRAF6, plays a pivotal role in TLR4-mediated signals to activate NF-κB.
    The Journal of biological chemistry. 11/2014;
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    ABSTRACT: Recent evidence shows that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6) ubiquitinated, and contributes to bactericidal activity during Toll-like receptor (TLR) signaling. Here, we first report a new regulatory role for ECSIT in TLR4 signaling. On TLR4 stimulation, endogenous ECSIT forms a molecular complex if p65/p50 NF- Κ: Bs. Our biochemical studies show that ECSIT specifically interacted with p65/p50 NF- Κ: Bs, which colocalized in the nucleus. Interestingly, these effects were critically dependent on ubiquitination of the ECSIT lysine (K) 372 residue. K372A mutant ECSIT did not interact with p65/p50 NF- Κ: Bs, and markedly attenuated nuclear colocalization. Additionally, ECSIT-knockdown THP-1 cells could not activate NF- Κ: B DNA-binding activities of p65 and p50, production of proinflammatory cytokines, and NF- Κ: B-dependent gene expression in response to TLR4 stimulation. However, these activities were markedly restored by expressing the wild-type ECSIT protein but not the K372A mutant ECSIT protein. These date strongly suggest that the ubiquitination of ECSIT might have the regulation of NF- Κ: B activity in TLR4 signaling.
    Molecular biology of the cell. 10/2014;
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    Sae Mi Wi, Ki-Young Lee
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    ABSTRACT: It is debatable whether AMP-activated protein kinase (AMPK) activation is involved in anti-apoptotic or pro-apoptotic signaling. AICAR treatment increases AMPK-α1 phosphorylation, decreases intracellular reactive oxygen species (ROS) levels, and significantly increases Annexin V-positive cells, DNA laddering, and caspase activity in human myeloid cell. AMPK activation is therefore implicated in apoptosis. However, AMPK-α1-knockdown THP-1 cells are more sensitive to apoptosis than control THP-1 cells are, suggesting that the apoptosis is AMPK-independent. Low doses of AICAR induce cell proliferation, whereas high doses of AICAR suppress cell proliferation. Moreover, these effects are significantly correlated with the downregulation of intracellular ROS, strongly suggesting that AICAR-induced apoptosis is critically associated with the inhibition of NADPH oxidase by AICAR. Collectively, our results demonstrate that in AICAR-induced apoptosis, intracellular ROS levels are far more relevant than AMPK activation.
    Immune Network 10/2014; 14(5):241-8.
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    ABSTRACT: Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is key regulator in the signals transduced by pro-inflammatory cytokines and toll-like receptors (TLRs). The regulatory mechanism of TAK1 in response to various tissue types and stimuli remains incompletely understood. Here, we show that ribosomal S6 kinase 1 (S6K1) negatively regulates TLR-mediated signals by inhibiting TAK1 activity. S6K1 overexpression causes a marked reduction in NF-κB and AP-1 activity induced by TLR2 or TLR4 stimulation. In contrast, S6K1(-/-) and S6K1-knockdown cells display enhanced production of inflammatory cytokines. Moreover, S6K1(-/-) mice exhibit decreased survival in response to challenge of LPS. We found that S6K1 inhibits TAK1 kinase activity by interfering with the interaction between TAK1 and TAB1, a key regulator protein for TAK1 catalytic function. Upon stimulation with TLR ligands, S6K1 deficiency causes a marked increase in TAK1 kinase activity that in turn induces a substantial enhancement of NF-κB-dependent gene expression, indicating that S6K1 is negatively involved in the TLR signaling pathway by the inhibition of TAK1 activity. Our findings contribute to understanding the molecular pathogenesis of the impaired immune responses seen in type 2 diabetes where S6K1 plays a key role in driving both insulin resistance and modulating TLR signaling.
    Molecular and Cellular Biology 11/2013; · 5.04 Impact Factor
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    ABSTRACT: Salt-inducible kinases (SIKs) are a family of related serine-threonine kinases and are involved in controlling various metabolisms such as liver glucose homeostasis, hepatic lipogenesis, steroidogenesis, and adipogenesis. Here we investigated the regulatory role of SIK proteins in Toll-like receptor 4 (TLR4)-mediated signaling. Overexpression of SIK1 and SIK3, but not SIK2, significantly inhibited nuclear factor-κB activity in response to lipopolysaccharide stimulation and affected the expression of proinflammatory cytokines. In contrast, both SIK1(KD) and SIK3(KD) Raw 264.7 cells exhibit dramatic elevations of nuclear factor-κB activation and activations of downstream signaling molecules, such as TGF-β-activated kinase 1, p38, and c-Jun N-terminal kinase, in response to TLR4 stimulation, indicating that SIK1 and SIK3 are negatively involved in the TLR4-mediated signaling. Through biochemical studies, we found that SIK1 and SIK3 interact with TGF-β-activated kinase 1-binding protein 2 (TAB2), and interrupt the functional complex of TAB2-TNF receptor-associated factor 6 (TRAF6). Interestingly, the molecular interruption is induced to suppress the ubiquitination of TRAF6 in response to TLR4 stimulation. These result suggest that SIK1 and SIK3 negatively regulate TLR4-mediated signaling through the interruption of TAB2-TRAF6 complex and thereby the inhibition of ubiquitination of TRAF6. The present findings can be useful for a better understanding of multilevel interactions between the metabolic and immune systems.
    Molecular Endocrinology 09/2013; · 4.75 Impact Factor
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    ABSTRACT: Recent reports have suggested that metformin has anti-inflammatory and anti-tissue remodeling properties. We investigated the potential effect of metformin on airway inflammation and remodeling in asthma. The effect of metformin treatment on airway inflammation and pivotal characteristics of airway remodeling were examined in a murine model of chronic asthma generated by repetitive challenges with ovalbumin and fungal-associated allergenic protease. To investigate the underlying mechanism of metformin, oxidative stress levels and AMP-activated protein kinase (AMPK) activation were assessed. To further elucidate the role of AMPK, we examined the effect of 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) as a specific activator of AMPK and employed AMPKα1-deficient mice as an asthma model. The role of metformin and AMPK in tissue fibrosis was evaluated using a bleomycin-induced acute lung injury model and in vitro experiments with cultured fibroblasts. Metformin suppressed eosinophilic inflammation and significantly reduced peribronchial fibrosis, smooth muscle layer thickness, and mucin secretion. Enhanced AMPK activation and decreased oxidative stress in lungs was found in metformin-treated asthmatic mice. Similar results were observed in the AICAR-treated group. In addition, the enhanced airway inflammation and fibrosis in heterozygous AMPKα1-deficient mice were induced by both allergen and bleomycin challenges. Fibronectin and collagen expression was diminished by metformin through AMPKα1 activation in cultured fibroblasts. Therefore metformin reduced both airway inflammation and remodeling at least partially through the induction of AMPK activation and decreased oxidative stress. These data provide insight into the beneficial role of metformin as a novel therapeutic drug for chronic asthma.
    Biochemical pharmacology 10/2012; · 4.25 Impact Factor
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    ABSTRACT: BACKGROUND: Antioxidants have been suggested to alleviate the pathophysiological features of asthma, and grape seed proanthocyanidin extract (GSPE) has been reported to have powerful antioxidant activity. PURPOSE: This study was performed to determine whether GSPE has a therapeutic effect on allergic airway inflammation in both acute and chronic murine model of asthma. METHODS: Acute asthma model was generated by intraperitoneal sensitization of ovalbumin (OVA) with alum followed by aerosolized OVA challenges, whereas chronic asthma model was induced by repeated intranasal challenges of OVA with fungal protease twice a week for 8 weeks. GSPE was administered by either intraperitoneal injection or oral gavage before OVA challenges. Airway hyperresponsiveness (AHR) was measured, and airway inflammation was evaluated by bronchoalveolar lavage (BAL) fluid analysis and histopathological examination of lung tissue. Lung tissue levels of various cytokines, chemokines, and growth factors were analyzed by quantitative polymerase chain reaction and ELISA. Glutathione assay was done to measure oxidative burden in lung tissue. RESULTS: Compared to untreated asthmatic mice, mice treated with GSPE showed significantly reduced AHR, decreased inflammatory cells in the BAL fluid, reduced lung inflammation, and decreased IL-4, IL-5, IL-13, and eotaxin-1 expression in both acute and chronic asthma models. Moreover, airway subepithelial fibrosis was reduced in the lung tissue of GSPE-treated chronic asthmatic mice compared to untreated asthmatic mice. Reduced to oxidized glutathione (GSH/GSSG) ratio was increased after GSPE treatment in acute asthmatic lung tissue. CONCLUSION: GSPE effectively suppressed inflammation in both acute and chronic mouse models of asthma, suggesting a potential role of GSPE as a therapeutic agent for asthma.
    Journal of Clinical Immunology 07/2012; · 3.38 Impact Factor
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    ABSTRACT: Polycations such as polybrene (PB) are routinely used for most retroviral vector-mediated gene transfer studies because they can increase the infectivity of retroviruses. However, it was not systematically determined if addition of the polycation is an essential prerequisite for all retroviral transductions. To test this, we measured the effects of the polycation on transduction efficiency using various combinations of target cells and pseudotyped viral envelope (Env) proteins. Here, we show polycations do not always increase retroviral transduction efficiency and that their enhancing effect depends on both the type of target cells and Env proteins. The findings presented here also suggest that high transduction rates can be achieved in primary neural stem cells in vitro and in vivo by choosing an appropriate Env protein for pseudotyping without using polycations which are potentially toxic to primary cells and may change the intrinsic characteristics of cells.
    Neurochemistry International 03/2012; 60(8):846-51. · 2.66 Impact Factor
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    ABSTRACT: Sustained increase in [Ca(2+)](c) (Δ[Ca(2+)](c)) is a critical early signal from T-cell receptor (TCR/CD3). In general, Ca(2+)-release activated Ca(2+) channels (CRAC) are responsible for the Ca(2+) influx and Δ[Ca(2+)](c) after TCR/CD3 stimulation. However, T cells also express Ca(2+)-permeable nonselective cation channels such as TRPM2 and TRPC. Gd(3+) is a relatively selective blocker for CRAC at micromolar concentrations. Here, Jurkat T cells were used to investigate the Gd(3+)-resistant Ca(2+) influx (Δ[Ca(2+)](c,Gd)) induced by concanavalin A (ConA, 1 μg/ml), a widely used mitogenic agent for T cells, or by anti-CD3 Ab (αCD3). αCD3-induced Δ[Ca(2+)](c) was partly (~60%) inhibited by 1 μM Gd(3+) while thapsigargin-induced Δ[Ca(2+)] was almost completely abolished. ConA-induced Δ[Ca(2+)] was mostly inhibited by 1 μM Gd(3+) during the early phase (<30 s of ConA application) and became resistant during the late phase (>2 min). Induction of Δ[Ca(2+)](c,Gd) by αCD3 and ConA was inhibited by 2-aminoethoxydiphenyl borate (2-APB) and by N-(p-amylcinnamoyl) anthranilic acid, indicating that TRPM2 and TRPC are involved in this process. Treatment with Pyr-3, a TRPC3-specific inhibitor, potently suppressed Δ[Ca(2+)](c,Gd) by αCD3 (IC(50), 0.16 μM). Patch clamp experiments demonstrated that the TRPM2 channels were activated by ConA, and the TRPC-like channels were activated by αCD3. Our present study suggests that TRPM2 and TRPC3 are activated by ConA and TCR/CD3, respectively, in Jurkat T cells and are responsible for the induction of Δ[Ca(2+)](c,Gd).
    Pflügers Archiv - European Journal of Physiology 02/2012; 463(2):309-18. · 4.87 Impact Factor
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    ABSTRACT: Oxidative stress is involved in the pathogenesis of asthma, and peroxiredoxins (PRDX) may be critical in controlling intracellular oxidative stress. The aim of this study was to evaluate expressions of PRDX and their hyperoxidized forms in asthmatic individuals. The levels of expression of PRDX1, PRDX2, PRDX3, and PRDX6 and their hyperoxidized forms (PRDX-SO(3)) were measured in PBMCs from asthma patients and control subjects. In addition, cells from these subjects were treated with hydrogen peroxide (H(2)O(2)) and their intracellular concentrations of reactive oxygen species (ROS) were measured. The ratios of hyperoxidized to total PRDX (PRDX-SO(3/)PRDX) in PBMCs were significantly higher in asthma patients than in normal subjects and were correlated with disease severity, with the highest ratio seen in patients with severe asthma. Furthermore, H(2)O(2) treatment of PBMCs, particularly lymphocytes, increased intracellular ROS concentrations with greater and more persistent increases observed in cells from asthmatic than from control subjects. Hyperoxidation of PRDX may serve as a biomarker of asthma severity and may predict enhanced susceptibility to oxidative stress load in PBMCs of asthmatics.
    Life sciences 01/2012; 90(13-14):502-8. · 2.56 Impact Factor
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    ABSTRACT: Unexplained chronic cough is a common condition without specific causes. A hyperreactivity of the cough reflex has been suggested as a mechanism for inducing chronic cough. We hypothesized that nitrosative stress in the upper airway might play a role in cough hypersensitivity by causing neurochemical abnormalities. Fifty-one patients with unexplained chronic cough and 27 controls were enrolled. A capsaicin cough provocation test was performed to determine cough sensitivity. Nitrosative stress in the upper airway was assessed by quantifying 3-nitrotyrosine (3-NT) immunostaining in nasal epithelial cells (NECs) and measuring nasal nitric oxide (nNO). The effect of NO on airway epithelium was investigated by measuring the levels of substance P (SP) in nasal lavage fluid and evaluating SP expression in airway epithelial cells. Based on the results of the capsaicin test, patients were divided into two groups: a cough hypersensitivity (CHS) group and a normal cough sensitivity (NCS) group. The levels of 3-NT immunoreactivity in NECs were significantly higher in CHS (49 ± 2.9%) than in NCS (27 ± 3.3%) and controls (12 ± 1.6%), a pattern that was also reflected in the values of nNO (350 ± 43, 215 ± 23, and 138 ± 23 ppb in CHS, NCS, and controls, respectively). SP concentration was also elevated in nasal lavage fluids from CHS (746 ± 28 pg/mL) compared with that from NCS (624 ± 40 pg/mL) and controls (526 ± 41 pg/mL). SP expression in airway epithelial cells was greatly enhanced by exposure to NO donor, which was attenuated by pretreatment with either NO scavenger or NO synthase inhibitor. Increased nitrosative stress in the upper airway may play a role in the pathogenesis of unexplained chronic cough with CHS through enhanced secretion of SP.
    American Journal of Rhinology and Allergy 01/2012; 26(1):e10-4.
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    ABSTRACT: Mitogen-activated protein kinase kinase kinases (MAP3Ks) are activated by a wide spectrum of extracellular stimuli and are involved in various cellular events including proinflammatory and oxidative damage response through activations of two specific transcription factors, nuclear factor κB (NF-κB) and activator protein-1 (AP-1). Although members of the MAP3K family have both overlapping and distinct functions, the inter-regulatory mechanism of MAP3Ks remains largely unknown. In this study we demonstrated that transforming growth factor-β-activated kinase 1 (TAK1)-TAK1-binding protein 1 (TAB1) complex negatively regulates ASK1-mediated signaling, and TAB2 reciprocally regulates TAK1-induced NF-κB and apoptosis signal-regulating kinase 1 (ASK1)-mediated AP-1 activations through the TAK1-TAB2 interaction and the interferences of TAK1-ASK1 interaction. TAK1 interacted with the N or C terminus of ASK1 through the C-terminal TAB2 binding domain of TAK1, with resultant inhibition of ASK1-induced AP-1 activation. Interestingly, the interaction between TAK1 and TAB2 significantly attenuated the ASK1-TAK1 interaction through the competitive interaction with ASK1 to TAK1 and resulted in the activations of TAK1-induced activations of NF-κB and AP-1. More interestingly, H(2)O(2)- and TNF-α-induced apoptosis in TAK1-deficient mouse embryo fibroblast cells were dramatically enhanced by overexpression of ASK1, whereas the apoptosis was markedly inhibited by the overexpression of TAK1. Overall, these results demonstrate that TAK1 and its adapter protein, TAB2, reciprocally regulate both TAK1- and ASK1-mediated signaling pathways to direct the activations of NF-κB and AP-1.
    Journal of Biological Chemistry 12/2011; 287(5):3381-91. · 4.65 Impact Factor
  • Eunna Choi, Ki-Young Lee, Dongwoo Shin
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    ABSTRACT: MgtR is a 30 amino acid peptide that is encoded from the mgtCBR operon. This peptide has recently been demonstrated to interact with the MgtC virulence protein and lead to MgtC degradation. In the present study, we reveal that the MgtA Mg(2+) transporter is another protein under the direct control of the MgtR peptide. Salmonella expresses the MgtA transporter only in Mg(2+) depleted conditions. We determined that the MgtR peptide limits levels of the MgtA protein at low Mg(2+) concentrations. MgtA expression increased in a Salmonella strain lacking MgtR but decreased in a strain overexpressing MgtR. Moreover, we found that the MgtR peptide is necessary for the MgtA protein to be induced at the normal timing upon Mg(2+) starvation. The MgtR peptide did not affect transcription of the mgtA gene but specifically bound to the MgtA transporter in vivo, resembling the features of MgtR-regulated MgtC expression. MgtR-mediated regulation of MgtA expression was biologically significant because the lack of MgtR enhanced Salmonella growth in low Mg(2+).
    Biochemical and Biophysical Research Communications 12/2011; 417(1):318-23. · 2.28 Impact Factor
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    ABSTRACT: Ex vivo expansion of CD34(+) stem cells in contact culture between hCD34(+)CD38(-)Lin(-) cord blood stem cells and human delta-like-expressing AFT024 feeder cells revealed increased amounts of stemness-related proteins such as HoxB4, GATA2, Bmi-1, and p21 and anti-apoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1, and phospho-Bad, when compared with control or noncontact culture. Production of human IL-6 (hIL-6) was markedly elevated in the culture, but was profoundly inhibited by treatment with γ-secretase inhibitor. In addition, Notch-induced activation of STAT3 was directly involved in gene expression of hIL-6 and soluble hIL-6Rα, indicating the close linkage between Notch signaling and hIL-6 production. Furthermore, depletion of soluble hIL-6 (with hIL-6-specific antibodies) and inhibition of IL-6-mediated signals (with a Jak1 inhibitor and wortmannin) severely affected the maintenance of self-renewal of hCD34(+) cord blood cells. It was also observed that the ex vivo expanded CD34(+) cord blood cells were induced to reconstitute human immune cells in nonobese diabetic mice with severe combined immunodeficiency when compared with freshly isolated CD34(+) cord blood cells. Together, these results strongly demonstrate that Notch signaling in the "cell-to-cell contact" between hCD34(+) cord blood and delta-like-expressing AFT024 feeder cells facilitates maintenance of self-renewal of hCD34(+) cord blood cells through direct regulation of hIL-6 production.
    American Journal Of Pathology 11/2011; 180(1):351-64. · 4.60 Impact Factor
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    ABSTRACT: Esco2 is an acetyltransferase that is required for the establishment of sister chromatid cohesion. Roberts-SC phocomelia (RBS) syndrome caused by the mutations of Esco2 gene, is an autosomal recessive development disorder characterized by growth retardation, limb reduction and craniofacial abnormalities including cleft lip and palate. Here, we show that Esco2 protein co-immunoprecipitates with Notch but not with CBF1. Esco2 represses the transactivational activity of Notch protein in an acetyltransferase-independent manner. Chromatin immunoprecipitation experiments suggest that Esco2 might regulate the activity of NICD-CBF1 via attenuating NICD binding to CBF1 on the promoter of Hes1, the downstream target gene of Notch. Furthermore, we demonstrate that the overexpression of Esco2 promotes the neuronal differentiation of P19 embryonic carcinoma cells and C17.2 neural progenitor cells and the knockdown of Esco2 by siRNA blocks the differentiation. The inhibitory effects of Notch protein on neuronal differentiation of P19 cells was suppressed by Esco2 overexpression. Taken together, our study suggests that Esco2 may play an important role in neurogenesis by attenuating Notch signaling to promote neuronal differentiation.
    Cellular Signalling 11/2011; 23(11):1876-84. · 4.47 Impact Factor
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    ABSTRACT: Oxidative stress is implicated in the pathogenesis of allergic asthma and remains an attractive target for the prevention of the disease. Herein, we investigated the anti-inflammatory effects of apocynin, a NADPH oxidase (NOX) inhibitor, in both in vitro and in vivo allergen-induced experimental asthma mediated by Th2 hyperresponsiveness. Apocynin showed potential antioxidant activities and inhibitory effects on the activation of redox-sensitive transcription factors, such as NF-κB and AP-1, induced by pro-inflammatory stimuli, such as TNF-α, lipopolysaccharide and Poly I:C, and that inhibited the production of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6. In in vivo experimental asthma model, moreover, apocynin significantly attenuated ovalbumin-induced airway hyperresponsiveness and inflammation, as shown by the attenuation of total inflammatory cell and soluble product influx into bronchoalveolar lavage fluid, such as macrophages, eosinophils, IL-4, IL-5, IL-12, IL-13 and TNF-α. Apocynin also significantly reduced lung inflammation in the tissues. Altogether, these results suggest that apocynin may be useful in the treatment of inflammatory diseases induced by oxidative stress through NOX activity.
    Immunology and Cell Biology 06/2011; 90(4):441-8. · 3.93 Impact Factor
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    ABSTRACT: Regulation of B cell receptor (BCR)-induced Ca(2+) signaling by CD40 co-stimulation was compared in long-term BCR-stimulated immature (WEHI-231) and mature (Bal-17) B cells. In response to long-term pre-stimulation of immature WEHI-231 cells to α-IgM antibody (0.5~48 hr), the initial transient decrease in BCR-induced [Ca(2+)](i) was followed by spontaneous recovery to control level within 24 hr. The recovery of Ca(2+) signaling in WEHI-231 cells was not due to restoration of internalized receptor but instead to an increase in the levels of PLCγ2 and IP(3)R-3. CD40 co-stimulation of WEHI-231 cells prevented BCR-induced cell cycle arrest and apoptosis, and it strongly inhibited the recovery of BCR-induced Ca(2+) signaling. CD40 co-stimulation also enhanced BCR internalization and reduced expression of PLCγ2 and IP(3)R-3. Pre-treatment of WEHI-231 cells with the antioxidant N-acetyl-L-cysteine (NAC) strongly inhibited CD40-mediated prevention of the recovery of Ca(2+) signaling. In contrast to immature WEHI-231 cells, identical long-term α-IgM pre-stimulation of mature Bal-17 cells abolished the increase in BCR-induced [Ca(2+)](i), regardless of CD40 co-stimulation. These results suggest that CD40-mediated signaling prevents antigen-induced cell cycle arrest and apoptosis of immature B cells through inhibition of sustained BCR-induced Ca(2+) signaling.
    Korean Journal of Physiology and Pharmacology 06/2011; 15(3):179-87. · 1.00 Impact Factor
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    ABSTRACT: In terms of the function and reconstitution efficacy of human immune cells, co-transplantation of human fetal tissues, such as thymus and liver, with CD34(+) hematopoietic stem cells (HSCs) has potential advantages in the generation of humanized mice. To examine the effects of bone tissues in the reconstitution of human immune cells, particularly in B cells, we generated a new humanized mice co-transplanted with human fetal thymus (hFT)/fetal bone (hFB) tissues and human fetal liver-derived CD34(+) cells. Humanized mice exhibited effective reconstitution of human immune cells earlier compared to control humanized mice. In terms of quantity, the number of immune cells, such as human T, B, and monocyte/macrophages was significantly increased. Furthermore, significant increase of B cell progenitors and immature/naïve B cells could be detected in the bone marrow and spleen of humanized mice. Our results demonstrate that co-transplantation of hFB tissue may facilitate the reconstitution of human B and T cells, and therefore the humanized model may be used to develop therapeutic human antibodies for clinical use.
    Journal of Clinical Immunology 05/2011; 31(4):699-709. · 3.38 Impact Factor
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    ABSTRACT: We aimed to study the involvement of Kir3.1 channel in TLR4-mediated signaling. LPS stimulation induced the recruitment of TLR4 and Kir3.1 into the lipid raft in THP-1 cells. Treatment with Tertiapin-Q, an inhibitor of Kir3.1, markedly abolished the recruitment of TLR4 into the lipid raft and inhibited the LPS-induced NF-κB activation, resulting in decreased production of TNF-α, IL-1β, and IL-6. To verify the specific role of the Kir3.1 channel, we generated Kir3.1-knockdown THP-1 cells. The Kir3.1(KD) THP-1 cells exhibited inhibition of NF-κB activation and production of these pro-inflammatory cytokines in response to TLR4 stimulation. Taken together, our results demonstrate that the Kir3.1 channel is involved in the TLR4-mediated signal at an early event by facilitating the recruitment of TLR4 into lipid raft.
    Biochemical and Biophysical Research Communications 03/2011; 407(4):687-91. · 2.28 Impact Factor
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    ABSTRACT: In this study, we explore the possibility of human T cell development in the liver of humanized mice generated by intrahepatic injection of CD34+ hCB cells into conditioned NOD/SCID/IL-2Rγnull(NSG) newborn mice. The intrahepatic injection of CD34+ hCB cells led to effective reconstitution of human myeloid and lymphoid lineage cells. In contrast to the previously reported Rag2−/−γc−/− humanized mice, interestingly, the thymus function of humanized NSG mice was markedly reduced in terms of its size and cell contents, whereas the livers of humanized NSG mice profoundly contained double-positive (DP), hCD4 and hCD8 single positive (SP), hCD34+hCD38lohCD1a− (TSP), hCD34+hCD38hihCD1a− (ETP), and hCD34+hCD38+hCD1a+ (pre-T cells) cells. Furthermore, immunostaining of the liver revealed that human T cells were co-localized with hDCs. Taken together, our results demonstrate that the intrahepatic injection of hCD34+ hCB cells can facilitate human T cell development in the livers of humanized NSG mice.
    Clinical Immunology 01/2011; 139(3):321-335. · 3.77 Impact Factor

Publication Stats

878 Citations
208.06 Total Impact Points


  • 2008–2014
    • Sungkyunkwan University
      • Department of Molecular and Cell Biology
      Sŏul, Seoul, South Korea
    • MEDIPOST Biomedical Research Institute
      Sŏul, Seoul, South Korea
  • 2012
    • Inje University
      Kŭmhae, South Gyeongsang, South Korea
  • 2006–2012
    • Ulsan University Hospital
      Urusan, Ulsan, South Korea
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
  • 2010
    • Seegene Institute of Life Sciences
      Sŏul, Seoul, South Korea
  • 2002–2006
    • Ewha Womans University
      Sŏul, Seoul, South Korea
    • Yonsei University
      • Department of Biotechnology
      Seoul, Seoul, South Korea
    • University of Seoul
      • College of Engineering
      Seoul, Seoul, South Korea
  • 2005
    • Seoul National University Hospital
      • Department of Internal Medicine
      Sŏul, Seoul, South Korea
  • 2004–2005
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States