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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Bmal1 (Brain and muscle arnt-like, or Arntl) is a bHLH/PAS domain transcription factor central to the transcription/translation feedback loop of the circadian clock. Mast cells are crucial for effector functions in allergic reaction and their activity follows a circadian rhythm. However, the functional roles of Bmal1 in mast cells remain to be determined. PURPOSE: This study aimed to elucidate the specific roles of Bmal1 in IgE-dependent mast cell degranulation. RESULTS: IgE-dependent degranulation was enhanced in bone marrow-derived mast cells (BMMCs) derived from Bmal1-deficient mice (Bmal1-KO mice) compared to that in BMMCs derived from wild-type mice (WT mice) in the absence of 2-Mercaptoethanol (2-ME) in culture. Mast cell-deficient KitW-sh mice reconstituted with Bmal1-KO BMMCs showed more robust passive cutaneous anaphylactic (PCA) reactions, an in vivo model of IgE-dependent mast cell degranulation, than KitW-sh mice reconstituted with WT BMMCs. In the absence of 2-ME in culture, the mRNA expression of the anti-oxidative genes NF-E2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), and heme oxygenase-1 (HO-1) was lower and reactive oxygen species (ROS) generation was higher in Bmal1-KO BMMCs than in WT BMMCs at steady state. The IgE-dependent ROS generation and degranulation were enhanced in Bmal1-KO BMMCs compared to WT BMMCs in the absence of 2-ME in culture. The addition of 2-ME into the culture abrogated or weakened the differences in anti-oxidative gene expression, ROS generation, and IgE-dependent degranulation between WT and Bmal1-KO BMMCs. CONCLUSION: The current findings suggest that Bmal1 controls the expression of anti-oxidative genes in mast cells and Bmal1 deficiency enhanced IgE-dependent degranulation associated with promotion of ROS generation. Thus, Bmal1 may function as a key molecule that integrates redox homeostasis and effector functions in mast cells.

DOI： 10.1016/j.bbrc.2023.149295

PubMed

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DOI： 10.1111/all.15954

PubMed

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

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Language：English  

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

DOI： 10.1038/s41598-019-53132-2

PubMed

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DOI： 10.3389/fnut.2019.00128

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

AIMS: The sensation of bladder fullness (SBF) is triggered by the release of ATP. Therefore, the aim of this study was to investigate whether time-dependent changes in the levels of stretch-released ATP in mouse primary-cultured urothelial cells (MPCUCs) is regulated by circadian rhythm via clock genes. METHODS: MPCUCs were derived from wild-type and Clock mutant mice (ClockΔ19/Δ19 ), presenting a nocturia phenotype. They were cultured in elastic silicone chambers. Stretch-released ATP was quantified every 4 h by ATP photon count. An experiment was also performed to determine whether ATP release correlated with the rhythm of the expression of Piezo1, TRPV4, VNUT, and Connexin26 (Cx26) in MPCUCs regulated by clock genes with circadian rhythms. MPCUCs were treated with carbenoxolone, an inhibitor of gap junction protein; were derived from VNUT-KO mice; or treated with Piezo1-siRNA, TRPV4-siRNA, and Cx26-siRNA. RESULTS: Stretch-released ATP showed time-dependent changes in wild-type mice and correlated with the rhythm of the expression of Piezo1, TRPV4, VNUT, and Cx26. However, these rhythms were disrupted in ClockΔ19/Δ19 mice. Carbenoxolone eliminated the rhythmicity of ATP release in wild-type mice. However, time-dependent ATP release changes were maintained when a single gene was deficient such as VNUT-KO, Piezo1-, TRPV4-, and Cx26-siRNA. CONCLUSIONS: ATP release in the bladder urothelium induces SBF and may have a circadian rhythm regulated by the clock genes. In the bladder urothelium, clock gene abnormalities may disrupt circadian ATP release by inducing Piezo1, TRPV4, VNUT, and Cx26. All these genes can trigger nocturia.

DOI： 10.1002/nau.23793

PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

We previously showed that bladder functions are controlled by clock genes with circadian rhythm. The sensation of bladder fullness (SBF) is sensed by mechano-sensor such as Piezo1 and TRPV4 in the mouse bladder urothelium. However, functional circadian rhythms of such mechano-sensors remain unknown. To investigate functional circadian changes of these mechano-sensors, we measured circadian changes in stretch-evoked intracellular Ca2+ influx ([Ca2+] i ) using mouse primary cultured urothelial cells (MPCUCs). Using Ca2+ imaging, stretch-evoked [Ca2+] i was quantified every 4 h in MPCUCs derived from wild-type (WT) and Clock Δ19/Δ19 mice, which showed a nocturia phenotype. Furthermore, a Piezo1 inhibitor GsMTx4 and a TRPV4 inhibitor Ruthenium Red were applied and stretch-evoked [Ca2+] i in MPCUCs was measured to investigate their contribution to SBF. Stretch-evoked [Ca2+] i showed a circadian rhythm in the WT mice. In contrast, Clock Δ19/Δ19 mice showed disrupted circadian rhythm. The administration of both GsMTx4 and Ruthenium Red eliminated the circadian rhythm of stretch-evoked [Ca2+] i in WT mice. We conclude that SBF may have a circadian rhythm, which is created by functional circadian changes of Piezo1 and TRPV4 being controlled by clock genes to be active during wakefulness and inactive during sleep. Abnormalities of clock genes disrupt SBF, and induce nocturia.

DOI： 10.1038/s41598-018-23115-w

Scopus

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: To investigate circadian gene expressions in the mouse bladder urothelium to establish an experimental model and study the functions of the circadian rhythm. METHODS: The gene expression rhythms of the clock genes, mechano-sensors such as Piezo1 and TRPV4, ATP release mediated molecules (ARMM) such as Cx26 and VNUT were investigated in mouse primary cultured urothelial cells (UCs) of wild-type (WT) and Clock mutant (ClockΔ19/Δ19 ) mice using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting analysis. The long-term oscillation of the clock genes in UC was investigated by measuring bioluminescence from UC isolated from Period2luciferase knock-in mice (Per2::luc) and Per2::luc with ClockΔ19/Δ19 using a luminometer. The mRNA expression rhythms after treatment with Clock short interfering RNA (siRNA) were also measured to compare differences between Clock point mutations and Clock deficiency. RESULTS: The UCs from WT mice showed the time-dependent gene expressions for clock genes, mechano-sensors, and ARMM. The abundances of the products of these genes also correlated with the mRNA expression rhythms in UCs. The bioluminescence of Per2::Luc in UCs showed a circadian rhythm. By contrast, all the gene expressions rhythms observed in WT mice were abrogated in the ClockΔ19/Δ19 mice. Transfection with Clock siRNA in UCs had the same effect as the Clock mutation. CONCLUSIONS: We demonstrated that the time-dependent gene expressions, including clock genes, mechano-sensors, and ARMM, were reproducible in UCs. These findings demonstrated that UCs have the potential to progress research into the circadian functions of the lower urinary tract regulated by clock genes.

DOI： 10.1002/nau.23400

PubMed

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

DOI： 10.1016/j.jid.2017.07.838

Scopus

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Interleukin-17 producing CD4(+) T helper (Th17) cells are a key immune lineage that protects against bacterial and fungal infections at mucosal surfaces. At steady state, Th17 cells are abundant in the small intestinal mucosa of mice. There are several mechanisms for regulating the population of Th17 cells in the small intestine, reflecting the importance of maintaining their numbers in the correct balance. Here we demonstrate the existence of a time-of-day dependent variation in the frequency of Th17 cells in the lamina propria of the small intestine in wild-type mice, which was not observed in mice with a loss-of function mutation of the core circadian gene Clock or in mice housed under aberrant light/dark conditions. Consistent with this, expression of CCL20, a chemokine that regulates homeostatic trafficking of Th17 cells to the small intestine, exhibited circadian rhythms in the small intestine of wild-type, but not Clock-mutated, mice. In support of these observations, the magnitude of ovalbumin (OVA)-specific antibody and T-cell responses in mice sensitized with OVA plus cholera toxin, a mucosal Th17 cell dependent adjuvant, was correlated with daily variations in the proportion of Th17 cells in the small intestine. These results suggest that the proportion of Th17 cells in the small intestine exhibits a day night variation in association with CCL20 expression, which depends on circadian clock activity. The findings provide novel insight into the regulation of the Th17 cell population in the small intestine at steady state, which may have translational potential for mucosal vaccination strategies. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2017.06.038

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The salivary gland is rhythmically controlled by sympathetic nerve activation from the suprachiasmatic nucleus (SCN), which functions as the main oscillator of circadian rhythms. In humans, salivary IgA concentrations reflect circadian rhythmicity, which peak during sleep. However, the mechanisms controlling this rhythmicity are not well understood. Therefore, we examined whether the timing of parasympathetic (pilocarpine) or sympathetic (norepinephrine; NE) activation affects IgA secretion in the saliva. The concentrations of saliva IgA modulated by pilocarpine activation or by a combination of pilocarpine and NE activation were the highest in the middle of the light period, independent of saliva flow rate. The circadian rhythm of IgA secretion was weakened by an SCN lesion and Clock gene mutation, suggesting the importance of the SCN and Clock gene on this rhythm. Adrenoceptor antagonists blocked both NE- and pilocarpine-induced basal secretion of IgA. Dimeric IgA binds to the polymeric immunoglobulin receptor (pIgR) on the basolateral surface of epithelial cells and forms the IgA-pIgR complex. The circadian rhythm of Pigr abundance peaked during the light period, suggesting pIgR expression upon rhythmic secretion of IgA. We speculate that activation of sympathetic nerves during sleep may protect from bacterial access to the epithelial surface through enhanced secretion of IgA.

DOI： 10.1038/s41598-017-09438-0

Web of Science

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Background: Interleukin-33 (IL-33) is an alarmin cytokine that binds to the interleukin 1 receptor-like 1 protein ST2. Clock is a key circadian gene that is essential for endogenous clockworks in mammals. This study investigated whether Clock temporally regulated IL-33-mediated responses in mast cells.
Methods: The kinetics of IL-33-mediated IL-6, IL-13, and TNF-alpha productions were compared between bone marrow-derived mast cells (BMMCs) from wild-type and Clock-mutated mice (Clock(Delta 19/Delta 19) mice). The kinetics of the neutrophil influx into the peritoneal cavity or expression of IL-13 and Gob-5 in the lung in response to IL-33 were compared between wild-type and Clock(Delta 19/Delta 19) mice. We also examined the kinetics of ST2 expression in mast cells and its association with Clock expression.
Results: There was a time-of-day-dependent variation in IL-33-mediated IL-6, IL-13, and TNF-alpha production in wild-type BMMCs, which was absent in Clock-mutated BMMCs. IL-33-induced neutrophil infiltration into the peritoneal cavity also showed a time-of-day-dependent variation in wild-type mice, which was absent in Clock(Delta 19/Delta 19) mice. Furthermore, IL-33-induced IL-13 and Gob-5 expression in the lung exhibited a time-of-day-dependent variation in wild-type mice. These temporal variations in IL-33 mediated mast cell responses were associated with temporal variations of ST2 expression in mast cells. In addition, CLOCK bound to the promoter region of ST2 and Clock deletion resulted in down-regulation of ST2 expression in mast cells.
Conclusions: CLOCK temporally gates mast cell responses to IL-33 via regulation of ST2 expression. Our findings provide novel insights into IL-33/mast cell-associated physiology and pathologies. Copyright (C) 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V.

DOI： 10.1016/j.alit.2017.02.004

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DOI： 10.1016/j.alit.2019.09.004

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BACKGROUND & AIMS: Mesalamine is a first-line drug for treatment of inflammatory bowel diseases (IBD). However, its mechanisms are not fully understood. CD4+ Foxp3+ regulatory T cells (Tregs) play a potential role in suppressing IBD. This study determined whether the anti-inflammatory activity of mesalamine is related to Treg induction in the colon. METHODS: We examined the frequencies of Tregs in the colons of wild-type mice, mice deficient for aryl hydrocarbon receptor (AhR
-/-
mice), and bone marrow-chimeric mice lacking AhR in hematopoietic cells (BM-AhR
-/-
mice), following oral treatment with mesalamine. We also examined the effects of mesalamine on transforming growth factor (TGF)-β expression in the colon. RESULTS: Treatment of wild-type mice with mesalamine increased the accumulation of Tregs in the colon and up-regulated the AhR target gene Cyp1A1, but this effect was not observed in AhR-/- or BM-AhR-/- mice. In addition, mesalamine promoted in vitro differentiation of naive T cells to Tregs, concomitant with AhR activation. Mice treated with mesalamine exhibited increased levels of the active form of TGF-β in the colon in an AhR-dependent manner and blockade of TGF-β signaling suppressed induction of Tregs by mesalamine in the colon. Furthermore, mice pretreated with mesalamine acquired resistance to dextran sodium sulfate-induced colitis. CONCLUSIONS: We propose a novel anti-inflammatory mechanism of mesalamine for colitis: induction of Tregs in the colon via the AhR pathway, followed by TGF-β activation.

DOI： 10.1016/j.jcmgh.2017.03.010

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

AimsThe pathophysiologies of nocturia (NOC) and nocturnal polyuria (NP) are multifactorial and their etiologies remain unclear in a large number of patients. Clock genes exist in most cells and organs, and the products of Clock regulate circadian rhythms as representative clock genes. Clock genes regulate lower urinary tract function, and a newly suggested concept is that abnormalities in clock genes cause lower urinary tract symptoms. In the present study, we investigated the voiding behavior of Clock mutant (Clock(19/19)) mice in order to determine the effects of clock genes on NOC/NP.
MethodsMale C57BL/6 mice aged 8-12 weeks (WT) and male C57BL/6 Clock(19/19) mice aged 8 weeks were used. They were bred under 12hr light/dark conditions for 2 weeks and voiding behavior was investigated by measuring water intake volume, urine volume, urine volume/void, and voiding frequency in metabolic cages in the dark and light periods.
ResultsNo significant differences were observed in behavior patterns between Clock(19/19) and WT mice. Clock(19/19) mice showed greater voiding frequencies and urine volumes during the sleep phase than WT mice. The diurnal change in urine volume/void between the dark and light periods in WT mice was absent in Clock(19/19) mice. Additionally, functional bladder capacity was significantly lower in Clock(19/19) mice than in WT mice.
ConclusionsWe demonstrated that Clock(19/19) mice showed the phenotype of NOC/NP. The Clock(19/19) mouse may be used as an animal model of NOC and NP. Neurourol. Urodynam. 36:1034-1038, 2017. (c) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/nau.23062

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DOI： 10.1371/journal.pone.0168234

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DOI： 10.1371/journal.pone.0168234

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Background: Sublingual immunotherapy (SLIT) is a safe and effective treatment for allergic rhinitis (AR). However, many issues regarding SLIT remain to be resolved, including the optimal timing of administration. This study investigated the effect of time of day on SLIT efficacy with the goal of optimizing the therapeutic outcome. Methods: We performed prophylactic SLIT at different times of day (10 a. m. or 10 p. m.) in 2 mouse models of AR: an ovalbumin (OVA)-induced AR model and Cry j 1-induced AR model, and compared the effects. Results: In the OVA-induced AR model, mice sublingually receiving OVA at 10 a. m. exhibited a greater decrease in total and OVA-specific IgE levels than mice treated at 10 p. m. In addition, mice treated at 10 a. m. exhibited reductions in OVA-specific IL-4, IL-10, and IL-13 production by splenocytes relative to mice treated at 10 p. m. Furthermore, we observed a more efficient capture of sublingually administered OVA in submandibular lymph nodes at 10 a. m. than at 10 p. m. in mice. Similar results were observed in the Cry j 1-induced AR model using Japanese cedar pollen extract for SLIT. Conclusions: Given the allergen-specific antibody and T cell responses, we suggest that SLIT may be more effective in the resting phase than in the active phase (note that mice are nocturnal animals). Thus, we propose that a chronotherapeutic approach should be considered for SLIT to maximize its effectiveness. (C) 2016 S. Karger AG, Basel

DOI： 10.1159/000450954

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.jid.2016.01.030

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

To develop a new therapeutic monoclonal Antibody (mAb) for Hodgkin lymphoma (HL), we immunized a BALB/c mouse with live HL cell lines, alternating between two HL cell lines. After hybridization, we screened the hybridoma clones by assessing direct cytotoxicity against a HL cell line not used for immunization. We developed this strategy for establishing mAb to reduce the risk of obtaining clonotypic mAb specific for single HL cell line. A newly established mouse anti-human mAb (4713) triggered cytoskeleton-dependent, but complement- and caspase-independent, cell death in HL cell lines, Burkitt lymphoma cell lines, and advanced adult T-cell leukemia cell lines. Intravenous injection of mAb 4713 in tumor-bearing SCID mice improved survival significantly. mAb 4713 was revealed to be a mouse antihuman pan-HLA class II mAb. Treatment with this mAb induced the formation of large pores on the surface of target lymphoma cells within 30 min. This finding suggests that the cell death process induced by this anti-pan HLA-class II mAb may involve the same death signals stimulated by a cytolytic anti-pan MHC class I mAb that also induces large pore formation. This multifaceted study supports the therapeutic potential of mAb 4713 for various forms of lymphoma.

DOI： 10.1371/journal.pone.0150496

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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The aryl hydrocarbon receptor (AhR) pathway is now considered an important pharmacological target for many human diseases. This study examined the effects of grape seed extract (GSE) obtained from the Koshu grape variety on AhR activity. The Koshu-derived GSE inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated AhR activation in vivo and in vitro. These results suggest that Koshu GSE has an antagonistic effect on TCDD-induced AhR activation. Furthermore, gavage administration of TCDD resulted in the elevation of liver function, but administration of Koshu GSE together with TCDD did not elevate serum aspartate aminotransaminase (AST) and alanine transaminase (ALT) levels. These results suggest that Koshu GSE may have the potential to prevent liver disorders. © 2013 by the American Society for Enology and Viticulture. All rights reserved.

DOI： 10.5344/ajev.2012.11131

Scopus

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

Various features, components, and functions of the immune system present daily variations. Immunocompetent cell counts and cytokine levels present variations according to the time of day and the sleep-wake cycle. Moreover, different immune cell types, such as macrophages, natural killer cells, and lymphocytes, contain a circadian molecular clockwork. The biological clocks intrinsic to immune cells and lymphoid organs, together with inputs from the central pacemaker of the suprachiasmatic nuclei via humoral and neural pathways, regulate the function of cells of the immune system, including their response to signals and their effector functions. Consequences of this include, for example, the daily variation in the response to an immune challenge (e. g., bacterial endotoxin injection) and the circadian control of allergic reactions. The circadian-immune connection is bidirectional, because in addition to this circadian control of immune functions, immune challenges and immune mediators (e. g., cytokines) were shown to have strong effects on circadian rhythms at the molecular, cellular, and behavioral levels. This tight crosstalk between the circadian and immune systems has wide-ranging implications for disease, as shown by the higher incidence of cancer and the exacerbation of autoimmune symptoms upon circadian disruption.

DOI： 10.3109/07420528.2013.782315

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Language：English   Publishing type：(MISC) Summary of the papers read (international conference)   Publisher：SPRINGER TOKYO  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：(MISC) Summary of the papers read (international conference)   Publisher：NATURE PUBLISHING GROUP  

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

The goal of this research was to examine the role of TWEAK in normal disc cells and to investigate its potential role in disc degeneration. We performed histological examinations of disc tissues and assessed the role of the novel cytokine TWEAK using murine organ disc culture. The expression of both TWEAK and its receptor, Fn14, in discs was confirmed by immunohistochemistry and quantitative real-time PCR. TWEAK induced disc cells to generate MMP-3 in a dose- and time-dependent manner. This induction was strongly inhibited in the presence of a neutralizing antibody to TWEAK or a chimeric Fn14/Fc fusion protein. In disc tissues derived from TNF-alpha receptor 1- or TNF-alpha receptor 2-deficient mice, recombinant TWEAK modestly induced MMP-3. In contrast, in disc cultures lacking TWEAK, tissues from wild-type mice or receptor-deficient mice failed to express MMP-3. Furthermore, aggrecan expression was potently abrogated in a time-dependent manner in the presence of recombinant TWEAK. This is the first report to confirm expression of TWEAK and its receptor Fn14 in murine intervertebral disc tissues. The data suggest that TWEAK plays a role in MMP-3 up-regulation and aggrecan down-regulation in disc tissues, resulting in proteoglycan degradation and promotion of disc degeneration. (C) 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

DOI： 10.1002/jor.20445

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.56.1116_1

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.56.1142_3

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Background CDK5 is a member of proline-directed serine/threonin kinases. Although its cDNA was originally cloned as a homologue to those for the other members of the cyclin-dependent kinase (CDK) family, CDK5 has been shown to function differently from other CDKs. CDK5 is activated by non-cyclin partners, p35 and p39, and important during brain development by influencing adhesion, migration and differentiation of neurones.
Objectives We sought to investigate the expression and functions of CDK5 in human keratinocytes.
Methods Expression of CDK5/p35, interaction of CDK5/p35 with adhesion molecules, and its roles in cell-cell and cell-matrix adhesion were studied by reverse transcriptase-polymerase chain reaction, immunoblotting and aggregation/adhesion assays in primary cultured normal human keratinocytes from infant foreskins and a human keratinocyte HaCaT cell line. Localization of CDK5 and p35 in normal human epidermis and psoriatic epidermis was studied by immunohistochemistry.
Results Both CDK5 and p35 were expressed in primary cultured keratinocytes, HaCaT cells and normal human epidermis. Roscovitine, an inhibitor of CDK5, enhanced Ca2+-dependent (cadherin-dependent) aggregation of HaCaT cells whereas it inhibited adhesion of HaCaT cells to fibronectin associated with reduced active states of beta 1 integrin. Interestingly, psoriatic skin showed reduced CDK5 and p35 expression in the lower half of the epidermis, which might be associated with decreased amount of activated beta 1 integrin in the epidermis of psoriatic skin.
Conclusions CDK5/p35 may be involved in cell-cell and cell-matrix adhesion in human keratinocytes by differently regulating cadherins and integrins. Furthermore, reduced expression of CDK5/p35 in the epidermis might be involved in the pathogenesis of psoriasis.

DOI： 10.1111/j.1365-2133.2005.06583.x

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Background: Transforming growth factor (TGF)-beta induces fibroblast contraction, which is implicated in wound heating and keloid formation. SB-431542 is a novel specific inhibitor of TGF-beta type I receptor kinase activity.
Objective : We sought to determine whether SB-431542 inhibited TGF-beta-induced fibroblast contraction.
Methods : We used an in vitro type I collagen get contraction assay with normal or keloid dermal fibroblasts incorporated.
Results : TGF-beta induced contraction of collagen gets with normal dermal fibroblasts incorporated, which was efficiently suppressed by SB-431542. Keloid fibroblasts showed higher basal contraction of collagen gets in the absence of TGF-beta than normal fibroblasts, which was enhanced by addition of TGF-beta. SB-431542 suppressed both the basal and TGF-beta-enhanced contraction of collagen gets by keloid fibroblasts. These inhibitory effects of SB-431542 were associated with suppression of TGF-beta-induced alpha-smooth muscle actin (alpha-SMA) expression and phosphorylation of Smad2 in normal and keloid fibroblasts.
Conclusion : SB-431542 can suppress TGF-beta-induced contraction of collagen get by normal and keloid dermal fibroblasts. Importantly, SB-431542 can inhibit basal contraction of collagen get by keloid fibroblasts. These results suggest that an inhibitor of TGF-beta type I receptor kinase activity may have therapeutic potential for excessive skin contraction as observed in keloid. (c) 2005 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All. rights reserved.

DOI： 10.1016/j.jdermsci.2005.01.013

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.54.1084_3

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：順天堂大学  

CiNii Books

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

The equilibrium between the production and degradation of collagen is rigorously controlled by a number of growth factors and cytokines. Interferon alfa (IFN-alpha) is now widely used for the treatment of chronic hepatitis C, which can improve serum levels of fibrotic markers and the degree of hepatic fibrosis, not only in patients who responded to therapy but also in those in whom it is ineffective. These findings may suggest that IFN-alpha possesses direct antifibrotic effects in addition to its antiviral activity. However, in contrast to IFN-gamma, which has been shown to suppress collagen gene transcription, little is known about the mechanisms responsible for the antifibrotic effects of IFN-alpha. Here, we report that IFN-alpha, when administered into transgenic mice harboring the alpha2(I) collagen gene (COL1A2) promoter sequence, significantly repressed promoter activation and prevented the progression of hepatic fibrosis induced by carbon tetrachloride injection. Transient transfection assays indicated that IFN-alpha decreased the steady-state levels of COL1A2 messenger RNA (mRNA) and inhibited basal and TGF-beta/Smad3-stimulated COL1A2 transcription in activated hepatic stellate cells (HSC). These inhibitory effects of IFN-alpha on COL1A2 transcription were exerted through the interaction between phosphorylated Stat1 and p300. Blocking of the IFN-alpha signal by overexpressing the intracellular domain-deleted IFN receptor increased basal COL1A2 transcription and abolished the inhibitory effects of IFN-alpha. In conclusion, our results indicate that IFN-alpha antagonizes the TGF-beta/Smad3-stimulated COL1A2 transcription in vitro and suppresses COL1A2 promoter activation in vivo, providing a molecular basis for antifibrotic effects of IFN-alpha.

DOI： 10.1053/jhep.2003.50408

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Background: Interleukin (IL)-13 is a pleiotropic cytokine, which shares many biological functions with IL-4. The receptor subunits of IL-13 consist of IL-4Ralpha, IL-13Ralpha1 and IL-13Ralpha2. The regulatory mechanisms of the IL-13Ralpha expression in the keratinocytes of certain skin disease have not been known. Objective: To clear the roles of IL-13 and the regulatory mechanisms of its receptor in atopic dermatitis (AD) and psoriasis. Method: The expression of IL-13Ralpha1 in the skin of AD and psoriasis was investigated by immunohistochemistry. The regulation of IL-13Ralpha mRNA in the skin and human primary keratinocyte (HPK) was investigated by quantitative PCR. The secretion of IL-6 and RANTES from HPK was measured by ELISA. Results: The expression of IL-13Ralpha1 was more prominent on the suprabasal keratinocytes in the skin of AD and striking increase of staining was observed on all layers of keratinocyte in the skin of psoriasis. The mRNA of IL-13Ralpha1, but not of IL-13Ralpha2 was overexpressed in both skin of AD and psoriasis. In vitro experiment using HPK demonstrated that IFN-gamma, IL-13 but not IL-4 could up-regulate the mRNA expression of IL-13Ralpha1. In contrast, IL-13Ralpha2 mRNA expression was up-regulated by IFN-gamma plus IL-4. Furthermore, the stimulation of HPK with IFN-gamma plus IL-13 and/or IL-4 resulted in significant enhancement of IL-6 and RANTES secretion. Conclusion: These findings indicate that IL-4 and IL-13 have different regulatory effects on the expression of IL-13Ralpha1 and alpha2, and the overexpression of IL-13Ralpha1 may play some roles in the pathogenesis of chronic stage of AD or psoriasis. (C) 2003 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/S0923-1811(03)00148-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Transforming growth factor-beta (TGF-beta) and interferon-gamma ( IFN-gamma) exert antagonistic effects on collagen synthesis in human dermal fibroblasts. We have recently shown that Y box-binding protein YB-1 mediates the inhibitory effects of IFN-gamma on alpha2(I) procollagen gene (COL1A2) transcription through the IFN-gamma response element located between - 161 and - 150. Here we report that YB-1 counter-represses TGF-beta-stimulated COL1A2 transcription by interfering with Smad3 bound to the upstream sequence around - 265 and subsequently by interrupting the Smad3-p300 interaction. Western blot and immunofluorescence analyses using inhibitors for Janus kinases or casein kinase II suggested that the casein kinase II-dependent signaling pathway mediates IFN-gamma-induced nuclear translocation of YB-1. Down-regulation of endogenous YB-1 expression by double-stranded YB-1-specific RNA abrogated the transcriptional repression of COL1A2 by IFN-gamma in the absence and presence of TGF-beta. In transient transfection assays, overexpression of YB-1 in human dermal fibroblasts exhibited antagonistic actions against TGF-beta and Smad3. Physical interaction between Smad3 and YB- 1 was demonstrated by immunoprecipitation-Western blot analyses, and electrophoretic mobility shift assays using the recombinant Smad3 and YB- 1 proteins indicated that YB- 1 forms a complex with Smad3 bound to the Smad-binding element. Glutathione S-transferase pull-down assays showed that YB- 1 binds to the MH1 domain of Smad3, whereas the central and carboxyl-terminal regions of YB- 1 were required for its interaction with Smad3. YB- 1 also interferes with the Smad3-p300 interaction by its preferential binding to p300. Altogether, the results provide a novel insight into the mechanism by which IFN-gamma/ YB-1 counteracts TGF-beta/Smad3. They also indicate that IFN-gamma/YB-1 inhibits COL1A2 transcription by dual actions: via the IFN-gamma response element and through a cross-talk with the TGF-beta/Smad signaling pathway.

DOI： 10.1074/jbc.M302339200

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Neurogenin3 ( ngn3) is a transcription factor that is essential for the differentiation of pancreatic endocrine cells. To investigate the signaling pathway that regulates ngn3 expression, we used AR42J- B13 cells as a model of the differentiation of pancreatic islets. In these cells, treatment with activin A and hepatocyte growth factor ( HGF) induced the expression of ngn3. Reporter gene analysis using human ngn3 gene ( NEUROG3) promoter fragments of various lengths identified the region between - 402 and - 327 bp of NEUROG3 as an activin A- and HGF- responsive DNA sequence. This DNA sequence normally functions as a repressor in AR42J- B13 cells, but treatment with activin A and HGF negates the repressor activity. Interestingly, function of the activin A- and HGF- responsive sequence was not influenced by the overexpression of the Smad inhibitory factor, Smad7. Instead, activin A and HGF activation was inhibited by overexpression of a dominant- negative mutant of transforming growth factor- beta- activated kinase 1 ( TAK1), or mitogen- activated protein kinase kinase 3 ( MKK3), or by treatment with a p38 MAPK- specific inhibitor, SB203580. Activin A and HGF function through the TAK1- MKK3- p38 MAPK pathway to relieve transcription repressors located between - 402 and - 326 bp on the NEUROG3 promoter, and consequently activate ngn3 expression and endocrine differentiation of AR42J- B13 cells.

DOI： 10.1074/jbc.M302684200

Web of Science

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.52.313_2

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Smad7 is a major inhibitory regulator of transforming growth factor (TGF)-beta signaling. Smad7 expression is induced by TGF-beta itself and other signaling pathways, indicating a key role for Smad7 in feedback or cross-talk control of TGF-beta signaling. Recent reports have implicated Smad7 as a crucial regulator of TGF-beta activity in human disease; aberrant expression of Smad7 is involved in inflammatory bowel disease and scleroderma. Thus, modulation of Smad7 expression could provide a novel therapeutic basis for TGF-beta-associated disorders.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Toll-like receptor 2 (TLR2) and TLR4 play important roles in the early innate immune response to microbial challenge. To clarify the functional roles of TLRs 2 and 4 in mast cells, we examined bone marrow-derived mast cells (BMMCs) from TLR2 or TLR4 gene-targeted mice. Peptidoglycan (PGN) from Staphylococcus aureus stimulated mast cells in a TLR2-dependent manner to produce TNF-alpha, IL-4, IL-5, IL-6, and IL-13, but not IL-1beta. In contrast, LPS from Escherichia coli stimulated mast cells in a TLR4-dependent manner to produce TNF-alpha, IL-1beta, IL-6, and IL-13, but not IL-4 nor IL-5. Furthermore, TLR2- but not TLR4-dependent mast cell stimulation resulted in mast cell degranulation and Ca2+ mobilization. In a mast cell-dependent model of acute sepsis, TLR4 deficiency of BMMCs in mice resulted in significantly higher mortality because of defective neutrophil recruitment and production of proinflammatory cytokines in the peritoneal cavity. Intradermal injection of PGN led to increased vasodilatation and inflammation through TLR2-dependent activation of mast cells in the skin. Taken together, these results suggest that direct activation of mast cells via TLR2 or TLR4 by respective microligands contributes to innate and allergic immune responses.

DOI： 10.1172/JCI200214704

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Induction of alpha(E)beta(7) expression on T cells by transforming growth factor (TGF)-beta is thought to be important for intestinal intraepithelial T lymphocyte (IEL) entry into the epithelial compartment. However, there has been no in vivo evidence that up-regulation of alpha(E)beta(7) expression on T cells by TGF-beta is critical for the selective localization of intestinal IEL in the epithelial area. We have recently established transgenic mice expressing Smad7 under the control of a distal Ick promoter where TGF-beta/Smad signaling is specifically blocked in mature T cells. Here we showed that TGF-beta-mediated up-regulation of alpha(E)beta(7) was impaired on T cells isolated from the Smad7 transgenic mice associated with reduced numbers of intestinal IEL when compared with that in wild-type littermates. These results indicated that failure to induce alpha(E)beta(7) on T cells by TGF-beta resulted in reduced numbers of intestinal IEL, suggesting the importance of alpha(E)beta(7) expression by TGF-beta in selective localization of intestinal IEL.

Web of Science

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING LTD  

Background Atopic dermatitis is a chronic, relapsing inflammatory disorder characterized by pruritic and eczematous skin lesions. Transforming growth factor (TGF)-beta(1) has been implicated in the suppression of inflammatory responses.
Objective The purpose of this study is to determine whether TGF-beta(1) suppresses skin lesions in a mouse model of atopic dermatitis.
Methods We used the NC/Nga strain of mice as an in vivo model of atopic dermatitis. The effects of exogenous TGF-beta(1) on atopic dermatitis-like skin lesions in NC/Nga mice were evaluated clinically, histologically and immunologically.
Results Subcutaneous injection of recombinant TGF-beta(1) macroscopically suppressed eczematous skin lesions in NC/Nga mice associated with reduced serum immunoglobulin E (IgE) levels. Histological analysis showed that TGF-beta(1) significantly inhibited the infiltration of inflammatory cells such as mast cells and eosinophils into the skin of NC/Nga mice. Spontaneous interferon (IFN)-gamma production from splenocytes of NC/Nga mice was down-regulated by the treatment with TGF-beta(1) and neutralizing antibody against IFN-gamma inhibited skin lesions in NC/Nga mice. The inhibitory effect of TGF-beta(1) on the skin lesions lasted at least 1 week after cessation of the treatment.
Conclusion These findings indicate that TGF-beta(1) suppressed atopic dermatitis-like skin lesions in NC/Nga mice at least in part through down-regulation of IFN-gamma. These results suggest that TGF-beta(1) may have a therapeutic potential for atopic dermatitis.

Web of Science

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.51.941_1

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.51.1036_2

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.51.907_3

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.51.942_1

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Academic Press Inc.  

DOI： 10.1006/bbrc.2001.5887

Scopus

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

By using a serial analysis of gene expression (SAGE), we have identified a novel full-length cDNA that is preferentially expressed in human cord blood-derived mast cells. The predicted protein showed unique primary structure with a nuclear localization signal ((N) over bar LS), a sterile alpha motif S (A) over barM), and a Src homology 3 domain (SH3) (termed Nash1). Nash1 was mapped to human chromosome 21q11.1 and highly expressed in spleen, liver, peripheral blood, and mast cell lines. In consistent with the presence of NLS, Nash1 was localized in the nucleus. Interestingly, screening gene databases for Nash1-related sequences revealed the existence of a Nash1-related gene termed SLY that was preferentially detected in lymphoid cells. We also found at least two additional candidates for this gene family in the database. These findings suggested that Nash1 and Nash1-related proteins consisted of a novel family of signaling/adaptor proteins, and Nash1 might function as a signaling component of mast cells, possibly in the nucleus. (C) 2001 Academic Press.

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

IF:10.213

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Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Transforming growth factor beta1 (TGF-beta1) is produced by many types of cells that are activated in the asthmatic response. Recent studies have highlighted this cytokine as an important negative regulator in an experimental model of asthma, Although the role of TGF-beta1 in human asthma remains obscure, data derived from animal models have encouraged the further investigation of such suppression mechanisms in order to develop novel therapies for asthma.

Web of Science

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.50.902_4

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Hepatic stellate cells (HSC) are the main producers of type I collagen in fibrotic liver, and transforming growth factor-β (TGF-β) plays critical roles in stimulating collagen gene expression in the cells mainly at the level of transcription. We have previously identified an upstream sequence of α2(I) collagen gene (COL1A2) that is essential for its basal and TGF-β-stimulated transcription in skin fibroblasts and HSC. We designated this region the TGF-β-responsive element (TbRE). Recently Smad3, an intracellular mediator of TGF-β signal transduction, has been shown to bind to the TbRE and stimulate COL1A2 transcription when overexpressed in skin fibroblasts. In the present study, we demonstrate increased transcription of COL1A2 and plasminogen activator inhibitor-1 (PAI-1) genes and low response to TGF-β in an activated HSC clone derived from a cirrhotic liver. Western blot analyses indicated constitutive phosphorylation of Smad3 in the cells. Immunofluorescence studies revealed that, in contrast to Smad2 that translocated from the cytoplasm to the nucleus upon TGF-β treatment, Smad3 and Smad4 were present in the nucleus irrespective of ligand stimulation. Increased COL1A2 and PAl-1 gene transcription in the cells was not affected by overexpression of inhibitory Smad7. Altogether, the results correlate abnormality in TGF-β/Smad signaling with pathologically accelerated collagen gene transcription in activated HSC. © 2001 Wiley-Liss, Inc.

DOI： 10.1002/1097-4652(2001)9999:9999<00::AID-JCP1059>3.0.CO;2-S

Scopus

PubMed

Language：English   Publisher：Japanese Society of Allergology  

DOI： 10.15036/arerugi.50.909_2

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.50.899_4

Authorship：Lead author   Language：Japanese   Publisher：医歯薬出版  

CiNii Books

Other Link： http://search.jamas.or.jp/link/ui/2001165140

Language：Japanese   Publisher：The Japanese Society for Connective Tissue  

CiNii Books

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1006/bbrc.2000.2403

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English  

DOI： 10.1084/jem.192.2.151

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

DOI： 10.1159/000053626

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CiNii Books

Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.48.227

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/intimm/10.4.387

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PubMed

CiNii Books

Total pages：608   Responsible for pages：53-55-   Language：Japanese  

Responsible for pages：379-395-   Language：English  

Responsible for pages：233-248-   Language：English  

Event date： 2023.10

Language：Japanese   Presentation type：Symposium workshop panel(nominated)  

Venue：東京  

Event date： 2023.10

Language：Japanese   Presentation type：Symposium workshop panel(public)  

Venue：東京  

Event date： 2023.10

Language：English   Presentation type：Oral presentation(general)  

Event date： 2023.10

Language：English   Presentation type：Oral presentation(general)  

Event date： 2023.9

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：横浜  

Event date： 2023.7

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Venue：東京  

Event date： 2023.6

Language：English   Presentation type：Oral presentation(general)  

Venue：Hamburg, Germany  

Event date： 2023.6

Language：English   Presentation type：Oral presentation(general)  

Venue：Hamburg, Germany  

Event date： 2023.5

Language：Japanese   Presentation type：Symposium workshop panel(nominated)  

Venue：東京  

Event date： 2023.2

Language：English   Presentation type：Oral presentation(general)  

Venue：San Antonio, USA  

Event date： 2023.2

Language：Japanese   Presentation type：Oral presentation(keynote)  

Venue：鹿児島  

Event date： 2022.12

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2022.12

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：宇都宮  

Event date： 2022.10

Language：English   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Event date： 2022.10

Language：Japanese   Presentation type：Symposium workshop panel(nominated)  

Venue：東京  

Event date： 2022.3

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Venue：東京（秋葉原）  

Event date： 2021.12

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Venue：仙台  

Event date： 2021.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京（秋葉原）  

Event date： 2021.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京（秋葉原）  

Event date： 2021.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京（秋葉原）  

Event date： 2021.11

Language：Japanese   Presentation type：Symposium workshop panel(nominated)  

Venue：沖縄  

Event date： 2021.11

Language：Japanese   Presentation type：Symposium workshop panel(nominated)  

Venue：沖縄  

Event date： 2021.11

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Event date： 2021.10

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Event date： 2021.10

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Venue：横浜  

Event date： 2021.10

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：横浜  

Event date： 2021.10

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：横浜  

Event date： 2020.10

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Event date： 2019.6

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Event date： 2018.9

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Event date： 2018.8

Language：Japanese   Presentation type：Public discourse, seminar, tutorial, course, lecture and others  

Event date： 2018.5

Language：English   Presentation type：Poster presentation  

Venue：Florida, USA  

Event date： 2018.5

Language：English   Presentation type：Poster presentation  

Venue：Florida, USA  

Event date： 2018.3

Language：English   Presentation type：Symposium workshop panel(public)  

Event date： 2017.12

Language：English   Presentation type：Poster presentation  

Event date： 2017.12

Language：English   Presentation type：Poster presentation  

Event date： 2017.12

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：神戸  

Event date： 2017.10

Language：English   Presentation type：Oral presentation(general)  

Event date： 2017.9

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：山梨  

Event date： 2017.9

Language：Japanese   Presentation type：Symposium workshop panel(nominated)  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2017.6

Language：English   Presentation type：Oral presentation(invited, special)  

Event date： 2017.3

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.12

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2016.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.11

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.10

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.9

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.8

Language：English   Presentation type：Oral presentation(invited, special)  

Event date： 2016.6

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Event date： 2016.6

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.5

Language：English   Presentation type：Oral presentation(invited, special)  

Event date： 2016.5

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.4

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.4

Language：Japanese   Presentation type：Media report,etc.  

Event date： 2016.4

Language：English   Presentation type：Oral presentation(invited, special)  

Event date： 2016.3

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.3

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.2

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：三重県鳥羽市  

Event date： 2016.1

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2015.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2015.12

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：甲府  

Event date： 2015.12

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：静岡市  

Event date： 2015.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2015.11

Language：English   Presentation type：Oral presentation(invited, special)  

Event date： 2015.10

Language：English   Presentation type：Oral presentation(general)  

Event date： 2015.9

Language：English   Presentation type：Oral presentation(general)  

Event date： 2015.9

Language：English   Presentation type：Oral presentation(general)  

Event date： 2015.8

Language：Japanese   Presentation type：Oral presentation(general)  

Event date： 2015.5

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2015.5

Language：Japanese   Presentation type：Oral presentation(general)  

Event date： 2015.5

Language：Japanese   Presentation type：Oral presentation(general)  

Event date： 2015.3

Language：English   Presentation type：Oral presentation(general)  

Event date： 2014.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2014.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2014.11

Language：Japanese   Presentation type：Oral presentation(general)  

Event date： 2014.10

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：東京  

Event date： 2014.10

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2014.9

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：千葉　幕張メッセ  

Event date： 2014.9

Language：English   Presentation type：Oral presentation(general)  

Event date： 2014.2

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：メルバルク京都  

Event date： 2013.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2013.11

Language：Japanese   Presentation type：Oral presentation(general)  

Event date： 2013.11

Language：English   Presentation type：Oral presentation(invited, special)  

Event date： 2013.11

Language：Japanese   Presentation type：Oral presentation(general)  

Event date： 2013.10

Language：Japanese   Presentation type：Oral presentation(general)  

Event date： 2013.10

Language：English   Presentation type：Oral presentation(invited, special)  

Event date： 2013.10

Language：English   Presentation type：Oral presentation(invited, special)  

Event date： 2013.7

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：ウェスティン都ホテル（京都市）  

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：パシフィコ横浜（横浜市）  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation(general)  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：山梨県中央市  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：大阪  

Event date： 2013.3

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：大阪  

Event date： 2013.2

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：大分県由布市  

Event date： 2012.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2012.11

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：大阪市  

Event date： 2012.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：大阪市  

Event date： 2012.10

Language：Japanese   Presentation type：Oral presentation(general)  

Event date： 2012.10

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：名古屋  

Event date： 2012.10

Language：English   Presentation type：Oral presentation(general)  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：熊本市  

Event date： 2012.9

Language：English   Presentation type：Oral presentation(general)  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：山梨県甲府市  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：山梨県甲府市  

Event date： 2012.5

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：東京  

Event date： 2012.3

Language：English   Presentation type：Oral presentation(general)  

Event date： 2012.2

Language：English   Presentation type：Oral presentation(invited, special)  

Event date： 2011.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2011.12

Language：English   Presentation type：Oral presentation(general)  

Event date： 2011.11

Language：English   Presentation type：Oral presentation(general)  

Event date： 2011.11

Language：English   Presentation type：Oral presentation(general)  

Event date： 2011.11

Language：English   Presentation type：Oral presentation(general)  

Event date： 2011.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：名古屋  

Event date： 2011.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2011.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2011.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2011.11

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：東京  

Event date： 2011.11

Language：Japanese   Presentation type：Oral presentation(invited, special)  

Venue：山梨県中央市  

Event date： 2011.9

Language：English   Presentation type：Oral presentation(general)  

Event date： 2011.7

Language：English   Presentation type：Oral presentation(general)  

Event date： 2011.4

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：栃木県  

Event date： 2011.1

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：北海道  

Event date： 2011.1

Language：English   Presentation type：Oral presentation(general)  

Event date： 2010.12

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：横浜  

Event date： 2010.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京都  

Event date： 2010.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京都