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PubMed | University of California at San Francisco, CMIC Pharma Science Co., Louis Pasteur Center for Medical Research, Kyoto University and Tenri Hospital
Type: | Journal: Scientific reports | Year: 2016

Oxidative stress plays a pivotal role in the pathogenesis of asthma. Aquaporin-3 (AQP3) is a small transmembrane water/glycerol channel that may facilitate the membrane uptake of hydrogen peroxide (H2O2). Here we report that AQP3 potentiates ovalbumin (OVA)-induced murine asthma by mediating both chemokine production from alveolar macrophages and T cell trafficking. AQP3 deficient (AQP3(-/-)) mice exhibited significantly reduced airway inflammation compared to wild-type mice. Adoptive transfer experiments showed reduced airway eosinophilic inflammation in mice receiving OVA-sensitized splenocytes from AQP3(-/-) mice compared with wild-type mice after OVA challenge, consistently with fewer CD4(+) T cells from AQP3(-/-) mice migrating to the lung than from wild-type mice. Additionally, in vivo and vitro experiments indicated that AQP3 induced the production of some chemokines such as CCL24 and CCL22 through regulating the amount of cellular H2O2 in M2 polarized alveolar macrophages. These results imply a critical role of AQP3 in asthma, and AQP3 may be a novel therapeutic target.


Aoi W.,Kyoto Prefectural University | Naito Y.,Kyoto Prefectural University of Medicine | Takagi T.,Kyoto Prefectural University of Medicine | Tanimura Y.,Kyoto Prefectural University of Medicine | And 12 more authors.
Gut | Year: 2013

Objective: Several epidemiological studies have shown that regular exercise can prevent the onset of colon cancer, although the underlying mechanism is unclear. Myokines are secreted skeletal muscle proteins responsible for some exercise-induced health benefits including metabolic improvement and anti-inflammatory effects in organs. The purpose of this study was to identify new myokines that contribute to the prevention of colon tumorigenesis. Methods: To identify novel secreted muscle-derived proteins, DNA microarrays were used to compare the transcriptome of muscle tissue in sedentary and exercised young and old mice. The level of circulating secreted protein acidic and rich in cysteine (SPARC) was measured in mice and humans that performed a single bout of exercise. The effect of SPARC on colon tumorigenesis was examined using SPARC-null mice. The secretion and function of SPARC was examined in culture experiments. Results: A single bout of exercise increased the expression and secretion of SPARC in skeletal muscle in both mice and humans. In addition, in an azoxymethane-induced colon cancer mouse model, regular low-intensity exercise significantly reduced the formation of aberrant crypt foci in wild-type mice but not in SPARC-null mice. Furthermore, regular exercise enhanced apoptosis in colon mucosal cells and increased the cleaved forms of caspase-3 and caspase-8 in wild-type mice but not in SPARC-null mice. Culture experiments showed that SPARC secretion from myocytes was induced by cyclic stretch and inhibited proliferation with apoptotic effect of colon cancer cells. Conclusions: These findings suggest that exercise stimulates SPARC secretion from muscle tissues and that SPARC inhibits colon tumorigenesis by increasing apoptosis.


Horinaka M.,Kyoto Prefectural University of Medicine | Yoshida T.,Kyoto Prefectural University of Medicine | Kishi A.,Louis Pasteur Center for Medical Research | Akatani K.,Louis Pasteur Center for Medical Research | And 4 more authors.
FEBS Letters | Year: 2010

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an endogenous cytokine that induces apoptosis in malignant tumor cells. Here, we show for the first time that lactobacilli induce TRAIL production in human peripheral blood mononuclear cells (PBMC). Treatment with lactobacilli induced TRAIL on the cell surface of PBMC and in culture medium. The TRAIL production induced by lactobacilli partially depends on IFN-α and IFN-γ. Lactobacilli treatment facilitated NK activity of PBMC against prostate cancer cells. Moreover, TRAIL neutralization antibody efficiently prevented the NK activity. Our results indicate that lactobacilli facilitate NK activity through TRAIL production, and raise the possibility of a new TRAIL-based strategy against malignant tumors. © 2009 Federation of European Biochemical Societies.


Yoshida K.,National Hospital Organization Osaka National Hospital | Yamazaki H.,Kyoto Prefectural University of Medicine | Takenaka T.,National Hospital Organization Osaka National Hospital | Kotsuma T.,National Hospital Organization Osaka National Hospital | And 8 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: To investigate the feasibility of our novel image-based high-dose-rate interstitial brachytherapy (HDR-ISBT) for uterine cervical cancer, we evaluated the dose-volume histogram (DVH) according to the recommendations of the Gynecological GEC-ESTRO Working Group for image-based intracavitary brachytherapy (ICBT). Methods and Materials: Between June 2005 and June 2007, 18 previously untreated cervical cancer patients were enrolled. We implanted magnetic resonance imaging (MRI)-available plastic applicators by our unique ambulatory technique. Total treatment doses were 30-36 Gy (6 Gy per fraction) combined with external beam radiotherapy (EBRT). Treatment plans were created based on planning computed tomography with MRI as a reference. DVHs of the high-risk clinical target volume (HR CTV), intermediate-risk CTV (IR CTV), and the bladder and rectum were calculated. Dose values were biologically normalized to equivalent doses in 2-Gy fractions (EQD2). Results: The median D90 (HR CTV) and D90 (IR CTV) per fraction were 6.8 Gy (range, 5.5-7.5) and 5.4 Gy (range, 4.2-6.3), respectively. The median V100 (HR CTV) and V100 (IR CTV) were 98.4% (range, 83-100) and 81.8% (range, 64-93.8), respectively. When the dose of EBRT was added, the median D90 and D100 of HR CTV were 80.6 Gy (range, 65.5-96.6) and 62.4 Gy (range, 49-83.2). The D2cc of the bladder was 62 Gy (range, 51.4-89) and of the rectum was 65.9 Gy (range, 48.9-76). Conclusions: Although the targets were advanced and difficult to treat effectively by ICBT, MRI-aided image-based ISBT showed favorable results for CTV and organs at risk compared with previously reported image-based ICBT results. © 2010 Elsevier Inc. All rights reserved.


Nagata K.,Kyoto Prefectural University of Medicine | Maruyama K.,Kyoto Prefectural University of Medicine | Uno K.,Louis Pasteur Center for Medical Research | Shinomiya K.,Kyoto Prefectural University of Medicine | And 7 more authors.
Investigative Ophthalmology and Visual Science | Year: 2012

PURPOSE. Levels of some cytokines are significantly higher in the vitreous fluid of patients with acute uveitis than in normal vitreous fluid. The authors sought to determine which proinflammatory cytokines were upregulated in the vitreous fluid of patients with ocular sarcoidosis. METHODS. Samples of vitreous fluid were collected from patients with sarcoid uveitis and from nonsarcoid control patients with idiopathic epiretinal membrane. The levels of 27 proinflammatory cytokines were measured with a multiplex beads array system. Postvitrectomy macular thickness was also measured by using spectral domain optical coherence tomography (SD-OCT). To assess the relationship between cytokine levels and disease stage, the authors divided patients into three groups based on macular thickness 1 month after operation. RESULTS. The vitreous levels of 17 cytokines were significantly higher in patients with ocular sarcoidosis than in nonsarcoid controls. Serum levels of interferon γ-induced protein 10 (IP- 10) were also higher in ocular sarcoidosis patients than in nonsarcoid controls. Conversely, serum levels of interleukin (IL) 15 in ocular sarcoidosis patients were lower than in the control group. Analysis of cytokine levels and macular thickness revealed that IL-1ra, IL-4, IL-8, IFN-γ, IP-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1β, and regulated on activation, normal T-cell expressed and secreted (RANTES) were significantly upregulated in patients with thin cystoid macular edema group. CONCLUSIONS. Patients with ocular sarcoidosis had elevated levels of proinflammatory cytokines in vitreous fluids. Different cytokines might contribute to different stages of macular edema. © 2012 The Association for Research in Vision and Ophthalmology, Inc.


Kamide Y.,Gunma University | Utsugi M.,Gunma University | Dobashi K.,Gunma University | Ono A.,Gunma University | And 6 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

Background: Glutathione redox status, changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione, plays a significant role in various aspects of cellular function. In this study, we examined whether intracellular glutathione redox status in human dendritic cells (DCs) regulates the polarization of Th1/Th2 balance. Methods: Human monocyte-derived DCs (MD-DCs) treated with glutathione reduced form ethyl ester (GSH-OEt) or L-buthionine-(S,R)-sulfoximine (BSO) were stimulated by lipopolysaccharide (LPS), and the levels of polarization cytokines were measured. Next, DCs matured by LPS or thymic stromal lymphopoietin (TSLP) were cocultured with allogeneic CD4 + naive T cells and Th1/Th2 balance was evaluated by cytokine production from the primed T cells. Results: Monocyte-derived DCs exposed to GSH-OEt and BSO had increased and decreased intracellular GSH contents, respectively. Lipopolysaccharide-induced interleukin (IL)-27 production was enhanced by GSH-OEt and suppressed by BSO, but neither GSH-OEt nor BSO affected the expression of HLA-DR, CD80, CD83, or CD86. Mature GSH-OEt-treated MD-DCs enhanced interferon (IFN)-γ production from CD4 + T cells compared with nontreated MD-DCs, and small interfering RNA (siRNA) against IL-27 suppressed the effect of GSH-OEt on IFN-γ production. Additionally, although human myeloid DCs activated by TSLP (TSLP-DCs) prime naïve CD4 + T cells to differentiate into Th2 cells, treatment of TSLP-DCs with GSH-OEt reduced IL-13 production and enhanced IFN-γ production by CD4 + T cells. Interleukin-27 siRNA attenuated the inhibitory effect of GSH-OEt on Th2 polarization. Conclusion: Our results reveal that Th1 and Th2 responses are controlled by intracellular glutathione redox status in DCs through IL-27 production. © 2011 John Wiley & Sons A/S.


PubMed | Tohoku University and Louis Pasteur Center for Medical Research
Type: Journal Article | Journal: PloS one | Year: 2015

Type I interferons (IFNs) are secreted by many cell types upon stimulation via pattern recognition receptors and bind to IFN-/ receptor (IFNAR), which is composed of IFNAR1 and IFNAR2. Although type I IFNs are well known as anti-viral cytokines, limited information is available on their role during fungal infection. In the present study, we addressed this issue by examining the effect of IFNAR1 defects on the host defense response to Cryptococcus neoformans. In IFNAR1KO mice, the number of live colonies was lower and the host immune response mediated not only by Th1 but also by Th2 and Th17-related cytokines was more accelerated in the infected lungs than in WT mice. In addition, mucin production by bronchoepithelial cells and expression of MUC5AC, a major core protein of mucin in the lungs, were significantly higher in IFNAR1KO mice than in WT mice. This increase in mucin and MUC5AC production was significantly inhibited by treatment with neutralizing anti-IL-4 mAb. In contrast, administration of recombinant IFN-A/D significantly suppressed the production of IL-4, but not of IFN- and IL-17A, in the lungs of WT mice after cryptococcal infection. These results indicate that defects of IFNAR1 led to improved clearance of infection with C. neoformans and enhanced synthesis of IFN- and the IL-4-dependent production of mucin. They also suggest that type I IFNs may be involved in the negative regulation of early host defense to this infection.


Aihara K.,Kyoto University | Oga T.,Kyoto University | Chihara Y.,Kyoto University | Harada Y.,Kyoto University | And 6 more authors.
Sleep and Breathing | Year: 2013

Purpose: The presence of both systemic and airway inflammation has been suggested in obstructive sleep apnea (OSA) by increased levels of inflammatory biomarkers in the circulation and respiratory specimens. We aimed to investigate the relationship between systemic and airway inflammation in OSA. Methods: This study was conducted by simultaneously measuring various biomarkers both in serum and induced sputum of 43 patients. We compared the relationships of these biomarker levels with polysomnographic data and obesity measurements and also investigated their interrelationships between systemic and local compartments. We also assessed the relation of inflammatory markers with proximal airway resistance measured by impulse oscillometry. Results: In multiple regression analyses, each measured serum biomarker [leptin, interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF)] significantly correlated with waist circumference or fat area determined by computed tomography. In contrast, regarding airway inflammation, sputum IL-6, IL-8, TNF-α, and VEGF significantly correlated with OSA severity as indicated by the respiratory disturbance index or oxygen desaturation indices. Sputum IL-6, IL-8, TNF-α, and VEGF were significantly related to sputum neutrophil number, and sputum IL-8 and TNF-α were related to proximal airway resistance independently of body mass index. There were no significant interrelationships between the same biomarkers in serum and induced sputum. Conclusions: Systemic and airway inflammation in OSA might be differently regulated by OSA itself and comorbid obesity, depending on the type of cytokine. Although we did not find apparent interrelationships between systemic and local compartments, further studies are needed to clarify this concept. © 2012 Springer-Verlag.


Fujita S.,Louis Pasteur Center for Medical Research
Neuroscience Research | Year: 2014

In 1960s, histological study on developing CNS led us to a novel finding that the periventricular layer ("Matrix" of W. His) of fetal neocortex is composed solely of the matrix cells. Application of 3H-thymidine autoradiography revealed "elevator movement" of the matrix cells. Following the stage of pure matrix cell proliferation (Stage I), stage of neuron production (Stage II) ensues, and when Stage II is over, stage of gliogenesis (Stage III) follows immediately; first, glioblasts, then astrocytes, oligodendrocytes and microglia differentiate, in sequence.As for the mechanism of the switching, recent progress in molecular research on dynamism of the chromatin and transcription-factors revealed the irreversible epigenetic changes controlling the switch. In Stage I of cytogenesis, axial ectodermal cells escape from irreversible differentiation into epidermis, and change into matrix cells composing the neural plate. In Stage II, some matrix cells, in which proneural genes are activated, exit cell cycle to become neurons. When Stage II ends, the neural-repressor REST/NRSBF is up regulated and occupies RE-1 silencer region to irreversibly inactivate neuron-specific genes including the type II Na+ channel, thereby matrix cells can now only produce non-excitable cells, i.e., glial cells. This is the Stage III of cytogenesis of the CNS. © 2014 Published by Elsevier Ireland Ltd.


Okuno K.,Kinki University | Uno K.,Louis Pasteur Center for Medical Research
Asian Pacific Journal of Cancer Prevention | Year: 2011

This study investigated the influence of Lentinula edodes mycelia extract (LEM), an oral immunomodulator, on immune function and adverse events from chemotherapy. Subjects comprised 1 gastric and 7 colorectal cancer patients. The first course of treatment was chemotherapy alone and the second was chemotherapy plus concomitant administration of LEM. Adverse events and interferon (IFN)-γ production by CD4+ T, CD8+ T and CD56+ NK/NKT cells were evaluated at the end of each course. Grade 1 or 2 adverse events were observed at the end of the first course for 6 of 8 patients. In comparison, no patients displayed any adverse events at the end of the second course. Tendencies toward improved IFN-γ production by CD4+ T, CD8+ T and CD56+ NK/NKT cells were also seen. These results suggest that concomitant use of LEM with chemotherapy can decrease the incidence of adverse effects from cancer chemotherapy among patients with advanced cancer.

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