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Young Rae Ji,
Hei Jung Kim,
Dong Hoon Yu, Ki Beom Bae,
Seo Jin Park,
Jun Koo Yi,
Nari Kim,
Si Jun Park,
Sanggyu Lee,
Sung-Hyun Kim,
Myoung Ok Kim,
Zae Young Ryoo
[show abstract]
[hide abstract]
ABSTRACT: To investigate the role of Roquin, a RING-type ubiquitin ligase family member, we used transgenic mice having enforced Roquin expression in T cells, with collagen-induced arthritis (CIA). Wild-type (WT) and Roquin transgenic (Tg) mice were immunized with bovine type-II collagen (CII). Arthritis severity was evaluated by clinical score, histopathologic CIA severity, pro-inflammatory and anti-inflammatory cytokine levels, anti-CII antibody levels, and populations of Th1, Th2, germinal center B cells, and follicular helper T cells in CIA. T-cell proliferation in vitro and cytokine levels were determined to assess the response to CII. Roquin Tg mice developed more severe CIA and joint destruction compared with WT mice. Production of TNF-α, IFN-γ, IL-6 and pathogenic anti-collagen CII-specific IgG and IgG2a antibodies was increased in Roquin Tg mice. In addition, in vitro T-cell assays showed increased proliferation and pro-inflammatory cytokine production in response to CII as a result of enforced Roquin expression in T cells. Furthermore, the Th1/Th2 balance was altered by an increased Th1 and decreased Th2 population. These findings suggest that overexpression of Roquin exacerbates the development of CIA and enforced expression of Roquin in T cells may promote autoimmune diseases such as CIA.
Journal of Biological Chemistry 10/2012; · 4.77 Impact Factor
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Dong Hoon Yu,
Jun Koo Yi,
Hyung Soo Yuh,
Seo Jin Park,
Hei Jung Kim, Ki Beom Bae,
Young Rae Ji,
Na Ri Kim,
Si Jun Park,
Do Hyung Kim,
Sung Hyun Kim,
Myoung Ok Kim,
Jeong Woong Lee,
Zae Young Ryoo
[show abstract]
[hide abstract]
ABSTRACT: Oxidative stress such as reactive oxygen species (ROS) within the inflamed joint have been indicated as being involved as inflammatory mediators in the induction of arthritis. Correlations between extracellular- superoxide dismutase (EC-SOD) and inflammatory arthritis have been shown in several animal models of RA. However, there is a question whether the over-expression of EC-SOD on arthritic joint also could suppress the progression of disease or not. In the present study, the effect on the synovial tissue of experimental arthritis was investigated using EC-SOD over-expressing transgenic mice. The over-expression of EC- SOD in joint tissue was confirmed by RT-PCR and immunohistochemistry. The degree of the inflammation in EC-SOD transgenic mice was suppressed in the collagen-induced arthritis model. In a cytokine assay, the production of pro-inflammatory cytokines such as, IL-1β, TNFα, and matrix metalloproteinases (MMPs) was decreased in fibroblast-like synoviocyte (FLS) but not in peripheral blood. Histological examination also showed repressed cartilage destruction and bone in EC-SOD transgenic mice. In conclusion, these data suggest that the over-expression of EC-SOD in FLS contributes to the activation of FLS and protection from joint destruction by depressing the production of the pro-inflammatory cytokines and MMPs. These results provide EC-SOD transgenic mice with a useful animal model for inflammatory arthritis research.
Experimental and Molecular Medicine 06/2012; 44(9):529-35. · 2.48 Impact Factor
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Jun-Koo Yi,
Hei-Jung Kim,
Dong-Hoon Yu,
Seo-Jin Park,
Mi-Jung Shin,
Hyung-Soo Yuh, Ki-Beom Bae,
Young-Rae Ji,
Na-Ri Kim,
Si-Jun Park,
Jae-Young Kim,
Hyun-Shik Lee,
Sang-Gyu Lee,
Du Hak Yoon,
Byung-Hwa Hyun,
Wan-Uk Kim,
Zae-Young Ryoo
[show abstract]
[hide abstract]
ABSTRACT: Calcineurin-binding protein 1 (CABIN-1) regulates calcineurin phosphatase activity as well as the activation, apoptosis, and inflammatory responses of fibroblast-like synoviocytes (FLS), which actively participate in the chronic inflammatory responses in rheumatoid arthritis (RA). However, the mechanism of action of CABIN-1 in FLS apoptosis is not clear. This study was undertaken to define the regulatory role of CABIN-1 in FLS from mice with collagen-induced arthritis (CIA).
Transgenic mice overexpressing human CABIN-1 in joint tissue under the control of a type II collagen promoter were generated. Expression of human CABIN-1 (hCABIN-1) in joints and FLS was determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. The expression of cytokines, matrix metalloproteinases (MMPs), and apoptosis-related genes in FLS was determined by enzyme-linked immunosorbent assay, gelatin zymography, and RT-PCR, respectively. Joints were stained with hematoxylin and eosin and with tartrate-resistant acid phosphatase for histologic analysis.
Human CABIN-1-transgenic mice with CIA had less severe arthritis than wild-type mice with CIA, as assessed according to hind paw thickness and histologic features. The milder arthritis was accompanied by significantly enhanced apoptosis in transgenic mice, evidenced by a significantly greater number of TUNEL-positive cells in synovial tissue. Expression of inflammatory cytokines and MMPs in the transgenic mice with CIA was reduced, and they exhibited decreased Akt activation and increased expression of p53, caspase 3, caspase 9, and Bax.
Our findings demonstrate that hCABIN-1 plays a critical role in promoting apoptosis of FLS and in attenuating inflammation and cartilage and bone destruction in RA. These results help elucidate the pathogenic mechanisms of RA and suggest that CABIN-1 is a potential target for treatment of this disease.
Arthritis & Rheumatism 01/2012; 64(7):2191-200. · 7.87 Impact Factor
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Dong Hoon Yu,
Jun Ku Yi,
Seo Jin Park,
Myoung Ok Kim,
Hei Jung Kim,
Hyung Soo Yuh, Ki Beom Bae,
Young Rae Ji,
Hyun Shik Lee,
Sang Gyu Lee,
Yeon Sik Choo,
Jae Young Kim,
Du Hak Yoon,
Byung Hwa Hyun,
Zae Young Ryoo
[show abstract]
[hide abstract]
ABSTRACT: Calcineurin (CN) is a calcium- and calmodulin-dependent serine/threonine phosphatase. In immune cells, CN controls the activity of a wide range of transcription factors, including nuclear factor of activated T, nuclear factor-kappa B, c-fos, and Elk-1. CN plays an important role in synoviocyte activation and arthritis progression in vivo and this function is tightly linked to dysregulated intracellular Ca(2+) store and Ca(2+) response triggered by proinflammatory cytokines. In the present study, transgenic mice expressing human calcineurin-binding protein 1 (hCabin1) were generated, driven by type II collagen promoter, and the efficiency of these mice was investigated by experimental arthritis. These transgenic mice successfully expressed hCabin1 in joint tissue as well as other organs such as liver, heart, and brain. The overexpression of hCabin1 reduced the disease severity during collagen-induced arthritis. In fibroblast-like synoviocytes (FLSs) from hCabin1 transgenic mice, the productions of these cytokines, including interleukin (IL)-2, IL-4, and IFN-γ, were decreased and matrix metalloproteinases were also depressed in transgenic mice FLS. In addition, these effects were only found in the joint tissue, which is a major inflammation site. These findings will provide a better knowledge of the pathogenic mechanisms of rheumatoid arthritis and a potential animal model of the chronic inflammatory conditions, including atherosclerosis and transplantation.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 12/2011; 32(1):6-11. · 1.63 Impact Factor
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Nari Kim, Ki Beom Bae,
Myoung Ok Kim,
Dong Hoon Yu,
Hei Jung Kim,
Hyung Soo Yuh,
Young Rae Ji,
Si Jun Park,
Sol Kim,
Kyu-Hee Son,
Sang-Joon Park,
Duhak Yoon,
Dong-Seok Lee,
Sanggyu Lee,
Hyun-Shik Lee,
Tae-Yoon Kim,
Zae Young Ryoo
[show abstract]
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ABSTRACT: Atopic dermatitis (AD) is a chronically relapsing, noncontagious pruritic skin disease with two phases: acute and chronic. Previous studies have shown that the cysteine protease cathepsin S (CTSS) is linked to inflammatory processes, including atherosclerosis and asthma. The possibility that this or other cysteine proteases might cause itching or be part of a classical ligand-receptor signaling cascade has not been previously considered. Recently, CTSS was shown to be a ligand for proteinase-activated receptor-2 (PAR-2), which is associated with itching. In this study, we show that CTSS-overexpressing transgenic (TG) mice spontaneously develop a skin disorder similar to chronic AD. The results of this study suggest that CTSS overexpression triggers PAR-2 expression in dendritic cells (DCs), resulting in the promotion of CD4(+) differentiation, which is involved in major histocompatibility complex (MHC) class II expression. In addition, we investigated mast cells and macrophages and found significantly higher mean levels of T helper type 1 (Th1) cell-associated cytokines than T helper type 2 (Th2) cell-associated cytokines in CTSS-overexpressing TG mice. These results suggest that increased PAR-2 expression in DCs as a result of CTSS overexpression induces scratching behavior and Th1 cell-associated cytokine expression, and can trigger chronic AD symptoms.
Journal of Investigative Dermatology 12/2011; 132(4):1169-76. · 6.31 Impact Factor
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Hei Jung Kim,
Young Rae Ji,
Myoung Ok Kim,
Dong Hoon Yu,
Mi Jung Shin,
Hyung Soo Yuh, Ki Beom Bae,
Seo jin Park,
Jun Koo Yi,
Na Ri Kim,
Si Jun Park,
Du Hak Yoon,
Won-Ha Lee,
Sanggyu Lee,
Zae Young Ryoo
[show abstract]
[hide abstract]
ABSTRACT: The T-cell receptor (TCR) engages with an antigen and initiates a signaling cascade that leads to the activation of transcription factors. Roquin, a protein encoded by the RC3H1 gene and characterized as an immune regulator, was recently identified as a novel RING-type ubiquitin ligase family member, but the mechanisms by which Roquin regulates T-cell responses are unclear. We used the EL-4 murine lymphoma cell line to elucidate the role of Roquin in vitro. Roquin-overexpressing EL-4 cells became hyper-responsive after anti-CD3/CD28 stimulation in vitro and were a major source of the cytokines IL-2 and TNF-α. Upon activation, these cells showed particularly enhanced production of IL-2 and TNF-α. To clarify the important role played by Roquin in T-cell responses ex vivo, we generated T-cell-specific Roquin transgenic (Tg) mice. Roquin-Tg CD4(+) T-cells showed enhanced production of IL-2 and TNF-α in response to TCR stimulation with anti-CD28 co-stimulation. Further studies are necessary to investigate the role of Roquin in the regulation of primary T-cell activation, survival, and differentiation.
Biochemical and Biophysical Research Communications 11/2011; 417(1):280-6. · 2.48 Impact Factor
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Ki Beom Bae,
Myoung Ok Kim,
Dong Hoon Yu,
Mi Jung Shin,
Hei Jung Kim,
Hyung Soo Yuh,
Young Rae Ji,
Jae-Young Kim,
Jin Man Kim,
Byung Hwa Hyun,
Hwi Cheul Lee,
Won Kyong Chang,
Soo Bong Park,
Do Hyung Kim,
Hyun-Shik Lee,
Yeon-Sik Choo,
Sanggyu Lee,
Zae Young Ryoo
[show abstract]
[hide abstract]
ABSTRACT: The transcription factor Juxtaposed with another zinc finger gene 1 (JAZF1) is a zinc finger protein that binds to the nuclear orphan receptor TR4. Recent evidence indicates that TR4 receptor functions as both a positive and negative regulator of transcription, but the role of JAZF1 in transcriptional mechanisms has not been elucidated. Recently, the incidence rate of congenital heart malformations was reported to be significantly elevated in patients who had neurofibromatosis 1 (NF1) with chromosomal microdeletion syndrome. Furthermore, Joined to JAZF1 (SUZ12) is expressed at high levels in the hearts of adult patients with NF1 microdeletion syndrome. Therefore, we hypothesized that ectopic expression of JAZF1 may lead to cardiac malformations that deleteriously affect the survival of neonates and adults. We sought to elucidate the role of JAZF1 in cardiac development using a Jazf1-overexpressing (Jazf1-Tg) mouse model. In Jazf1-Tg mice, Jazf1 mRNA expression was significantly elevated in the heart. Jazf1-Tg mice also showed cardiac defects, such as high blood pressure, electrocardiogram abnormalities, apoptosis of cardiomyocytes, ventricular non-compaction, and mitochondrial defects. In addition, we found that the expression levels of pro-apoptotic genes were elevated in the hearts of Jazf1-Tg mice. These findings suggest that Jazf1 overexpression may induce heart failure symptoms through the upregulation of pro-apoptotic genes in cardiomyocytes.
Transgenic Research 01/2011; 20(5):1019-31. · 2.75 Impact Factor
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Young Rae Ji,
Myoung Ok Kim,
Sung Hyun Kim,
Dong Hun Yu,
Mi Jung Shin,
Hei Jung Kim,
Hyung Soo Yuh, Ki Beom Bae,
Jae Young Kim,
Hum Dai Park,
Sang Gyu Lee,
Byung Hwa Hyun,
Zae Young Ryoo
[show abstract]
[hide abstract]
ABSTRACT: Wnt/Wg genes play a critical role in the development of various organisms. For example, the Wnt/beta-catenin signal promotes heart formation and cardiomyocyte differentiation in mice. Previous studies have shown that RGS19 (regulator of G protein signaling 19), which has Galpha subunits with GTPase activity, inhibits the Wnt/beta-catenin signal through inactivation of Galpha(o). In the present study, the effects of RGS19 on mouse cardiac development were observed. In P19 teratocarcinoma cells with RGS19 overexpression, RGS19 inhibited cardiomyocyte differentiation by blocking the Wnt signal. Additionally, several genes targeted by Wnt were down-regulated. For the in vivo study, we generated RGS19-overexpressing transgenic (RGS19 TG) mice. In these transgenic mice, septal defects and thin-walled ventricles were observed during the embryonic phase of development, and the expression of cardiogenesis-related genes, BMP4 and Mef2C, was reduced significantly. RGS19 TG mice showed increased expression levels of brain natriuretic peptide and beta-MHC, which are markers of heart failure, increase of cell proliferation, and electrocardiogram analysis shows abnormal ventricle repolarization. These data provide in vitro and in vivo evidence that RGS19 influenced cardiac development and had negative effects on heart function.
Journal of Biological Chemistry 09/2010; 285(37):28627-34. · 4.77 Impact Factor
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Young Rae Ji,
Myoung Ok Kim,
Sung Hyun Kim,
Dong Hun Yu,
Mi Jung Shin,
Hei Jung Kim,
Hyung Soo Yuh, Ki Beom Bae,
Jae Young Kim,
Hum Dai Park,
Sang Gyu Lee,
Byung Hwa Hyun,
Zae Young Ryoo
[show abstract]
[hide abstract]
ABSTRACT: Wnt/Wg genes play a critical role in the development of various organisms. For example, the Wnt/β-catenin signal promotes
heart formation and cardiomyocyte differentiation in mice. Previous studies have shown that RGS19 (regulator of G protein signaling 19), which has Gα subunits with GTPase activity, inhibits the Wnt/β-catenin signal through inactivation of Gαo. In the present study, the effects of RGS19 on mouse cardiac development were observed. In P19 teratocarcinoma cells with
RGS19 overexpression, RGS19 inhibited cardiomyocyte differentiation by blocking the Wnt signal. Additionally, several genes
targeted by Wnt were down-regulated. For the in vivo study, we generated RGS19-overexpressing transgenic (RGS19 TG) mice. In these transgenic mice, septal defects and thin-walled
ventricles were observed during the embryonic phase of development, and the expression of cardiogenesis-related genes, BMP4
and Mef2C, was reduced significantly. RGS19 TG mice showed increased expression levels of brain natriuretic peptide and β-MHC,
which are markers of heart failure, increase of cell proliferation, and electrocardiogram analysis shows abnormal ventricle
repolarization. These data provide in vitro and in vivo evidence that RGS19 influenced cardiac development and had negative effects on heart function.
Journal of Biological Chemistry 09/2010; 285(37):28627-28634. · 4.77 Impact Factor
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Mi Jung Shin,
Jeong-Han Lee,
Dong Hoon Yu,
Hye Jung Kim, Ki Beom Bae,
Hyung Soo Yuh,
Myoung Ok Kim,
Byung-Hwa Hyun,
Sanggyu Lee,
Raekil Park,
Zae Young Ryoo
[show abstract]
[hide abstract]
ABSTRACT: The circling (cir/cir) mouse is a murine model for human nonsyndromic deafness DFNB6. Transmembrane inner ear (tmie) is the causative gene and its mutation through deletion of a 40-kilobase genomic region including tmie leads to deafness. The function of Tmie is unknown. To better understand the function of Tmie, we focused on the spatiotemporal expression of tmie in the rat cochlea by using a Tmie-specific antibody. Results showed that tmie expression was prominent in early postnatal rat cochleas in the stereocilia bundles of hair cells. The Tmie signal spread from the stereocilia to the hair cell body region and on to organ of Corti cells. No Tmie signal was observed in cell nuclei; Tmie was localized to the cytoplasm. Because Tmie is predicted to have 1 or 2 transmembrane domains, we postulate that it is localized to membrane-based organelles or the plasma membrane. Our results imply that Tmie exists in the cytoplasm and may have a key role in the maturation and structure of stereocilia bundles in developing hair cells. After hair cell maturation, Tmie is thought to be involved in the maintenance of organ of Corti cells.
Comparative medicine 08/2010; 60(4):288-94. · 1.05 Impact Factor
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[show abstract]
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ABSTRACT: This experimental study evaluated the effectiveness and safety of using cyanoacrylate adhesive for sutureless colonic anastomosis and as a protective seal to prevent leakage.
Sixty male Sprague-Dawley rats (300 +/- 10 g, 9 weeks old) were divided into three groups: in group I, the anastomosis was sutured in a single layer with 5-0 polypropylene; in group II, the anastomosis was fixed using N-butyl-2-cyanoacrylate (Histoacryl(R)); and in group III, the anastomosis was sutured and then sealed with N-butyl-2-cyanoacrylate. The rats were sacrificed on postoperative day 7. The anastomoses among the three groups were compared by measuring wound infection, anastomotic leakage, anastomotic stricture, adhesion formation, anastomotic bursting pressure, and histological appearance.
No anastomotic leakage was observed in any group. Anastomotic stricture was significantly more extensive in groups II and III (p < 0.001). Bursting pressure was significantly lower in groups II and III (168 +/- 58, 45 +/- 21, and 60 +/- 38 mmHg for groups I to III, respectively, p < 0.001). The severity of inflammatory reactions was significantly greater and collagen deposition was significantly lower in groups II and III (p < 0.05).
N-butyl-2-cyanoacrylate could be a useful method for sutureless colonic anastomosis based on the absence of anastomotic leakage, but it may impede healing of the colonic anastomosis. In addition, when used to seal sutured colonic anastomoses, cyanoacrylate may have a negative influence on anastomotic healing. The clinical use of N-butyl-2-cyanoacrylate in colonic anastomosis does not appear to be acceptable and safer anastomotic methods or alternative forms of cyanoacrylate should be developed.
International Journal of Colorectal Disease 05/2010; 25(5):601-6. · 2.38 Impact Factor
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[show abstract]
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ABSTRACT: A human monoclonal antibody can be a good method for tumor diagnosis and treatment. This study is aimed at the generation of human antibody fragments against urokinase plasminogen activator (uPA) known to be related to tumor metastasis using the naive human antibody phage display library. Three clones--A2, A8, and E4--were selected from 1 x 10(10) sized human naïve antibody phage library using BIAcore rescue and screen. Clone A8 was finally selected by flow cytometry against Hep3 and HT1080, uPA overexpressing tumor cell lines. A8 clone consisted of 324 bp lambda and 402 bp heavy chains. The affinity (K(D)) of purified A8 antibody fragments was 1.44 x 10(-8) M(-1). The antibody fragment was reacted with HT1080 in a dose-dependent manner but not reacted with LS513 normal fibroblast. In this study, uPA specific human monoclonal antibody fragment A8 was made with BIAcore selection. Selected A8 was bound specifically to uPA expressed on the tumor cell surface. Further study for the application of A8 antibody clones will be needed.
Hybridoma (2005) 04/2010; 29(2):147-52. · 0.42 Impact Factor
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Hyunji Lee,
Ji Hyun Kim,
Sung Yeun Yang,
Jihye Kong,
Minkyung Oh,
Dae Hoon Jeong,
Jae-Il Chung, Ki Beom Bae,
Jin Yong Shin,
Kwan Hee Hong,
Inhak Choi
[show abstract]
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ABSTRACT: To associate the global gene expression of B7/CD28 family transcripts with pathologic features of colon cancer, we determined the B7/CD28 family transcripts in peripheral blood mononuclear cells (PBMCs) from normal subjects and patients with adenomatous polyps and colon cancer, and correlated the results with pathologic features of colon cancer.
PBMCs from age-matched normal subjects and patients with adenomatous polyps and colon cancer were analyzed for peripheral blood transcripts (PBTs) of B7/CD28 family using real-time PCR. Differences in expression levels of B7/CD28 PBTs across all cancer stages and between colon cancer patients with or without microscopic lymphovascular invasion (LVI) were analyzed.
The results showed a significant upregulation of PBTs of co-inhibitory molecules such as B7-H3 and PD-1 and a significant PBT downregulation of co-stimulatory molecules including CD28 and ICOS in colon cancer patients. Furthermore, the increase of B7-H3 PBT was strongly associated with tumor invasion (P = 0.025) and advanced TNM stages (P = 0.019), whereas the decline of co-stimulatory ligand B7-H2 PBT was related to regional lymph node metastasis (P = 0.028) and aggressive tumor invasion (P = 0.031). In addition, the ratios of PBT expression of CD28 family to B7 family such as CTLA-4 to B7-H2 and PD-1 to B7-H2 were significantly higher in colon cancer patients with microscopic LVI than in those without LVI (P = 0.001 and P = 0.016, respectively).
Our results suggest that B7/CD28 family PBTs may serve as valuable markers reflecting the pathological features of colon cancer.
Journal of Cancer Research and Clinical Oncology 02/2010; 136(9):1445-52. · 2.56 Impact Factor
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[show abstract]
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ABSTRACT: A 79-year-old man was diagnosed with scrub typhus based on fever, eschar, skin rash and a markedly elevated serum tsutsugamushi antibody and doxycycline was started. Five days later, hematochezia developed and multiple small bowel ulcerations with hemorrhage were seen on colonoscopy. Despite intensive therapy, the massive hematochezia worsened and the distal small bowel was resected. Multiple ulcerated lesions were identified pathologically as vasculitis caused by scrub typhus. This is the first reported case of pathologically proven small bowel involvement in scrub typhus infection.
World journal of gastrointestinal surgery. 02/2010; 2(2):47-50.
