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

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

DOI： 10.1111/all.15954

PubMed

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

Ethyl caffeate (EC) is a natural phenolic compound that is present in several medicinal plants used to treat inflammatory disorders. However, its anti-inflammatory mechanisms are not fully understood. Here, we report that EC inhibits aryl hydrocarbon receptor (AhR) signaling and that this is associated with its anti-allergic activity. EC inhibited AhR activation, induced by the AhR ligands FICZ and DHNA in AhR signaling-reporter cells and mouse bone marrow-derived mast cells (BMMCs), as assessed by AhR target gene expressions such as CYP1A1. EC also inhibited the FICZ-induced downregulation of AhR expression and DHNA-induced IL-6 production in BMMCs. Furthermore, the pretreatment of mice with orally administered EC inhibited DHNA-induced CYP1A1 expression in the intestine. Notably, both EC and CH-223191, a well-established AhR antagonist, inhibited IgE-mediated degranulation in BMMCs grown in a cell culture medium containing significant amounts of AhR ligands. Furthermore, oral administration of EC or CH-223191 to mice inhibited the PCA reaction associated with the suppression of constitutive CYP1A1 expression within the skin. Collectively, EC inhibited AhR signaling and AhR-mediated potentiation of mast cell activation due to the intrinsic AhR activity in both the culture medium and normal mouse skin. Given the AhR control of inflammation, these findings suggest a novel mechanism for the anti-inflammatory activity of EC.

DOI： 10.3390/ijms24129997

PubMed

Language：English   Publishing type：(MISC) Introduction and explanation (scientific journal)  

DOI： 10.1016/j.alit.2022.06.008.

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

DOI： 10.1172/jci.insight.146572.

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Allergology International  

DOI： 10.1016/j.alit.2019.09.004.

PubMed

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

The cell-autonomous circadian clock regulates IgE- and IL-33-mediated mast cell activation, both of which are key events in the development of allergic diseases. Accordingly, clock modifiers could be used to treat allergic diseases, as well as many other circadian-related diseases, such as sleep and metabolic disorders. The nuclear receptors REV-ERB-α and -β (REV-ERBs) are crucial components of the circadian clockwork. Efforts to pharmacologically target REV-ERBs using putatively specific synthetic agonists, particularly SR9009, have yielded beneficial effects on sleep and metabolism. Here, we sought to determine whether REV-ERBs are functional in the circadian clockwork in mast cells and, if so, whether SR9009 affects IgE- and IL-33-mediated mast cell activation. Bone marrow-derived mast cells (BMMCs) obtained from wild-type mice expressed REV-ERBs, and SR9009 or other synthetic REV-ERBs agonists affected the mast cell clockwork. SR9009 inhibited IgE- and IL-33-mediated mast cell activation in wild-type BMMCs in association with inhibition of Gab2/PI3K and NF-κB activation. Unexpectedly, these suppressive effects of SR9009 were observed in BMMCs following mutation of the core circadian gene Clock. These findings suggest that SR9009 inhibits IgE- and IL-33-mediated mast cell activation independently of the functional circadian clock activity. Thus, SR9009 or other synthetic REV-ERB agonists may have potential for anti-allergic agents.

DOI： 10.3390/ijms20246320

PubMed

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

DOI： 10.1038/s41598-019-54878-5

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

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

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

DOI： 10.1038/s41598-019-52449-2

PubMed

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

DOI： 10.1038/s41598-019-46517-w

PubMed

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

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

DOI： 10.1016/j.bbrc.2018.05.032

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (commerce magazine)  

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

Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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

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

Language：Japanese  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本排尿機能学会  

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

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

DOI： 10.1016/j.alit.2017.02.004.

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

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

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

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

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

DOI： 10.1159/issn.1018-2438

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

Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (others)  

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

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

DOI： 10.1016/j.juro.2016.02.1341

Web of Science

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

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

Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (others)  

Language：Japanese   Publishing type：Research paper (research society, symposium materials, etc.)  

Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (others)  

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

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

Language：Japanese  

J-GLOBAL

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

DOI： 10.1111/all.12596.

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

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (bulletin of university, research institution)  

Language：English  

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

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

DOI： 10.1016/j.jaci.2013.07.040.

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (scientific journal)  

Language：Japanese  

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：(MISC) Introduction and explanation (scientific journal)  

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

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

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

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

DOI： https://doi.org/10.1016/j.jaci.2011.02.006

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

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

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

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

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

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

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

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

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

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

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

DOI： 10.3945/jn.109.108761

PubMed

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

DOI： 10.1016/j.jaci.2008.09.022.

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

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

Event date： 2023.9

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

Venue：横浜   Country：Japan  

Event date： 2023.9

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

Venue：横浜   Country：Japan  

Language：Japanese   Presentation type：Poster presentation  

Event date： 2023.2

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

Venue：Sna Antonio, TX  

Event date： 2022.12

Language：Japanese   Presentation type：Poster presentation  

Venue：宇都宮  

Event date： 2022.6

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

Venue：京都  

Event date： 2021.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2021.11

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

Venue：沖縄  

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

Venue：沖縄  

Event date： 2021.10

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：横浜  

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：横浜  

Event date： 2021.9

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

Venue：福岡  

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

Venue：福岡  

Event date： 2018.5

Language：English   Presentation type：Oral presentation(general)  

Venue：Florida, USA  

Language：English   Presentation type：Oral presentation(general)  

Venue：Florida, USA  

Event date： 2018.3

Language：English   Presentation type：Poster presentation  

Language：English   Presentation type：Poster presentation  

Venue：香川  

Event date： 2017.12

Language：English   Presentation type：Poster presentation  

Event date： 2017.12

Language：Japanese   Presentation type：Poster presentation  

Venue：神戸  

Event date： 2017.10

Language：Japanese   Presentation type：Poster presentation  

Venue：京都  

Event date： 2017.7

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

Venue：鹿児島  

Event date： 2017.6

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

Venue：横浜  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2017.3

Language：English   Presentation type：Oral presentation(general)  

Event date： 2016.12

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： 2016.11

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： 2016.7

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

Event date： 2016.7

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

Venue：東京  

Event date： 2016.6

Language：Japanese   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： 2016.3

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： 2015.12

Language：English   Presentation type：Oral presentation(general)  

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： 2015.10

Language：English   Presentation type：Oral presentation(general)  

Event date： 2015.9

Language：English   Presentation type：Oral presentation(general)  

Event date： 2015.7

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： 2015.3

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

Venue：山梨  

Event date： 2014.5

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

Event date： 2012.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：大阪市  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：甲府市  

Event date： 2010.11

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：東京  

Event date： 2010.11

Language：Japanese   Presentation type：Other  

Venue：東京  

Event date： 2008.11

Language：English   Presentation type：Oral presentation(general)  

Venue：東京  

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

Award type：International academic award (Japan or overseas)  Country：Japan

Audience： General

Type：TV or radio program