記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1172/jci.insight.146572.

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Allergology International  

DOI： 10.1016/j.alit.2019.09.004.

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms20246320

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-019-54878-5

記述言語：英語  

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

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Natureresearch  

DOI： 10.1038/s41598-019-52449-2

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-019-46517-w

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/nau.23793

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2018.05.032

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-23115-w

Scopus

記述言語：日本語   出版者・発行元：(一社)日本泌尿器科学会総会事務局  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/nau.23400

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語  

DOI： 10.1016/j.jid.2017.07.838

PubMed

記述言語：日本語   出版者・発行元：(一社)日本泌尿器科学会総会事務局  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本排尿機能学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.1016/j.bbrc.2017.06.038

PubMed

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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-α productions were compared between bone marrow-derived mast cells (BMMCs) from wild-type and Clock-mutated mice (ClockΔ19/Δ19 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 ClockΔ19/Δ19 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-α 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 ClockΔ19/Δ19 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.

DOI： 10.1016/j.alit.2017.02.004

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

Web of Science

PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

At steady state, plasma histamine levels exhibit circadian variations with nocturnal peaks, which is implicated in the nighttime exacerbation of allergic symptoms. However, the regulatory mechanisms are largely unexplored. This study determined how steady-state plasma histamine levels are regulated and affected by environmental factors. We found that plasma histamine levels decreased in mast cell-deficient mice and their circadian variations were lost in mast cell-deficient mice reconstituted with bone marrow-derived mast cells (BMMCs) harboring a mutation in the circadian gene Clock. Clock temporally regulates expression of organic cation transporter 3 (OCT3), which is involved in histamine transport, in mast cells; OCT inhibition abolished circadian variations in plasma histamine levels. Mice housed under aberrant light/dark conditions or suffering from restraint stress exhibited de-synchronization of the mast cell clockwork, concomitant with the loss of circadian variations in OCT3 expression and plasma histamine levels. The degree of compound 48/80-induced plasma extravasation in mice was correlated with plasma histamine levels. Collectively, the mast cell clock mediates circadian regulation of plasma histamine levels at steady state, in part by controlling OCT3 expression, which can be modulated by stress. Additionally, we propose that plasma histamine levels potentiate mast cell-mediated allergic reactions.

DOI： 10.1038/srep39934

PubMed

記述言語：英語  

記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Objectives
Clock(Delta 19/Delta 19) mice is an experimental model mouse for nocturia (NOC). Using the bladder mucosa obtained from Clock(Delta 19/Delta 19) mice, we investigated the gene expression rhythms of mechanosensory cation channels such as transient receptor potential cation channel subfamily V member 4 (TRPV4) and Piezol, and main ATP release pathways including vesicular nucleotide transporter (VNUT) and Connexin26(Cx26), in addition to clock genes.
Materials and methods
Eight-to twelve-week-old male C57BL/6 mice (WT) and age-and sex-matched C57BL/6 Clock(Delta 19/Delta 19) mice, which were bred under 12-h light/dark conditions for 2 weeks, were used. Gene expression rhythms and transcriptional regulation mechanisms in clock genes, mechanosensor, Cx26 and VNUTwere measured in the mouse bladder mucosa, collected every 4 hours from WT and Clock(Delta 19/Delta 19) mice using quantitative RT-PCR, a Western blot analysis, and ChIP assays.
Results
WT mice showed circadian rhythms in clock genes as well as mechanosensor, Cx26 and VNUT. Their expression was low during the sleep phase. The results of ChIP assays showed Clock protein binding to the promotor regions and the transcriptional regulation of mechanosensor, Cx26 and VNUT. In contrast, all of these circadian expressions were disrupted in Clock(Delta 19/Delta 19) mice. The gene expression of mechanosensor, Cx26 and VNUT was maintained at a higher level in spite of the sleep phase.
Conclusions
Mechanosensor, Cx26 and VNUTexpressed with circadian rhythm in the mouse bladder mucosa. The disruption of circadian rhythms in these genes, induced by the abnormalities in clock genes, may be factors contributing to NOC because of hypersensitivity to bladder wall extension.

DOI： 10.1371/journal.pone.0168234

Web of Science

PubMed

記述言語：英語  

記述言語：日本語  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：英語   出版者・発行元：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.juro.2016.02.1341

Web of Science

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The circadian clock temporally gates signaling through the high-affinity IgE receptor (FcεRI) in mast cells, thereby generating a marked day/night variation in allergic reactions. Thus manipulation of the molecular clock in mast cells might have therapeutic potential for IgE-mediated allergic reactions. OBJECTIVE: We determined whether pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling was reduced (ie, when core circadian protein period 2 [PER2] is upregulated) resulted in suppression of IgE-mediated allergic reactions. METHODS: We examined the effects of PF670462, a selective inhibitor of the key clock component casein kinase 1δ/ε, or glucocorticoid, both of which upregulated PER2 in mast cells, on IgE-mediated allergic reactions both in vitro and in vivo. RESULTS: PF670462 or corticosterone (or dexamethasone) suppressed IgE-mediated allergic reactions in mouse bone marrow-derived mast cells or basophils and passive cutaneous anaphylactic reactions in mice in association with increased PER2 levels in mast cells or basophils. PF670462 or dexamethasone also ameliorated allergic symptoms in a mouse model of allergic rhinitis and downregulated allergen-specific basophil reactivity in patients with allergic rhinitis. CONCLUSION: Pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling is reduced can inhibit IgE-mediated allergic reactions. The results suggest a new strategy for controlling IgE-mediated allergic diseases. Additionally, this study suggests a novel mechanism underlying the antiallergic actions of glucocorticoids that relies on the circadian clock, which might provide a novel insight into the pharmacology of this drug in allergic patients.

DOI： 10.1016/j.jaci.2015.08.052

PubMed

記述言語：日本語  

記述言語：日本語  

記述言語：日本語   掲載種別：研究論文（研究会，シンポジウム資料等）  

記述言語：日本語  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

There are several reports suggesting that the pathophysiology of psoriasis may be associated with aberrant circadian rhythms. However, the mechanistic link between psoriasis and the circadian time-keeping system, "the circadian clock," remains unclear. This study determined whether the core circadian gene, Clock, had a regulatory role in the development of psoriasis. For this purpose, we compared the development of psoriasis-like skin inflammation induced by the Toll-like receptor 7 ligand imiquimod (IMQ) between wild-type mice and mice with a loss-of-function mutation of Clock. We also compared the development of IMQ-induced dermatitis between wild-type mice and mice with a loss-of-function mutation of Period2 (Per2), another key circadian gene that inhibits CLOCK activity. We found that Clock mutation ameliorated IMQ-induced dermatitis, whereas the Per2 mutation exaggerated IMQ-induced dermatitis, when compared with wild-type mice associated with decreased or increased IL-23 receptor (IL-23R) expression in γ/δ+ T cells, respectively. In addition, CLOCK directly bound to the promoter of IL-23R in γ/δ+ T cells, and IL-23R expression in the mouse skin was under circadian control. These findings suggest that Clock is a novel regulator of psoriasis-like skin inflammation in mice via direct modulation of IL-23R expression in γ/δ+ T cells, establishing a mechanistic link between psoriasis and the circadian clock.

DOI： 10.1038/jid.2015.316

PubMed

記述言語：日本語  

J-GLOBAL

記述言語：英語  

記述言語：英語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: It remains elusive how allergic symptoms exhibit prominent 24-hour variations. In mammals the circadian clocks present in nearly all cells, including mast cells, drive the daily rhythms of physiology. Recently, we have shown that the circadian clocks drive the daily rhythms in IgE/mast cell-mediated allergic reactions. However, the precise mechanisms, particularly the specific roles of the mast cell-intrinsic clockwork in temporal regulation, remain unclear. OBJECTIVE: We determined whether the mast cell clockwork contributes to the temporal regulation of IgE/mast cell-mediated allergic reaction. METHODS: The kinetics of a time of day-dependent variation in passive cutaneous anaphylactic reactions were compared between mast cell-deficient mice reconstituted with bone marrow-derived cultured mast cells generated from mice with a wild-type allele and a dominant negative type mutation of the key clock gene Clock. We also examined the temporal responses of wild-type and Clock-mutated bone marrow-derived cultured mast cells to IgE stimulation in vitro. Furthermore, factors influencing the mast cell clockwork were determined by using in vivo imaging. RESULTS: The Clock mutation in mast cells resulted in the absence of temporal variations in IgE-mediated degranulation in mast cells both in vivo and in vitro associated with the loss of temporal regulation of FcεRI expression and signaling. Additionally, adrenalectomy abolished the mast cell clockwork in vivo. CONCLUSION: The mast cell-intrinsic clockwork, entrained by humoral factors from the adrenal gland, primarily contributes to the temporal regulation of IgE/mast cell-mediated allergic reactions. Our results reveal a novel regulatory mechanism for IgE-mediated mast cell responses that might underlie the circadian pathophysiology in patients with allergic diseases.

DOI： 10.1016/j.jaci.2013.07.040

PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anaphylaxis is a severe systemic allergic reaction which is rapid in onset and potentially fatal, caused by excessive release of mediators including histamine and cytokines/chemokines from mast cells and basophils upon allergen/IgE stimulation. Increased prevalence of anaphylaxis in industrialized countries requires urgent needs for better understanding of anaphylaxis. However, the pathophysiology of the disease is not fully understood. Here we report that the circadian clock may be an important regulator of anaphylaxis. In mammals, the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes and entrains peripheral circadian clock present in virtually all cell types via neural and endocrine pathways, thereby driving the daily rhythms in behavior and physiology. We found that mechanical disruption of the SCN resulted in the absence of a time of day-dependent variation in passive systemic anaphylactic (PSA) reaction in mice, associated with loss of daily variations in serum histamine, MCP-1 (CCL2), and IL-6 levels. These results suggest that the central SCN clock controls the time of day-dependent variation in IgE-mediated systemic anaphylactic reaction, which may provide a novel insight into the pathophysiology of anaphylaxis.

DOI： 10.1155/2014/474217

PubMed

記述言語：日本語  

担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

PubMed

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background: Resveratrol is a bioactive polyphenol enriched in red wine that exhibits many beneficial health effects via multiple mechanisms. However, it is unclear whether resveratrol is beneficial for the prevention of food allergy. This study investigated whether resveratrol inhibited the development of food allergy by using a mouse model of the disease.
Methodology/Principal Findings: Mice fed standard diet or standard diet plus resveratrol were sensitized by intragastric administration of ovalbumin (OVA) and mucosal adjuvant cholera toxin (CT). Several manifestations of food allergy were then compared between the mice. The effects of resveratrol on T cells or dendritic cells were also examined by using splenocytes from OVA-specific T cell-receptor (TCR) transgenic DO11.10 mice or mouse bone marrow-derived dendritic cells (BMDCs) in vitro. We found that mice fed resveratrol showed reduced OVA-specific serum IgE production, anaphylactic reaction, and OVA-induced IL-13 and IFN-(a) over bar production from the mesenteric lymph nodes (MLNs) and spleens in comparison to the control mice, following oral sensitization with OVA plus CT. In addition, resveratrol inhibited OVA plus CT-induced IL-4, IL-13, and IFN-(a) over bar production in splenocytes from DO11.10 mice associated with inhibition of GATA-3 and T-bet expression. Furthermore, resveratrol suppressed the OVA plus CT-induced CD25 expression and IL-2 production in DO11.10 mice-splenocytes in association with decreases in CD80 and CD86 expression levels. Finally, resveratrol suppressed CT-induced cAMP elevation in association with decreases in CD80 and CD86 expression levels in BMDCs.
Conclusions/Significance: Ingestion of resveratrol prevented the development of a food allergy model in mice. Given the in vitro findings, resveratrol might do so by inhibiting DC maturation and subsequent early T cell activation and differentiation via downregulation of CT-induced cAMP activation in mice. These results suggest that resveratrol may have potential for prophylaxis against food allergy.

DOI： 10.1371/journal.pone.0044338

Web of Science

記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Increasing evidence suggests that the aryl hydrocarbon receptor (AhR) pathway has an important role in the regulation of inflammatory responses. Most recently, we have shown that the activation of the AhR pathway by a potent AhR agonist inhibits the development of dextran sodium sulfate (DSS)-induced colitis, a model of human ulcerative colitis, by the induction of prostaglandin E2 (PGE2) in the large intestine. Because several strains of probiotic lactic acid bacteria have been reported to inhibit DSS-induced colitis by unidentified mechanisms, we hypothesized that particular strains of lactic acid bacterium might have the potential to activate the AhR pathway, thereby inhibiting DSS-induced colitis. This study investigated whether there are specific lactic acid bacterial strains that can activate the AhR pathway, and if so, whether this AhR-activating potential is associated with suppression of DSS-induced colitis. By using AhR signaling reporter cells, we found that Lactobacillus bulgaricus OLL1181 had the potential to activate the AhR pathway. OLL1181 also induced the mRNA expression of cytochrome P450 family 1A1 (CYP1A1), a target gene of the AhR pathway, in human colon cells, which was inhibited by the addition of an AhR antagonist, α-naphthoflavon (αNF). In addition, mice treated orally with OLL1181 showed an increase in CYP1A1 mRNA expression in the large intestine and amelioration of DSS-induced colitis. Thus, OLL1181 can induce activation of the intestinal AhR pathway and inhibit DSS-induced colitis in mice. This strain of lactic acid bacterium has therefore the potential to activate the AhR pathway, which may be able to suppress colitis.

DOI： 10.1038/icb.2010.165

PubMed

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: IgE-mediated immediate-type skin reaction shows a diurnal rhythm, although the precise mechanisms remain uncertain. Period2 (Per2) is a key circadian gene that is essential for endogenous clockworks in mammals. OBJECTIVE: This study investigated whether Per2 regulates a time-of-day-dependent variation in IgE-mediated immediate-type skin reaction. METHODS: The kinetics of a passive cutaneous anaphylactic reaction were compared between wild-type mice and mice with a loss-of-function mutation of Per2 (mPer2(m/m) mice). The effects of adrenalectomy, aging, and dexamethasone on the kinetics of a passive cutaneous anaphylactic reaction were also examined. In addition, the extent of IgE-mediated degranulation in bone marrow-derived mast cells (BMMCs) was compared between wild-type and mPer2(m/m) mice. RESULTS: A time-of-day-dependent variation in a passive cutaneous anaphylactic reaction observed in wild-type mice was absent in mPer2(m/m) mice and in adrenalectomized and aged mice associated with the loss of rhythmic secretion of corticosterone. In addition, mPer2(m/m) mice showed decreased sensitivity to the inhibitory effects of dexamethasone on the passive cutaneous anaphylactic reactions. IgE-mediated degranulation in BMMCs was comparable between wild-type and mPer2(m/m) mice, but Per2 mutation decreased sensitivity to the inhibitory effects of dexamethasone on IgE-mediated degranulation in BMMCs. CONCLUSION: A circadian oscillator, Per2, regulates a time-of-day-dependent variation in a passive cutaneous anaphylactic reaction in mice. Per2 may do so by controlling the rhythmic secretion of glucocorticoid from adrenal glands and/or by gating the glucocorticoid responses of mast cells to certain times of the day (possibly when Per2 levels are high in mast cells).

DOI： 10.1016/j.jaci.2011.02.006

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aryl hydrocarbon receptor (AhR) recognizes numerous small xenobiotic and natural molecules, such as dioxin and natural chemicals, and is involved in the metabolism of these compounds. AhR also has a regulatory role in inflammatory responses. This study investigated whether the activation of the AhR pathway affects dextran sodium sulfate (DSS)-induced colitis, an ulcerative colitis-like model, in mice. DSS-induced colitis was ameliorated by pretreatment with a potent AhR activator, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in mice. In addition, the mice pretreated with TCDD showed increased prostaglandin E2 (PGE2) production in the colon, and inhibition of PGE2 production by indomethacin abrogated the inhibitory effects of TCDD on DSS-induced colitis. Collectively, the activation of the AhR pathway by TCDD may ameliorate DSS-induced colitis, at least in part, through PGE2 production.

DOI： 10.1038/icb.2010.35

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Both thymic stromal lymphopoietin (TSLP) and IL-13 are essential cytokines for the development of allergic inflammation. However, a causal link between TSLP and IL-13 has not yet been fully elucidated. This study aimed to investigate whether IL-13 induces TSLP expression and whether the induction contributes to the development of allergic inflammation. We found that IL-13 induced TSLP expression in mouse nasal tissue specimens in a Stat6-dependent manner. In addition, intranasal challenge of mice with IL-13 induced TSLP expression in the nasal epithelium. Importantly, intranasal IL-13 challenge induced eosinophilia and goblet cell hyperplasia in the nasal mucosa in mice, which was inhibited by the blockade of TSLP activity with anti-TSLP Ab. These findings suggest that TSLP is an important mediator of IL-13-driven allergic inflammation in the nasal mucosa. Taken together with the recent findings that IL-13 is a critical downstream element for TSLP-driven allergic inflammation, TSLP may function both upstream and downstream of IL-13, thus providing an additional rationale as to why TSLP plays such a central role in the development of allergic inflammation.

DOI： 10.1002/eji.200939302

PubMed

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Subtilase cytotoxin (SubAB) is the prototype of a newly identified family of AB(5) cytotoxins produced by Shiga toxigenic Escherichia coli. SubAB specifically cleaves the essential endoplasmic reticulum (ER) chaperone BiP (GRP78), resulting in the activation of ER stress-induced unfolded protein response (UPR). We have recently shown that the UPR following ER stress can suppress cellular responses to inflammatory stimuli during the later phase, in association with inhibition of NF-kappaB activation. These findings prompted us to hypothesize that SubAB, as a selective UPR inducer, might have beneficial effects on inflammation-associated pathology via a UPR-dependent inhibition of NF-kappaB activation. The pretreatment of a mouse macrophage cell line, RAW264.7, with a subcytotoxic dose of SubAB-triggered UPR and inhibited LPS-induced MCP-1 and TNF-alpha production associated with inhibition of NF-kappaB activation. SubA(A272)B, a SubAB active site mutant that cannot induce UPR, did not show such effects. In addition, pretreatment with a sublethal dose of SubAB, but not SubA(A272)B, protected the mice from LPS-induced endotoxic lethality associated with reduced serum MCP-1 and TNF-alpha levels and also prevented the development of experimental arthritis induced by LPS in mice. Collectively, although SubAB has been identified originally as a toxin associated with the pathogenesis of hemolytic uremic syndrome, the unique ability of SubAB to selectively induce the UPR may have the potential to prevent LPS-associated inflammatory pathology under subcytotoxic conditions.

DOI： 10.4049/jimmunol.0804066

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A major house dust mite allergen Der f 1 belongs to the papain-like cysteine protease family. This study investigated whether Der f 1 can cleave the latency-associated peptide (LAP) of transforming growth factor (TGF)-beta via its proteolytic activity and activate latent TGF-beta. We found that Der f 1 can cleave LAP and induce the activation of latent TGF-beta, leading to functional Smad signaling. Importantly, these actions of Der f 1 were inhibited by cysteine protease inhibitor E64 or inactivation of the protease activity by heat. Thus, latent TGF-beta may be a direct target of Der f 1 protease activity.

DOI： 10.1016/j.febslet.2009.05.030

PubMed

記述言語：日本語  

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3945/jn.109.108761

PubMed

記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Both active and passive smoking are considered to be risk factors for asthma development. However, the precise mechanisms involved remain elusive. Recently, thymic stromal lymphopoietin (TSLP) has been shown to play a key role in the development of T(H)2-type allergic inflammation in patients with asthma. OBJECTIVE: The aim of this study was to investigate whether there was a causal relationship between cigarette smoke exposure and TSLP expression in the lung. METHODS: We examined the effects of repeated intranasal exposure of cigarette smoke extract (CSE) on TSLP mRNA and protein expression in the mouse lung by means of real-time PCR, Western blotting, and immunohistochemistry. We also examined the effects of intranasal exposure of CSE plus ovalbumin (OVA) on T(H)2-type immune responses and lung pathology. RESULTS: Repeated exposure of CSE induced TSLP mRNA and protein expression, which was inhibited by treatment with antioxidative N-acetylcysteine and by TNF-alpha receptor I deficiency. In addition, the intranasal exposure of CSE simultaneously with OVA induced OVA-specific T(H)2-type immune responses and airway inflammation, which were inhibited by the blockade of the TSLP activity. CONCLUSION: CSE induced TSLP expression in the mouse lung in an oxidative stress-dependent and TNF-alpha receptor I-dependent manner, and when challenged simultaneously with an antigen, CSE promoted the development of airway inflammation in association with T(H)2-type immune responses.

DOI： 10.1016/j.jaci.2008.09.022

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To determine whether thymic stromal lymphopoietin (TSLP) plays a role in the resorption of herniated disc tissue. METHODS: The expression of TSLP messenger RNA (mRNA) and protein in mouse intervertebral disc cells was assessed by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), and immunohistochemical analysis. The ability of mouse intervertebral disc cells to respond to TSLP stimulation was examined by Western blot analysis, ELISA, and protein array analysis. Intracellular signaling pathways involved in TSLP signaling in mouse intervertebral disc cells were investigated using several chemical inhibitors. The role of TSLP in macrophage migration into the intervertebral disc was assessed by in vitro migration assay. Finally, TSLP expression in clinical specimens derived from patients with a herniated disc was examined by immunohistochemistry. RESULTS: Mouse intervertebral disc cells expressed TSLP mRNA and protein upon stimulation with NF-kappaB-activating ligands such as tumor necrosis factor alpha. In addition, the mouse intervertebral disc cells expressed the TSLP receptor and produced monocyte chemotactic protein 1 (MCP-1; CCL2) and macrophage colony-stimulating factor in response to TSLP stimulation. Both anulus fibrosus and nucleus pulposus intervertebral disc cells expressed MCP-1 upon TSLP stimulation, which was mediated via the phosphatidylinositol 3-kinase/Akt pathway. Consistently, the supernatants of TSLP-activated intervertebral disc cultures had the capacity to induce macrophage migration in an MCP-1-dependent manner. Finally, TSLP and MCP-1 were coexpressed in human herniated disc specimens in which macrophage infiltration into the tissue was observed. CONCLUSION: TSLP induced by NF-kappaB-activating ligands in intervertebral discs may contribute to the recruitment of macrophages to the intervertebral disc by stimulating MCP-1 production and may be involved in the resorption of herniated disc tissue.

DOI： 10.1002/art.23965

PubMed

開催年月日： 2022年12月

記述言語：日本語   会議種別：ポスター発表  

開催地：宇都宮  

開催年月日： 2022年6月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：京都  

開催年月日： 2021年11月

記述言語：日本語   会議種別：口頭（一般）  

開催地：東京  

記述言語：日本語   会議種別：口頭（一般）  

開催地：東京  

開催年月日： 2021年11月

記述言語：日本語   会議種別：口頭（招待・特別）  

開催地：沖縄  

記述言語：日本語   会議種別：口頭（招待・特別）  

開催地：沖縄  

開催年月日： 2021年10月

記述言語：日本語   会議種別：口頭（一般）  

開催地：横浜  

記述言語：日本語   会議種別：口頭（一般）  

開催地：横浜  

開催年月日： 2021年9月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：福岡  

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：福岡  

開催年月日： 2018年5月

記述言語：英語   会議種別：口頭（一般）  

記述言語：英語   会議種別：口頭（一般）  

開催地：Florida, USA  

開催年月日： 2018年3月

記述言語：英語   会議種別：ポスター発表  

開催地：香川  

記述言語：英語   会議種別：ポスター発表  

開催地：香川  

開催年月日： 2017年12月

記述言語：英語   会議種別：ポスター発表  

開催地：仙台  

開催年月日： 2017年12月

記述言語：日本語   会議種別：ポスター発表  

開催地：神戸  

開催年月日： 2017年10月

記述言語：日本語   会議種別：ポスター発表  

開催地：京都  

開催年月日： 2017年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：鹿児島  

開催年月日： 2017年6月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：横浜  

開催年月日： 2017年6月

記述言語：日本語   会議種別：口頭（一般）  

開催地：東京  

開催年月日： 2017年3月

記述言語：英語   会議種別：口頭（一般）  

開催地：London  

開催年月日： 2016年12月

記述言語：英語   会議種別：口頭（一般）  

開催地：沖縄県宜野湾市  

開催年月日： 2016年12月

記述言語：日本語   会議種別：口頭（一般）  

開催地：東京  

開催年月日： 2016年12月

記述言語：英語   会議種別：口頭（一般）  

開催地：沖縄県宜野湾市  

開催年月日： 2016年11月

記述言語：英語   会議種別：口頭（一般）  

開催地：名古屋市  

開催年月日： 2016年10月

記述言語：英語   会議種別：口頭（一般）  

開催地：Beijing  

開催年月日： 2016年9月

記述言語：英語   会議種別：口頭（一般）  

開催地：Tokyo  

開催年月日： 2016年7月

記述言語：日本語   会議種別：口頭（招待・特別）  

開催地：東京都新宿区  

開催年月日： 2016年7月

記述言語：日本語   会議種別：口頭（招待・特別）  

開催地：東京  

開催年月日： 2016年6月

記述言語：日本語   会議種別：口頭（招待・特別）  

開催地：東京  

開催年月日： 2016年5月

記述言語：英語   会議種別：口頭（一般）  

開催地：San Diego  

開催年月日： 2016年4月

記述言語：英語   会議種別：口頭（一般）  

開催地：仙台  

開催年月日： 2016年3月

記述言語：英語   会議種別：口頭（一般）  

開催地：Munich, Germany  

開催年月日： 2016年3月

記述言語：英語   会議種別：口頭（一般）  

開催地：ロサンゼルス  

開催年月日： 2016年2月

記述言語：日本語   会議種別：口頭（一般）  

開催地：三重県鳥羽市  

開催年月日： 2015年12月

記述言語：英語   会議種別：口頭（一般）  

開催地：Okayama  

開催年月日： 2015年12月

記述言語：日本語   会議種別：口頭（一般）  

開催地：静岡市  

開催年月日： 2015年11月

記述言語：日本語   会議種別：口頭（一般）  

開催地：東京  

開催年月日： 2015年10月

記述言語：英語   会議種別：口頭（一般）  

開催地：Montreal  

開催年月日： 2015年9月

記述言語：英語   会議種別：口頭（一般）  

開催地：札幌  

開催年月日： 2015年7月

記述言語：日本語   会議種別：口頭（一般）  

開催地：栃木  

開催年月日： 2015年5月

記述言語：日本語   会議種別：口頭（一般）  

開催地：東京  

開催年月日： 2015年5月

記述言語：日本語   会議種別：口頭（一般）  

開催地：東京  

開催年月日： 2015年3月

記述言語：日本語   会議種別：口頭（招待・特別）  

開催地：山梨  

開催年月日： 2014年5月

記述言語：日本語   会議種別：口頭（招待・特別）  

開催地：京都  

開催年月日： 2012年11月

記述言語：日本語   会議種別：口頭（一般）  

開催地：大阪市  

開催年月日： 2012年9月

記述言語：日本語   会議種別：口頭（一般）  

開催地：甲府市  

開催年月日： 2010年11月

記述言語：日本語   会議種別：口頭（一般）  

開催地：東京  

開催年月日： 2010年11月

記述言語：日本語   会議種別：その他  

開催地：東京  

開催年月日： 2008年11月

記述言語：英語   会議種別：口頭（一般）  

開催地：東京  

概日時計によるアレルギー反応の制御機構の解明

Nakamura Y, Harama D, Shimokawa N, Hara M, Suzuki R, Tahara Y, Ishimaru K, Katoh R, Okumura K, Ogawa H, Shibata S, Nakao A: Circadian clock gene Period2 regulates a time-of-day-dependent variation in

Period2遺伝子による即時型皮膚過敏反応の日内変動の調節

Nakamura Y, Harama D, Shimokawa N, Hara M, Suzuki R, Tahara Y, Ishimaru K, Katoh R, Okumura K, Ogawa H, Shibata S, Nakao A: Circadian clock gene Period2 regulates a time-of-day-dependent variation in