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1.  Restoration of ASC expression sensitizes colorectal cancer cells to genotoxic stress-induced caspase-independent cell death 
Cancer letters  2013;331(2):183-191.
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an essential component of the inflammasome complex, is frequently silenced by epigenetic methylation in many tumor cells. Here, we demonstrate that restoration of ASC expression in human colorectal cancer DLD-1 cells, in which ASC is silenced by aberrant methylation, potentiated cell death mediated by DNA damaging agent. Contrarily, ASC knockdown in HT-29 cells rendered cells less susceptible to etoposide toxicity. The increased susceptibility of ASC-expressing DLD-1 cells to genotoxic stress was independent of inflammasome or caspase activation, but partially dependent on mitochondrial ROS production and JNK activation. Thus, our data suggest that ASC expression in cancer cells is an important factor in determining their susceptibility to chemotherapy.
PMCID: PMC3627217  PMID: 23321501
ASC; DLD-1; Methylation; DNA damaging agent; Cell death
2.  Leptin and peroxisome proliferator-activated receptor γ expression in colorectal adenoma 
AIM: To investigate the expressions of leptin and peroxisome proliferator-activated receptor γ (PPARG) in relation to body mass index (BMI).
METHODS: We evaluated leptin and PPARG expression in 30 adenomas over 1 cm in size by immunohistochemical staining. In addition, clinicopathologic features including BMI were assessed.
RESULTS: PPARG and leptin expression showed a strong positive correlation (P = 0.035). The average BMI of the leptin-positive group was higher than that of the leptin-negative group (25.4 ± 3.4 kg/m2 vs 22.6 ± 2.4 kg/m2, P = 0.018), and leptin expression was significantly correlated with high BMI (P = 0.024). Leptin expression was more frequently observed in intermediate/high grade dysplasia than in low grade dysplasia (P = 0.030). However, PPARG expression was not correlated with BMI and grade of dysplasia.
CONCLUSION: BMI has influenced on the leptin expression of colorectal adenoma. The exact mechanism underlies the strong correlation between leptin and PPARG expression needs further study.
PMCID: PMC3280402  PMID: 22363123
Leptin; Peroxisome proliferator-activated receptor γ; Obesity; Body mass index; Colorectal adenoma
4.  Stone extraction balloon-guided repeat self-expanding metal stent placement 
Self-expanding metal stent (SEMS) placement offers safe and effective palliation in patients with upper gastrointestinal obstruction due to a malignancy. Well described complications of SEMS placement include tumor growth, obstruction, and stent migration. SEMS occlusions are treated by SEMS redeployment, argon plasma coagulation application, balloon dilation, and surgical bypass. At our center, we usually place the second SEMS into the first SEMS if there is complete occlusion by the tumor. We discovered an unusual complication during SEMS redeployment. The guidewire passed through the mesh of the first SEMS and caused the second SEMS to become entangled with the first SEMS. This led to the distortion and malfunction of the second SEMS, which worsened the gastric outlet obstruction. For lowering the risk of entanglement, we studied stone extraction balloon-guided repeat SEMS placement. This is the first report of a SEMS entangled by the mesh of the first SEMS and stone extraction balloon-guided repeat SEMS placement for lowering the risk of this complication.
PMCID: PMC2890952  PMID: 20572315
Gastric outlet obstruction; Self-expanding metal stent
5.  Clinical Characteristics of Colonic Diverticulosis in Korea: A Prospective Study 
The prevalence of colonic diverticulosis has been reported to be lower in Korea than in Western countries. This disease also shows markedly different characteristics in the Korean population. We describe herein a prospective investigation, based on colonoscopic examination, of the prevalence, clinical characteristics, and factors associated with colonic diverticulosis in Korea.
The prevalence of colonic diverticulosis has been reported to be lower in Korea than in Western countries. This disease also shows markedly different characteristics in the Korean population. We describe herein a prospective investigation, based on colonoscopic examination, of the prevalence, clinical characteristics, and factors associated with colonic diverticulosis in Korea.
The overall prevalence of colonic diverticulosis was 12.1% (103 / 848). The right side of the colon was involved in 84.5% of patients (87 / 103); patients with right side diverticula were, on average, younger than those with left side diverticulosis (p = 0.014). Multiple diverticula were observed in 60.2% (62 / 103) of patients. Age greater than 60 years, a high-fat diet, and alcohol consumption were significantly associated with the presence of colonic diverticulosis (p < 0.05).
The prevalence of colonic diverticulosis in Korea is increasing and is most commonly located in the right side of the colon. Further, old age and diet may affect the risk of development of this disease.
PMCID: PMC2880686  PMID: 20526386
Diverticulum, colon; Korea; Colonoscopy; Prospective studies
6.  Mycobacterium ulcerans infection as a cause of chronic diarrhea in an AIDS patient: A case report 
Chronic diarrhea is one of the most frequent gastro-intestinal manifestations in acquired immunodeficiency syndrome (AIDS). Protozoa and nontuberculous mycobacteria (NTM) are opportunistic pathogens that can easily infect these patients. Among the NTM, Mycobacterium avium complex (MAC) is the most frequently observed pathogen in HIV-infected patients. However, NTMs other than MAC have not been reported as a gastrointestinal pathogen as yet. We present a case of chronic diarrhea in an AIDS patient in whom Mycobacterium ulcerans and cryptosporidium co-infection is evidenced from colonic tissue.
PMCID: PMC2684015  PMID: 18205278
Mycobacterium ulcerans; Cryptosporidium; HIV; Chronic diarrhea
7.  Role of Regulatory T Cells in Transferable Immunological Tolerance to Bone Marrow Donor in Murine Mixed Chimerism Model 
Journal of Korean Medical Science  2013;28(12):1723-1728.
Constructing a bone marrow chimera prior to graft transplantation can induce donor-specific immune tolerance. Mixed chimerism containing hematopoietic cells of both recipient- and donor-origin has advantages attributed from low dose of total body irradiation. In this study, we explored the mechanism of mixed chimerism supplemented with depletion of Natural Killer cells. Mixed chimerism with C57BL/6 bone marrow cells was induced in recipient BALB/c mice which were given 450 cGy of γ-ray irradiation (n = 16). As revealed by reduced proliferation and cytokine production in mixed leukocyte reaction and ELISpot assay (24.6 vs 265.5), the allo-immune response to bone marrow donor was reduced. Furthermore, the induction of transferable immunological tolerance was confirmed by adoptive transfer and subsequent acceptance of C57BL/6 skin graft (n = 4). CD4+FoxP3+ regulatory T cells were increased in the recipient compartment of the mixed chimera (19.2% → 33.8%). This suggests that regulatory T cells may be therapeutically used for the induction of graft-specific tolerance by mixed chimerism.
PMCID: PMC3857366  PMID: 24339700
Bone Marrow Transplantation; Immune Tolerance; Natural Killer Cells; Regulatory T Cells
8.  High Rates of Detection of Respiratory Viruses in the Nasal Washes and Mucosae of Patients with Chronic Rhinosinusitis 
Journal of Clinical Microbiology  2013;51(3):979-984.
Respiratory viral infections are often implicated as triggers of chronic rhinosinusitis (CRS) flare-ups. However, there is a paucity of respiratory viral surveillance studies in CRS patients, and such studies could elucidate the potential role of viruses in promoting symptoms and aggravating mucosal inflammation. Therefore, a prospective case-control study was conducted to determine the prevalence of respiratory viruses in CRS patients and non-CRS controls. Nasal lavage fluids and turbinate epithelial cells were collected prospectively from 111 CRS patients and 50 controls. Multiplex PCR was used to identify common respiratory viruses in both sample types and the infection rate was compared between groups. Respiratory viruses were detected in 50.5% of lavage samples and in 64.0% of scraping samples from CRS patients. The overall infection rate was significantly different in CRS patients and controls (odds ratio, 2.9 in lavage and 4.1 in scraping samples). Multiple viral infections were detected more frequently in lavage samples from CRS patients than those from controls (P < 0.01; odds ratio, 7.7). Rhinovirus was the most prevalent virus and the only virus with a significantly different infection rate in CRS patients and controls in both samples (odds ratio, 3.2 in lavage and 3.4 in scraping samples). This study detected a higher prevalence of respiratory viruses in CRS patients than controls, suggesting that there may be significant associations between inflammation of CRS and respiratory viruses, particularly rhinovirus. Further studies should investigate the exact role of highly prevalent respiratory viruses in CRS patients during symptomatic aggravation and ongoing mucosal inflammation.
PMCID: PMC3592049  PMID: 23325817
9.  Photodynamic Therapy with Ablative Carbon Dioxide Fractional Laser for Treating Bowen Disease 
Annals of Dermatology  2013;25(3):335-339.
Topical photodynamic therapy (PDT) has been increasingly used to treat malignant skin tumors including the Bowen disease. However, patients could be displeased with the long incubation time required for conventional PDT.
We evaluated the efficacy and safety of PDT with a short incubation time of ablative CO2 fractional laser pretreatment for treating Bowen disease.
Ten patients were included. Just before applying the topical photosensitizer, all lesions were treated with ablative CO2 fractional laser, following the application of methyl aminolevulinate and irradiation with red light (Aktilite CL 128). Histological confirmation, rebiopsy, and clinical assessments were performed. Adverse events were also recorded.
Five of the ten (50%) lesions showed a complete response (CR) within three PDT sessions. After four treatment sessions, all lesions except one penile shaft lesion (90%) achieved clinical and histological CR or clinical CR only. The average number of treatments to CR was 3.70±1.70. The treatments showed favorable cosmetic outcomes and no serious adverse events.
The results suggest that pretreatment with an ablative fractional CO2 laser before PDT has similar treatment efficacy and requires a shorter photosensitizer incubation time compared with the conventional PDT method.
PMCID: PMC3756199  PMID: 24003277
Ablative carbon dioxide fractional laser; Bowen disease; Photodynamic therapy; Pretreatment
10.  Immunopathogenesis of Allergic Asthma: More Than the Th2 Hypothesis 
Asthma is a chronic obstructive airway disease that involves inflammation of the respiratory tract. Biological contaminants in indoor air can induce innate and adaptive immune responses and inflammation, resulting in asthma pathology. Epidemiologic surveys indicate that the prevalence of asthma is higher in developed countries than in developing countries. The prevalence of asthma in Korea has increased during the last several decades. This increase may be related to changes in housing styles, which result in increased levels of indoor biological contaminants, such as house dust mite-derived allergens and bacterial products such as endotoxin. Different types of inflammation are observed in those suffering from mild-to-moderate asthma compared to those experiencing severe asthma, involving markedly different patterns of inflammatory cells and mediators. As described in this review, these inflammatory profiles are largely determined by the involvement of different T helper cell subsets, which orchestrate the recruitment and activation of inflammatory cells. It is becoming clear that T helper cells other than Th2 cells are involved in the pathogenesis of asthma; specifically, both Th1 and Th17 cells are crucial for the development of neutrophilic inflammation in the airways, which is related to corticosteroid resistance. Development of therapeutics that suppress these immune and inflammatory cells may provide useful asthma treatments in the future.
PMCID: PMC3695232  PMID: 23814671
Allergic asthma; endotoxin; immunopathogenesis; T helper cell
11.  Predictive factors that influence the survival rates in liver cirrhosis patients with spontaneous bacterial peritonitis 
Clinical and molecular hepatology  2013;19(2):131-139.
Spontaneous bacterial peritonitis (SBP) has been known to greatly influence the survival rate of patients with liver cirrhosis. However, the factors that affect the survival rate in patients with SBP need to be clarified.
This study enrolled 95 liver cirrhosis patients diagnosed with SBP. The laboratory findings of their serum and ascitic fluid were examined and the characteristics of the isolated microorganisms in their peritoneal fluid were analyzed.
The proportion of patients with culture-positive SBP was 41.1%, and 47 microorganisms were isolated from the ascitic fluid. The proportions of cultured bacteria that were Gram negative and Gram positive were 57.4% and 40.4%, respectively. The proportions of Escherichia coli, Klebsiella species, and Streptococcus species were 25.5%, 19.1%, and 19.1%, respectively. Enterococcus species represented 12.8% of the microorganisms cultured. The overall survival rates at 6, 12, and 24 months were 44.5%, 37.4%, and 32.2%, respectively. There was no relationship between the bacterial factors and the survival rate in SBP. Multivariate analysis revealed that the presence of hepatocellular carcinoma (HCC; P=0.001), higher serum bilirubin levels (≥3 mg/dL, P=0.002), a prolonged serum prothrombin time (i.e., international normalized ratio >2.3, P<0.001), renal dysfunction (creatinine >1.3 mg/dL, P<0.001), and lower glucose levels in the ascitic fluid (<50 mg/dL, P<0.001) were independent predictive factors of overall survival rate.
HCC, higher serum bilirubin levels, a prolonged serum prothrombin time, renal dysfunction, and lower ascitic glucose levels are associated with higher mortality rates in cirrhotic patients with SBP.
PMCID: PMC3701845  PMID: 23837137
Liver cirrhosis; Peritonitis; Bacteria; Mortality; Risk factors
12.  Activation of Rice nicotianamine synthase 2 (OsNAS2) Enhances Iron Availability for Biofortification 
Molecules and Cells  2012;33(3):269-275.
Because micronutrients in human diets ultimately come from plant sources, malnutrition of essential minerals is a significant public health concern. By increasing the expression of nicotianamine synthase (NAS), we fortified the level of bioavailable iron in rice seeds. Activation of iron deficiency-inducible OsNAS2 resulted in a rise in Fe content (3.0-fold) in mature seeds. Its ectopic expression also increased that content. Enhanced expression led to higher tolerance of Fe deficiency and better growth under elevated pH. Mice fed with OsNAS2-D1 seeds recovered more rapidly from anemia, indicating that bioavailable Fe contents were improved by this increase in OsNAS2 expression.
PMCID: PMC3887711  PMID: 22228185
anemia; bioavailability; mouse; rice
13.  Miniprobe Endoscopic Ultrasonography Has Limitations in Determining the T Stage in Early Colorectal Cancer 
Gut and Liver  2013;7(2):163-168.
Mini-probe endoscopic ultrasonography (mEUS) is a useful diagnostic tool for accurate assessment of tumor invasion. The aim of this study was to estimate the accuracy of mEUS in patients with early colorectal cancer (ECC).
Ninety lesions of ECC underwent mEUS for pre-treatment staging. We divided the lesions into either the mucosal group or the submucosal group according to the mEUS findings. The histological results of the specimens were compared with the mEUS findings.
The overall accuracy for assessing the depth of tumor invasion (T stage) was 84.4% (76/90). The accuracy of mEUS was significantly lower for submucosal lesions compared to mucosal lesions (p=0.003) and it was lower for large tumors (≥2 cm) (p=0.034). The odds ratios of large tumors and submucosal tumors affecting the accuracy of T staging were 3.46 (95% confidence interval [CI], 1.05 to 11.39) and 6.25 (95% CI, 1.85 to 25.14), respectively. When submucosal tumors were combined with large size, the odds ratio was 14.67 (95% CI, 1.46 to 146.96).
The overall accuracy of T stage determination with mEUS was considerably high in patients with ECC; however, the accuracy decreased when tumor size was >2 cm or the tumor had invaded the submucosal layer.
PMCID: PMC3607769  PMID: 23560151
Colorectal neoplasms; Endosonography
14.  Vascular Endothelial Growth Factor Is a Key Mediator in the Development of T Cell Priming and Its Polarization to Type 1 and Type 17 T Helper Cells in the Airways 
Chronic inflammatory airway diseases including asthma are characterized by immune dysfunction to inhaled allergens. Our previous studies demonstrated that T cell priming to inhaled allergens requires LPS, which is ubiquitously present in household dust allergens. In this study, we evaluated the role of vascular endothelial growth factor (VEGF) in the development of T cell priming and its polarization to Th1 or Th17 cells when exposed to LPS-contaminated allergens. An asthma mouse model was induced by airway sensitization with LPS-contaminated allergens and then challenged with allergens alone. Therapeutic intervention was performed during allergen sensitization. The present study showed that lung inflammation induced by sensitization with LPS-contaminated allergens was decreased in mice with homozygous disruption of the IL-17 gene; in addition, allergen-specific Th17 immune response was abolished in IL-6 knockout mice. Meanwhile, in vivo production of VEGF was up-regulated by airway exposure of LPS. In addition, airway sensitization of allergen plus recombinant VEGF induced both type 1 and type 17 Th cell (Th1 and Th17) responses. Th1 and Th17 responses induced by airway sensitization with LPS-contaminated allergens were blocked by treatment with a pan-VEGF receptor (VEGFR; VEGFR-1 plus VEGFR-2) inhibitor during sensitization. These effects were accompanied by inhibition of the production of Th1 and Th17 polarizing cytokines, IL-12p70 and IL-6, respectively. These findings indicate that VEGF produced by LPS plays a key role in activation of naive T cells and subsequent polarization to Th1 and Th17 cells.
PMCID: PMC3385973  PMID: 19786548
15.  A HIF-1 Target, ATIA, Protects Cells from Apoptosis by Modulating the Mitochondrial Thioredoxin, TRX2 
Molecular cell  2011;42(5):597-609.
The regulation of apoptosis is critical for controlling tissue homeostasis and preventing tumor formation and growth. Reactive Oxygen Species (ROS) generation plays a key role in such regulation. Here, we describe a HIF-1 target, ATIA (anti-TNFα-induced apoptosis), which protects cells against TNFα- and hypoxia-induced apoptosis. Through the generation of ATIA knockout mice, we show that ATIA protects cells from apoptosis through regulating the function of the mitochondrial antioxidant, thioredoxin-2, and ROS generation. ATIA is highly expressed in human glioblastoma and ATIA knockdown in glioblastoma cells renders them sensitive to hypoxia-induced apoptosis. Therefore, ATIA is not only a HIF-1 target that regulates mitochondrial redox pathways but a potentially diagnostic marker and therapeutic target in human glioblastoma.
PMCID: PMC3138416  PMID: 21658601
16.  Characterization of Cases of Clostridium difficile Infection (CDI) Presenting at an Emergency Room: Molecular and Clinical Features Differentiate Community-Onset Hospital-Associated and Community-Associated CDI in a Tertiary Care Hospital▿ 
Journal of Clinical Microbiology  2011;49(6):2161-2165.
Definition of community-onset, hospital-acquired Clostridium difficile infection (CO-HA-CDI) is difficult in patients presenting with diarrhea at hospitals or outpatient clinics, especially 4 to 12 weeks after the last discharge. We performed C. difficile stool culture for 272 diarrheic patients visiting the emergency room (ER) between January 2006 and June 2010. C. difficile was isolated from 36 cases (13.2%), and isolation rates increased year by year, from 10.1% in 2008 to 12.4% in 2009 and 16.7% in 2010. Among 32 toxin-positive isolates, 13 (40.6%) and 19 (59.4%) were associated with CO-HA-CDI and community-acquired CDI (CA-CDI), respectively, if cases with CDI diagnosed within 12 weeks after discharge were considered hospital associated. The majority (70%) of CO-HA-CDI cases occurred within 2 weeks after hospital discharge, although the interval from discharge to onset of symptoms was as long as 10 weeks. We found via tcdA and tcdB and repetitive sequence PCR analysis, that toxin A-positive/toxin B-positive isolates were the most prevalent in both CO-HA-CDI (53.8%) and CA-CDI (94.7%) cases. Toxin A-negative/toxin B-positive isolates were also still highly associated with HA-CDI cases but were also observed in CA-CDI cases. Younger age, fewer underlying diseases, lack of prior antibiotic use, and genetic diversity of isolates in repetitive sequence PCR were the main characteristics in CA-CDI cases visiting the ER.
PMCID: PMC3122747  PMID: 21471341
17.  Heat Shock Proteins and Autophagy in Rats with Cerulein-Induced Acute Pancreatitis 
Gut and Liver  2011;5(4):513-520.
Heat shock proteins (HSPs) protect rats from cerulein-induced acute pancreatitis (AP) by preventing the subcellular redistribution of cathepsin B and the activation of trypsinogen. Autophagy plays a critical role in the secretion of digestive enzymes and triggering of cerulein-induced AP via the colocalization of trypsinogen and lysosomes. Therefore, using a rat cerulein-induced AP model, we investigated whether HSPs prevent AP by regulating autophagy.
Twelve hours after fed standard laboratory chow and water, the experimental groups (cerulein, water-immersion [WI]-cerulein and heat-shock [HS]-cerulein) and the control groups (control, WI, and HS) received one intraperitoneal injection of cerulein (50 µg/kg) or saline, respectively. All of the rats were sacrificed at 6 hours after injection. The severity of the AP was assessed based on the serum amylase level and the histological and electron microscopy findings. Western blotting was also performed for HSP60/70 and LC3B-II.
WI and HS induced HSP60 and HSP70, respectively. The induced HSP60/70 effectively prevented the development of cerulein-induced AP. Autophagy developed in the rats with cerulein-induced AP and was documented by the expression of LC3-II and electron microscopy findings. The WI-stressed rats and HS-treated rats did not develop cerulein-induced autophagy.
HSPs exert protective effects against cerulein-induced AP in rats by inhibiting autophagy.
PMCID: PMC3240797  PMID: 22195252
Acute pancreatitis; Autophagy; Heat shock protein
18.  Clinical Characteristics of Microscopic Colitis in Korea: Prospective Multicenter Study by KASID 
Gut and Liver  2011;5(2):181-186.
Microscopic colitis (MC) encompasses collagenous and lymphocytic colitis and is characterized by chronic diarrhea. In cases of MC, colonic mucosae are macroscopically normal, and diagnostic histopathological features are observed only upon microscopic examination. We designed a prospective multicenter study to determine the clinical features, pathological distribution in the colon and prevalence of MC in Korea.
We prospectively enrolled patients having watery diarrhea no more than 3 times a day between March 2008 and February 2009. We obtained patient histories and performed colonoscopies with random biopsies at each colon segment.
A total of 100 patients with chronic diarrhea were enrolled for a normal colonoscopy and stool exam. MC was observed in 22 patients (22%) (M:F 1.2:1; mean age, 47.5 years). Of those 22 patients, 18 had lymphocytic colitis and 4 had collagenous colitis. The entire colon was affected in only 3 cases (13.6%), the ascending colon in 6 cases (27.2%), the transverse colon in 3 cases (13.6%), and the left colon in 3 cases (13.6%). More than 2 segments were affected in 7 cases (31.8%). Nonsteroidal anti-inflammatory drug-associated MCs were observed in 4 cases (18.2%), 3 of which showed improved diarrhea symptoms following discontinuation of the medication. Frequently associated symptoms were abdominal pain and weight loss. Autoimmune diseases were observed in 4 cases (18.2%). Half of the 22 patients with MC improved with conservative care by loperamide or probiotics.
In a prospective multicenter study of Korean patients with chronic diarrhea, the frequency of MC was found to be approximately 20%, similar to the percentage observed in Western countries. Therefore, the identification of MC is important for the adequate management of Korean patients with chronic diarrhea.
PMCID: PMC3140663  PMID: 21814598
Chronic diarrhea; Microscopic colitis; Collagenous colitis; Lymphocytic colitis
19.  MicroRNAs modulate the noncanonical NF-κB pathway by regulating IKKα expression during macrophage differentiation 
Nature immunology  2010;11(9):799-805.
MicroRNAs are key regulators in many biological processes including cell differentiation. Here we show that during human monocyte-macrophage differentiation, the expression of the microRNAs miR-223, miR-15a, and miR-16 is dramatically decreased, leading to increased expression of the serine-threonine kinase IKKα in macrophages. In macrophages, higher IKKα expression in conjunction with stabilization of the kinase NIK induces elevated p52. Due to low RelB transcription factor expression in untreated macrophages, high p52 expression represses the basal level of both canonical and noncanonical NF-κB target genes. However, proinflammatory stimuli in macrophages result in greater induction of noncanonical NF-κB target genes. Thus a decrease in certain microRNAs likely prevents macrophage hyperaction yet primes the macrophage for certain responses to proinflammatory stimuli.
PMCID: PMC2926307  PMID: 20711193
20.  ATF3 Plays a Key Role in Kdo2-Lipid A-Induced TLR4-Dependent Gene Expression via NF-κB Activation 
PLoS ONE  2010;5(12):e14181.
Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3 deficient mice are more susceptible to endotoxic shock. This study addresses the role of ATF3 in the Kdo2-Lipid A-induced Toll-like receptor 4 (TLR4) signaling pathway in mouse embryonic fibroblasts (MEF). Kdo2-Lipid A upregulates ATF3 expression in wild type MEF cells and induces both nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) activation via the TLR4 signaling pathway, while neither of these pathways is activated in ATF3-/- MEF cells. Interestingly, in contrast to Kdo2-Lipid A, the activation of both NF-κB and JNK by TNF-α was normal in ATF3-/- MEF cells.
Methodology/Principal Findings
We found that several genes were dramatically upregulated in ATF3+/+ MEF cells in response to Kdo2-Lipid A treatment, while little difference was observed in the ATF3-/- MEF cells. However, we also found that the signal intensities of IκBζ in ATF3-/- MEF cells were substantially higher than those in wild type MEF cells upon microarray analyses, and upregulated IκBζ expression was detected in the cytosol fraction.
Our findings indicate that ATF3 deficiency affects Kdo2-Lipid A-induced TLR4 signaling pathways in MEF cells, that it may upregulate IκBζ expression and that the high levels of IκBζ expression in ATF3-/- cells disrupts Kdo2-Lipid A-mediated signaling pathways.
PMCID: PMC2996292  PMID: 21152039
21.  Role of inducible nitric oxide synthase on the development of virus-associated asthma exacerbation which is dependent on Th1 and Th17 cell responses 
Experimental & Molecular Medicine  2010;42(10):721-730.
Asthma is characterized by airway inflammation induced by immune dysfunction to inhaled antigens. Although respiratory viral infections are the most common cause of asthma exacerbation, immunologic mechanisms underlying virus-associated asthma exacerbation are controversial. Clinical evidence indicates that nitric oxide (NO) levels in exhaled air are increased in exacerbated asthma patients compared to stable patients. Here, we evaluated the immunologic mechanisms and the role of NO synthases (NOSs) in the development of virus-associated asthma exacerbation. A murine model of virus-associated asthma exacerbation was established using intranasal challenge with ovalbumin (OVA) plus dsRNA for 4 weeks in mice sensitized with OVA plus dsRNA. Lung infiltration of inflammatory cells, especially neutrophils, was increased by repeated challenge with OVA plus dsRNA, as compared to OVA alone. The neutrophilic inflammation enhanced by dsRNA was partly abolished in the absence of IFN-gamma or IL-17 gene expression, whereas unaffected in the absence of IL-13. In terms of the roles of NOSs, dsRNA-enhanced neutrophilic inflammation was significantly decreased in inducible NOS (iNOS)-deficient mice compared to wild type controls; in addition, this phenotype was inhibited by treatment with a non-specific NOS inhibitor (L-NAME) or an specific inhibitor (1400 W), but not with a specific endothelial NOS inhibitor (AP-CAV peptide). Taken together, these findings suggest that iNOS pathway is important in the development of virus-associated exacerbation of neutrophilic inflammation, which is dependent on both Th1 and Th17 cell responses.
PMCID: PMC2966746  PMID: 20841959
asthma; interferon-γ; interleukin-17; neutrophils; nitric oxide synthase type II; RNA viruses; Th1 cells
22.  Membrane-bound Fas Ligand requires RIP1 for efficient activation of caspase-8 within the DISC§ 
The serine-threonine kinase RIP1 was originally identified through its ability to bind to the death domain of Fas (CD95). RIP1 has been shown to be recruited to the Fas Death-Inducing Signaling Complex (DISC) and is required for the induction of necrotic cell death. Here we show that in Jurkat T lymphocytes, RIP1 is also necessary for the most efficient activation of downstream caspases by Fas when treated with membrane-bound Fas Ligand (memFasL), but not with agonistic antibodies or crosslinked soluble Fas Ligand. RIP1 participates in the FADD-mediated recruitment of caspase-8 to the Fas receptor complex in a manner that promotes caspase-8 activation. Crosslinking antibodies, such as CH11, bypass the requirement for RIP1 in caspase activation by initiating larger, though less efficient, DISC complexes, while memFasL initiates a smaller but more efficient DISC that functions, in part, by effectively incorporating more RIP1 into the complex. Consequently, RIP1 is likely a more integral part of physiological signaling through the Fas/CD95 receptor complex than previously recognized; at least when the signal is mediated by full-length membrane bound Fas Ligand. Crosslinked Soluble FasL, which also occurs physiologically, behaves similarly to the CH11 antibody, and may therefore be more likely to initiate non-apoptotic Fas signaling due to less RIP1 in the receptor complex. Thus, agonists that bind the same Fas receptor initiate mechanistically distinct pathways resulting in differential cytotoxicity.
PMCID: PMC2730434  PMID: 19641134
Fas/CD95; Caspase-8; Fas Ligand; RIP1
23.  Efficacy of Rifaximin Compared with Ciprofloxacin for the Treatment of Acute Infectious Diarrhea: A Randomized Controlled Multicenter Study 
Gut and Liver  2010;4(3):357-362.
Ciprofloxacin has been widely prescribed for acute infectious diarrhea. However, the resistance to this drug is increasing. Rifaximin is a novel but poorly absorbed rifamycin derivative. This study evaluated and compared the efficacies of rifaximin and ciprofloxacin for the treatment of acute infectious diarrhea.
We performed a randomized controlled multicenter study in Korea. Patients with acute diarrhea were enrolled and randomized to receive rifaximin or ciprofloxacin for 3 days. The primary efficacy endpoint was the time to last unformed stool (TLUS). Secondary endpoints were enteric wellness (reduction of at least 50% in the number of unformed stools during 24-hour postenrollment intervals), general wellness (subjective feeling of improvement), and proportion of patients with treatment failure.
Intent-to-treat analysis (n=143) showed no significant difference between the rifaximin and ciprofloxacin groups in the mean TLUS (36.1 hours vs 43.6 hours, p=0.163), enteric wellness (49% vs 57%, p=0.428), general wellness (67% vs 78%, p=0.189), or treatment failure rate (9% vs 12%, p=0.841). The adverse events did not differ significantly between the two groups.
These results suggest that rifaximin is as safe and effective as ciprofloxacin in the treatment of acute infectious diarrhea.
PMCID: PMC2956348  PMID: 20981213
Acute infectious diarrhea; Rifaximin; Ciprofloxacin
24.  IL-12-STAT4-IFN-γ axis is a key downstream pathway in the development of IL-13-mediated asthma phenotypes in a Th2 type asthma model 
Experimental & Molecular Medicine  2010;42(8):533-546.
IL-4 and IL-13 are closely related cytokines that are produced by Th2 cells. However, IL-4 and IL-13 have different effects on the development of asthma phenotypes. Here, we evaluated downstream molecular mechanisms involved in the development of Th2 type asthma phenotypes. A murine model of Th2 asthma was used that involved intraperitoneal sensitization with an allergen (ovalbumin) plus alum and then challenge with ovalbumin alone. Asthma phenotypes, including airway-hyperresponsiveness (AHR), lung inflammation, and immunologic parameters were evaluated after allergen challenge in mice deficient in candidate genes. The present study showed that methacholine AHR and lung inflammation developed in allergen-challenged IL-4-deficient mice but not in allergen-challenged IL-13-deficient mice. In addition, the production of OVA-specific IgG2a and IFN-γ-inducible protein (IP)-10 was also impaired in the absence of IL-13, but not of IL-4. Lung-targeted IFN-γ over-expression in the airways enhanced methacholine AHR and non-eosinophilic inflammation; in addition, these asthma phenotypes were impaired in allergen-challenged IFN-γ-deficient mice. Moreover, AHR, non-eosinophilic inflammation, and IFN-γ expression were impaired in allergen-challenged IL-12Rβ2- and STAT4-deficient mice; however, AHR and non-eosinophilic inflammation were not impaired in allergen-challenged IL-4Rα-deficient mice, and these phenomena were accompanied by the enhanced expression of IL-12 and IFN-γ. The present data suggest that IL-13-mediated asthma phenotypes, such as AHR and non-eosinophilic inflammation, in the Th2 type asthma are dependent on the IL-12-STAT4-IFN-γ axis, and that these asthma phenotypes are independent of IL-4Ralpha-mediated signaling.
PMCID: PMC2928926  PMID: 20592486
asthma; interferon-γ; interleukin-12; interleukin-13; respiratory hypersensitivity; Th2 cells
25.  Outer Membrane Vesicles Derived from Escherichia coli Induce Systemic Inflammatory Response Syndrome 
PLoS ONE  2010;5(6):e11334.
Sepsis, characterized by a systemic inflammatory state that is usually related to Gram-negative bacterial infection, is a leading cause of death worldwide. Although the annual incidence of sepsis is still rising, the exact cause of Gram-negative bacteria-associated sepsis is not clear. Outer membrane vesicles (OMVs), constitutively secreted from Gram-negative bacteria, are nano-sized spherical bilayered proteolipids. Using a mouse model, we showed that intraperitoneal injection of OMVs derived from intestinal Escherichia coli induced lethality. Furthermore, OMVs induced host responses which resemble a clinically relevant condition like sepsis that was characterized by piloerection, eye exudates, hypothermia, tachypnea, leukopenia, disseminated intravascular coagulation, dysfunction of the lungs, hypotension, and systemic induction of tumor necrosis factor-α and interleukin-6. Our study revealed a previously unidentified causative microbial signal in the pathogenesis of sepsis, suggesting OMVs as a new therapeutic target to prevent and/or treat severe sepsis caused by Gram-negative bacterial infection.
PMCID: PMC2893157  PMID: 20596524

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