東北大学研究者紹介

研究者詳細

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顔写真

セガワ　リヨウスケ

瀬川　良佑

Ryosuke Segawa

所属

病院　薬剤部

職名

助教

学位

博士（薬学）（東北大学）

researchmap

https://researchmap.jp/7000006984

J-GLOBAL ID

201401087467400408

経歴 5

2025年9月～継続中

東北大学病院薬剤部　助教
2019年4月～ 2025年8月

東北大学　薬学研究科　助教
2013年5月～ 2019年3月

東北大学大学院薬学研究科　生活習慣病治療薬学分野　助手
2012年4月～ 2013年4月

東北大学薬学研究科博士課程（中退）
2006年4月～ 2012年3月

東北大学薬学科

所属学協会 4

日本薬理学会
日本腎臓病薬物療法学会
日本薬学会
日本アレルギー学会

研究キーワード 4

免疫制御
アレルギー
表皮ケラチノサイト
TSLP

研究分野 1

ライフサイエンス / 薬系衛生、生物化学 /

論文 33

Mass Spectrometry-Based Characterization of Electrolytic Decomposition Products of Carbamazepine and Aripiprazole Under Different Electrode Conditions

Masamitsu Maekawa, Hayahito Ishii, Kenji Miyata, Shunsuke Yokomi, Ryosuke Segawa, Masaki Kumondai, Mayumi Sato, Masahiro Takeda, Yoshiteru Oshima, Masanori Imazeki, Satoshi Ohtsu, Kozo Yoshioka, Nariyasu Mano

Applied Sciences　2026年8月12日

DOI： 10.3390/app16168029 　
Alkyne Two-Phase Strategy: Rapid Generation of TK-285-Derived PROTACs as BRD4 Degraders. 国際誌

Hiroyuki Yamakoshi, Ryo Watanabe, Ryosuke Segawa, Ryosuke Ishihara, Ryo Tachibana, Genki Kudo, Shota Nagasawa, Satoshi Yamanaka, Ayano Ito, Hiroyuki Takeda, Tatsuya Sawasaki, Ryunosuke Yoshino, Takatsugu Hirokawa, Takayuki Doi, Noriyasu Hirasawa, Yoshiharu Iwabuchi

Journal of medicinal chemistry　69　(7)　8388-8416　2026年4月9日

DOI： 10.1021/acs.jmedchem.5c03771 　

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This study introduces a divergent synthetic strategy in linkerology using preassembled linkers to generate structural diversity. The approach was validated by developing bromodomain-containing protein 4 (BRD4)-targeting proteolysis-targeting chimeras (PROTACs) based on an "alkyne two-phase strategy," employing the BRD4 inhibitor TK-285 as the binding ligand. In the initial screening phase, alkyne-modified TK-285 derivatives were subjected to click chemistry to optimize linker length and the modification site, leading to the identification of TKP-5 as a potent degrader. TKP-5 exhibited stronger thymic stromal lymphopoietin─more suppressive activity than TK-285 and markedly suppressed IL-33 mRNA expression in a tape-stripping-induced skin injury model. In the subsequent optimization phase, late-stage diversification using 1,3-butadiyne-typed PROTAC intermediates revealed the critical contribution of the triazole moiety, supported by in silico analysis suggesting interaction with Trp81 of BRD4. The strategy is expected to be broadly applicable to modular functional molecules accessible via click chemistry.
Enarodustat suppresses thymic stromal lymphopoietin expression via hypoxia-inducible factor-mediated c-Jun N-terminal kinases dephosphorylation

Ryosuke Segawa, Makiko Yagisawa, Chihiro Miyata, Noriyasu Hirasawa

PLOS One　2026年1月23日

DOI： 10.1371/journal.pone.0341552 　
Carbon‐Based Particles Inhibit Antigen Penetration Into the Skin by Adsorbing the Antigen

Rin Ichinohe, Ryosuke Segawa, Takahisa Nakajo, Masahiro Hiratsuka, Takeharu Yoshii, Kritin Pirabul, Zhen‐Ze Pan, Hirotomo Nishihara, Noriyasu Hirasawa

Experimental Dermatology　34　(2)　2025年2月16日
出版者・発行元： Wiley
DOI： 10.1111/exd.70061 　

ISSN：0906-6705

eISSN：1600-0625

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ABSTRACT In most cases, atopic dermatitis (AD) is induced by allergic inflammation, with antigen penetration into the epithelial tissues of the skin being the first step in AD development. Accordingly, inhibiting the skin penetration of antigens is effective in preventing AD. We evaluated the ability of the following four types of particles to adsorb ovalbumin (OVA): titanium dioxide (TiO₂), silicon dioxide (SiO₂), carbon, and SiO₂ coated with one‐layer graphene (1LGCS). We found that metal oxide particles (TiO₂ and SiO₂) could adsorb OVA at pH 5.0, but their abilities decreased at pH 7.0 and 9.0. In contrast, the carbon‐based particles (carbon and 1LGCS) adsorbed OVA regardless of pH changes. Epicutaneous treatment with OVA resulted in an increase in the proportion of OVA‐positive Langerhans cells and dermal dendritic cells in the lymph nodes, along with elevated interleukin‐4 mRNA expression, indicating that OVA penetrated the epidermis and underlying tissues. When OVA was applied together with the particles, these responses were significantly reduced by the carbon‐based particles but were only partially or not inhibited by metal oxide particles. These findings indicated that antigen penetration was potently inhibited by the carbon‐based particles. Additionally, when mice were epicutaneously sensitised and challenged with OVA in the presence of carbon, the increase in OVA‐specific IgG1 and IgE levels was significantly inhibited. The efficiency of carbon‐based particles may be attributed to their stable adsorption of proteins despite pH changes on the skin surface. These findings may lead to the development of new treatments for AD with fewer side effects.
Oxoammonium salts exert antiviral effects against coronavirus via denaturation of their spike proteins

Ryosuke Segawa, Yusuke Sasano, Yusuke Hatakawa, Yuto Fujisawa, Shuhei Akutsu, Masanobu Uchimura, Ami Ikura, Kota Matsumoto, Kazuki Sone, Tomoyuki Oe, Yoshiharu Iwabuchi, Masashi Ito, Noriyasu Hirasawa

Scientific Reports　14　(1)　2024年12月

DOI： 10.1038/s41598-024-75097-7 　

eISSN：2045-2322
Identification of amino acids in transmembrane domains of mutated cytokine receptor-like factor 2 and interleukin-7 receptor α required for constitutive signal transduction. 国際誌

Rio Yamamoto, Ryosuke Segawa, Hiyori Kato, Yuya Niino, Takeshi Sato, Masahiro Hiratsuka, Noriyasu Hirasawa

Biochimica et biophysica acta. Biomembranes　1866　(7)　184359-184359　2024年10月

DOI： 10.1016/j.bbamem.2024.184359 　

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Cytokine receptor-like factor 2 (CRLF2) and interleukin-7 receptor α (IL-7Rα) form a receptor for thymic stromal lymphopoietin (TSLP). A somatic mutation consisting of the substitution of five amino acids (SLLLL) in the transmembrane domain of CRLF2 with three amino acids, including glutamic acid, isoleucine, and methionine (insEIM), which has been identified in acute lymphocytic leukemia, causes the TSLP-independent dimerization with IL-7Rα and activation. However, the dimerization mechanism remains unclear. In this study, we examined the involvement of the amino acids in the transmembrane domains of EIM CRLF2 and IL-7Rα in TSLP-independent activation. HEK293 cells were transfected with vectors encoding CRLF2 and IL-7Rα, or their mutants, in which the amino acid of the transmembrane domain was replaced with alanine. STAT5 phosphorylation was detected using western blotting, and receptor dimerization was analyzed using the NanoBiT assay. The substitution of glutamic acid within the insEIM mutation for alanine failed to cause the STAT5 phosphorylation in the absence of TSLP. Moreover, the alanine substation of the specific leucine residues in the transmembrane domains of both CRLF2 and IL-7Rα abrogated the TSLP-independent signal transduction and dimerization. The mutation of IL-7Rα W264 partially reduced the phosphorylation of STAT5 without affecting receptor dimerization. These results suggest that the amino acids in the transmembrane domains of EIM CRLF2 and IL-7Rα play at least three possible functions: interaction through hydrogen bonds, hydrophobic interaction, and signal transduction. Our findings contribute to a better understanding of the function of the transmembrane domains of cytokine receptors in their dimerization and signal transduction.
Biological Evaluation of Isosteric Applicability of 1,3-Substituted Cuneanes as m-Substituted Benzenes Enabled by Selective Isomerization of 1,4-Substituted Cubanes. 国際誌

Kan Fujiwara, Shota Nagasawa, Ryusei Maeyama, Ryosuke Segawa, Noriyasu Hirasawa, Takatsugu Hirokawa, Yoshiharu Iwabuchi

Chemistry (Weinheim an der Bergstrasse, Germany)　30　(11)　e202303548　2024年2月21日

DOI： 10.1002/chem.202303548 　

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We herein evaluate a biological applicability of 1,3-substituted cuneanes as an isostere of m-substituted benzenes based on its structural similarity. An investigation of a method to obtain 1,3-substituted cuneanes by selective isomerization of 1,4-substituted cubanes enables this attempt by giving a key synthetic step to obtain a cuneane analogs of pharmaceuticals having m-substituted benzene moiety. Biological evaluation of the synthesized analogs and in silico study of the obtained result revealed a potential usage of cuneane skeleton in medicinal chemistry.
Caspases downregulate nickel and hydrogen peroxide-induced IL-8 production via modification of c-Jun N-terminal kinases 国際誌

Ryusei Maeyama, Ryosuke Segawa, Ryo Onodera, Masahiro Hiratsuka, Noriyasu Hirasawa

Toxicology　501　153710-153710　2023年12月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.tox.2023.153710 　

ISSN：0300-483X

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Nickel (Ni) is a typical hapten in allergic contact dermatitis. However, it has been used in various metal materials due to its usefulness. Although Ni ions induce apoptosis of inflammatory cells and the expression of inflammatory cytokines such as interleukin-8 (IL-8), the effects of the apoptotic pathway on the signaling that induces cytokine production have not been sufficiently clarified. Here, we found that NiCl2-induced IL-8 production was enhanced by the pan-caspase inhibitor Z-VAD-FMK in THP-1 cells. Moreover, Z-VAD-FMK enhanced H2O2-induced and NiCl2-induced IL-8 production, but not TNF-α-induced one. The analyses of signaling pathways apparently showed that NiCl2- and H2O2-induced phosphorylation of c-Jun, but not TNF-α-induced one were enhanced by Z-VAD-FMK. The cleavages of p54c-Jun N-terminal kinase (JNK) as well as PARP was induced by NiCl2 and H2O2 but not by TNF-α. Finally, a JNK inhibitor, SP600125, inhibited Z-VAD-FMK-induced enhancement of IL-8 production. In summary, we showed that caspase activation in the apoptotic pathway actively downregulates the JNK-mediated activation of inflammatory cells. This study highlighted the significance of apoptosis in inflammatory diseases, including Ni-induced dermatitis.
Effect of N-glycosylation on constitutive signal transduction by mutated cytokine receptor-like factor 2. 国際誌

Rio Yamamoto, Ryosuke Segawa, Jianwei Liu, Tomoya Isaji, Jianguo Gu, Masahiro Hiratsuka, Noriyasu Hirasawa

Biochimica et biophysica acta. General subjects　1867　(11)　130465-130465　2023年11月

DOI： 10.1016/j.bbagen.2023.130465 　

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BACKGROUND: Cytokine receptor-like factor 2 (CRLF2) is a subunit of the receptor for thymic stromal lymphopoietin (TSLP). A somatic mutation (insEIM) in the transmembrane domains of CRLF2 has been identified in acute lymphocytic leukemia (ALL), and Glu-Ile-Met (EIM) CRLF2 induces constitutive activation of signals. However, the signaling mechanism remains unclear. METHODS: HEK293 cells were transfected with expression vectors encoding wild-type (WT), insEIM CRLF2, or their mutants which N-glycosylation site was replaced with a glutamine. Cell surface expression of CRLF2 was assessed by flow cytometry. Total CRLF2 and phosphorylated signal transducer and activator of transcription 5 (STAT5) were detected by western blotting. RESULTS: Three major species of CRLF2 (53-, 57- and 58-kDa) were identified. Deglycosylation analysis revealed that they were modified with complex-type and oligomannose-type glycans. The expression of both WT and EIM CRLF2 decreased in N-acetylglucosaminyltransferase (GnT)-I (MGAT1) knockout (KO) cells and slightly decreased in α1,6-fucosyltransferase (Fut8) KO cells compared to that in the control cells. In GnT-I or Fut8 KO cells, WT CRLF2 did not induce ligand-independent activation. Both WT and EIM CRLF2 contained four N-glycosylation sites. N55 of CRLF2 was required for the cell surface expression and activation by EIM CRLF2. CONCLUSIONS: We found that N-glycosylation of CRLF2 plays crucial roles for its cell surface expression and signaling. However, N-glycan processing in the Golgi apparatus does not seem to be essential for ligand-independent activation of EIM CRLF2. GENERAL SIGNIFICANCE: Our studies provide a crucial role of glycosylation in the cell surface expression of receptors.
Hypoxia-inducible factor prolyl hydroxylase inhibitors suppressed thymic stromal lymphopoietin production and allergic responses in a mouse air-pouch-type ovalbumin sensitization model. 国際誌

Ryosuke Segawa, Takuya Kyoda, Makiko Yagisawa, Tadanobu Muramatsu, Masahiro Hiratsuka, Noriyasu Hirasawa

International immunopharmacology　118　110127-110127　2023年5月

DOI： 10.1016/j.intimp.2023.110127 　

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Atopic dermatitis (AD) is an allergic skin disease, triggered by excessive type 2 immune reactions. Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that induces type 2 immune response through dendritic cell activation. Therefore, TSLP inhibitors may serve as novel antiallergic drugs. Hypoxia-inducible factor (HIF) activation in the epithelia contributes to several homeostatic phenomena, such as re-epithelialization. However, the effects of HIF activation on TSLP production and immune activation in the skin remain unclear. In this study, we found that selective HIF prolyl hydroxylase inhibitors (PHD inhibitors), which induce HIF activation, suppressed TSLP production in a mouse ovalbumin (OVA) sensitization model. PHD inhibitors also suppressed the production of tumor necrosis factor-alpha (TNF-α), which is a major inducer of TSLP production, in this mouse model and in a macrophage cell line. Consistent with these findings, PHD inhibitors suppressed OVA-specific IgE levels in the serum and OVA-induced allergic responses. Furthermore, we found a direct suppressive effect on TSLP expression in a human keratinocyte cell line mediated by HIF activation. Taken together, our findings suggest that PHD inhibitors exert antiallergic effects by suppressing TSLP production. Controlling the HIF activation system has therapeutic potential in AD.
Selective Induction of Thymic Stromal Lymphopoietin Expression by Novel Nitrogen-Containing Steroid Compounds in PAM-212 Cells 国際誌査読有り

Yu Wang, Ryosuke Segawa, Yan Weng, Katsuya Nakai, Keiichiro Ohashi, Masahiro Hiratsuka, Mieko Arisawa, Noriyasu Hirasawa

J. Transl. Autoimmun.　6　100186-100186　2023年1月

DOI： 10.1016/j.jtauto.2022.100186 　
Inhibition of thymic stromal lymphopoietin production by FK3453.

Ryosuke Segawa, Ryosuke Ishihara, Masahiro Hiratsuka, Noriyasu Hirasawa

Journal of pharmacological sciences　149　(4)　198-204　2022年8月

DOI： 10.1016/j.jphs.2022.05.005 　

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To prevent the onset and aggravation of allergic diseases, it is necessary to modulate excessive Th2-type immune responses. It is well accepted that thymic stromal lymphopoietin (TSLP) plays important roles in the change of Th1/Th2 balance to Th2 dominance and would be a druggable target. In this study, using a drug repositioning strategy, we identified 6-(2-amino-4-phenylpyrimidine-5-yl)-2-isopropylpyridazin-3(2H)-one (FK3453) as a novel inhibitor of TSLP production. FK3453 inhibited constitutive production of TSLP in the KCMH-1 mouse keratinocyte cell line and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced one in PAM212 cells. FK3453 also inhibited TSLP mRNA expression induced by a mixture of tumor necrosis factor alpha (TNF-α), interleukin (IL)-4, fibroblast-stimulation lipopeptide-1, and protease activated-receptor agonist and TPA in normal human epidermal keratinocytes (NHEKs). Although FK3453 inhibited TPA-induced IL-33 expression in NHEKs in addition to TSLP, it did not inhibit TNF-α and IL-6 production. In addition, FK3453 did not inhibit MAP kinase (ERK) phosphorylation. We have confirmed that topical treatment with FK3453 inhibited TSLP production in the lipopolysaccharide-induced air pouch-type inflammation model. FK3453 could be a lead compound for a novel type of medicine which prevents the onset and aggravation of allergic diseases.
PHD阻害剤によるTSLP産生抑制機構の解析

八木澤蒔子, 瀬川良佑, 田代尚之, 平澤典保

日本薬理学会年会要旨集　95　2-P-157　2022年
出版者・発行元：公益社団法人日本薬理学会
DOI： 10.1254/jpssuppl.95.0_2-p-157 　

eISSN：2435-4953

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Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays an important role in the regulation of skin immunity and is upregulated in the lesions of atopic dermatitis patients. Therefore, inhibitors of TSLP production are effective as therapeutic agents for atopic dermatitis. In our laboratory, we found that hypoxia condition and DMOG, a PHD inhibitor, suppressed the expression of TSLP in keratinocytes. In this study, we analyzed the mechanism by which PHD inhibitors suppress TSLP expression. TSLP mRNA expression was induced in human keratinocyte cell line HaCaT cells by combined stimulation with TNFα, IL-4, FSL-1, and PAR2 agonist (T4FP stimulation), which was inhibited by PHD inhibitors Roxadustat and Enarodustat. The knockdown of HIF1α by siRNA abolished the inhibitory effect of Enarodustat on TSLP expression. Chromatin immunoprecipitation assay suggested that HIF1α binds to the hypoxia response elements (HRE) on the TSLP promoter. In conclusion, this study demonstrated that PHD inhibitors suppressed TSLP mRNA expression induced by T4FP stimulation in HaCaT cells. The suppression of TSLP expression was found to be HIF1α-dependent. In addition, we found that HIF1α binds to the HRE on the TSLP promoter, suggesting that HIF1α may affect transcription by binding to the TSLP promoter.
A chalcone derivative suppresses TSLP induction in mice and human keratinocytes through binding to BET family proteins. 国際誌

Ryosuke Segawa, Hiroyuki Takeda, Takeshi Yokoyama, Momoha Ishida, Chihiro Miyata, Taiji Saito, Ryosuke Ishihara, Tomoya Nakagita, Yusuke Sasano, Naoki Kanoh, Yoshiharu Iwabuchi, Mineyuki Mizuguchi, Masahiro Hiratsuka, Noriyasu Hirasawa

Biochemical pharmacology　194　114819-114819　2021年12月

DOI： 10.1016/j.bcp.2021.114819 　

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Although treatments for allergic diseases have improved, side effects and treatment resistance remain as challenges. New therapeutic drugs for allergic diseases are urgently required. Thymic stromal lymphopoietin (TSLP) is a cytokine target for prevention and treatment of allergic diseases. Since TSLP is produced from epithelial cells in allergic diseases, TSLP inhibitors may be new anti-allergic drugs. We previously identified a new inhibitor of TSLP production, named 16D10. However, its target of action remained unclarified. In this study, we found proteins binding to 16D10 from 24,000 human protein arrays by AlphaScreen-based high-throughput screening and identified bromodomain and extra-terminal (BET) family proteins as targets. We also clarified the detailed mode of interaction between 16D10 and a BET family protein using X-ray crystallography. Furthermore, we confirmed that inhibitors of BET family proteins suppressed TSLP induction and IL-33 and IL-36γ expression in both mouse and human keratinocyte cell lines. Taken together, our findings suggest that BET family proteins are involved in the suppression of TSLP production by 16D10. These proteins can contribute to the pathology of atopic dermatitis via TSLP regulation in keratinocytes and have potential as therapeutic targets in allergic diseases.
Lactate released from human fibroblasts enhances Ni elution from Ni plate. 国際誌

Koji Kasai, Ryosuke Segawa, Ryo Onodera, Sanki Asakawa, Masahiro Hiratsuka, Noriyasu Hirasawa

Toxicology　453　152723-152723　2021年4月15日

DOI： 10.1016/j.tox.2021.152723 　

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Elution of Ni ions from medical devices induces inflammation and toxicity. We previously reported that elution of Ni ions from Ni wires induced COX-2 expression and increased lactate production, but whether lactate is involved in the further elution of Ni ions remains unclear. In this study, using KMST-6, a human fibroblast cell line, we examined the molecular mechanisms by which Ni ions increase lactate release and the role of lactate in enhancing the elution of Ni ions. When KMST-6 cells were incubated on a Ni plate or stimulated with NiCl2 (1 mM), the expression of glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), and the release of lactate were enhanced. The NiCl2 (1 mM)-induced expression of these genes was inhibited by a hypoxia-inducible factor-1α (HIF-1α) inhibitor, PX-478 (10-25 μM). Stimulation of cells with a prolyl hydroxylase domain (PHD) inhibitor, roxadustat, increased the expression of these genes, lactate release, and elution of Ni ions at 10 μM. A monocarboxylate transporter-4 (MCT4) inhibitor, syrosingopine, inhibited lactate release from roxadustat-treated cells and reduced the elution of Ni ions by the cells at 10 μM. Finally, syrosingopine (10 μM) reduced the elution of Ni ions by the cells from the Ni plate. These results suggest that elution of Ni ions from metals promotes the production of lactate via HIF-1α-mediated gene expression and causes further Ni elution. Thus, Ni ions show a positive feedback mechanism of Ni elution, and this step may be potentially targeted to protect against metal elution from metal devices.
[Search for Compounds Regulating TSLP Production].

Ryosuke Segawa

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan　141　(10)　1129-1135　2021年

DOI： 10.1248/yakushi.21-00129 　

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Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived immunostimulatory factor, which activates several immune cells such as dendritic cells, T cells, and mast cells. Recently, epithelial cell-derived TSLP has gained immense attention as a cytokine that induces allergic immune responses. Therefore, understanding the regulation of TSLP production is an important step in uncovering the pathophysiology of allergic diseases. Moreover, the compounds that regulate TSLP production can be used as therapeutic drugs for the treatment of allergic diseases. We aim to elucidate the detailed regulation of TSLP production from epithelial cells, and in doing so discovered new regulating factors and an inhibitor of TSLP production. This review article explains the role of TSLP in allergic diseases, its regulation, and our research results.
A chalcone derivative suppresses the induction of TSLP in mice and human keratinocytes and attenuates OVA-induced antibody production in mice. 国際誌査読有り

Ryosuke Segawa, Mika Shiraki, Shiori Sudo, Kenichi Shigeeda, Taiji Saito, Natsumi Mizuno, Takahiro Moriya, Takayuki Yonezawa, Je-Tae Woo, Masahiro Hiratsuka, Noriyasu Hirasawa

European journal of pharmacology　851　52-62　2019年5月15日

DOI： 10.1016/j.ejphar.2019.02.007 　

ISSN：0014-2999

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Thymic stromal lymphopoietin (TSLP) is a key epithelial-derived factor that aggravates allergic diseases. Therefore, TSLP inhibitors are candidate compounds for the treatment of allergic diseases. Previously, we reported that KCMH-1, a mouse keratinocyte cell line, constitutively produces TSLP. In this study, we tried to identify inhibitors of TSLP by screening 2169 compounds in KCMH-1 cells and found one such chalcone derivative (code no. 16D10). 16D10 inhibited TSLP expression and TSLP promoter activation in HaCaT cells, a human keratinocyte cell line. Although nuclear factor kappa-B (NF-κB) is a key transcription factor for the induction of TSLP, 16D10 did not inhibit the activation pathway of NF-κB, such as degradation of inhibitor of κB (IκB) and p65 nuclear translocation. 16D10 activated the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system, although this system was not involved in the inhibitory effect of 16D10. 16D10 also inhibited TSLP production in a lipopolysaccharide (LPS)- or ovalbumin (OVA)-induced air-pouch-type inflammation model. Further, repeated 16D10 administration diminished serum immunoglobulin G1 (IgG1) and IgE concentration in an OVA-induced air-pouch-type sensitization model. Taken together, these results indicate that 16D10 is an inhibitor of TSLP production and has an anti-allergic effect. This inhibitory effect is independent of the activation of NF-κB and the Keap1-Nrf2 system. Therefore, 16D10 could be a new type of candidate drug for allergic diseases.
A steroid alkaloid derivative 02F04 upregulates thymic stromal lymphopoietin expression slowly and continuously through a novel Gq/11-ROCK-ERK1/2 signaling pathway in mouse keratinocytes 国際誌査読有り

Weng Yan, Wang Jingwen, Yang Zhifu, Xi Miaomiao, Duan Jialin, Guo Chao, Yin Ying, Segawa Ryosuke, Moriya Takahiro, Yonezawa Takayuki, Cha Byung Yoon, Woo Je-Tae, Wen Aidong, Hirasawa Noriyasu

CELLULAR SIGNALLING　57　58-64　2019年5月

DOI： 10.1016/j.cellsig.2019.01.005 　

ISSN：0898-6568
Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes. 国際誌査読有り

Naoyuki Tashiro, Ryosuke Segawa, Ryozo Tobita, Sanki Asakawa, Natsumi Mizuno, Masahiro Hiratsuka, Noriyasu Hirasawa

PloS one　14　(11)　e0224705　2019年

DOI： 10.1371/journal.pone.0224705 　

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The expression of thymic stromal lymphopoietin (TSLP), a cytokine which greatly contributes to the induction of type I allergy, is upregulated in chronic inflammation such as atopic dermatitis and psoriasis. As hypoxia in the epidermis is important for maintaining skin homeostasis, we examined the regulation of TSLP expression by hypoxic conditions in normal skin epithelial tissues. TNF-α-induced expression of TSLP in human keratinocyte HaCaT and in mouse keratinocyte PAM212 cell lines were inhibited under hypoxic condition (1% O2), although the mRNA expressions of TNF-α, IL-6, IL-8, MCP-1, and VEGF-A were not inhibited. Hypoxia-mimicking conditions, which include NiCl2, CoCl2, and DMOG, an inhibitor of 2-oxoglutarate-dependent enzymes, also selectively inhibited TNF-α-induced TSLP expression. These results suggested that inactivation of prolyl hydroxylase by hypoxia and hypoxia-mimicking conditions is involved in the repression of TNF-α-induced TSLP expression. Interestingly, the inhibition of TSLP production by hypoxic treatment was significantly reversed by treatment with the HIF-2α antagonist but not with the HIF-1α inhibitor. DMOG-induced inhibition of TSLP promoter activity was dependent on the -71 to +185 bp promoter region, suggesting that the binding of HIF-2 to hypoxia response element (HRE) in this region repressed the TSLP expression. These results indicated that hypoxia and hypoxia-mimicking conditions inhibited TSLP expression via HIF-2 and HRE-dependent mechanisms. Therefore, PHD and HIF-2α could be a new strategy for treatment of atopic dermatitis and psoriasis.
All-Trans Retinoic Acid Enhances Antibody Production by Inducing the Expression of Thymic Stromal Lymphopoietin Protein. 国際誌査読有り

Takahiro Hatayama, Ryosuke Segawa, Natsumi Mizuno, Sumiko Eguchi, Hiroshi Akamatsu, Misaki Fukuda, Fumihisa Nakata, Warren J Leonard, Masahiro Hiratsuka, Noriyasu Hirasawa

Journal of immunology (Baltimore, Md. : 1950)　200　(8)　2670-2676　2018年4月15日

DOI： 10.4049/jimmunol.1701276 　

ISSN：0022-1767

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Many classical vaccines contain whole pathogens and, thus, may occasionally induce adverse effects, such as inflammation. Vaccines containing purified rAgs resolved this problem, but, owing to their low antigenicity, they require adjuvants. Recently, the use of several cytokines, including thymic stromal lymphopoietin (TSLP), has been proposed for this purpose. However, it is difficult to use cytokines as vaccine adjuvants in clinical practice. In this study, we examined the effects of all-trans retinoic acid (atRA) on TSLP production and Ag-induced Ab production. Application of atRA onto the ear lobes of mice selectively induced TSLP production without inducing apparent inflammation. The effects appeared to be regulated via retinoic acid receptors γ and α. Treatment with atRA was observed to enhance OVA-induced specific Ab production; however, this effect was completely absent in TSLP receptor-knockout mice. An enhancement in Ab production was also observed when recombinant hemagglutinin was used as the Ag. In conclusion, atRA was an effective adjuvant through induction of TSLP production. Therefore, we propose that TSLP-inducing low m.w. compounds, such as atRA, may serve as effective adjuvants for next-generation vaccines.
EGFR transactivation is involved in TNF-α-induced expression of thymic stromal lymphopoietin in human keratinocyte cell line. 国際誌査読有り

Segawa R, Shigeeda K, Hatayama T, Dong J, Mizuno N, Moriya T, Hiratsuka M, Hirasawa N

Journal of dermatological science　89　(3)　290-298　2018年3月

DOI： 10.1016/j.jdermsci.2017.12.008 　

ISSN：0923-1811
Nickel ions bind to HSP90β and enhance HIF-1α-mediated IL-8 expression. 国際誌査読有り

Asakawa S, Onodera R, Kasai K, Kishimoto Y, Sato T, Segawa R, Mizuno N, Ogasawara K, Moriya T, Hiratsuka M, Hirasawa N

Toxicology　395　45-53　2018年2月15日

DOI： 10.1016/j.tox.2018.01.006 　

ISSN：0300-483X
Zinc ions have a potential to attenuate both Ni ion uptake and Ni ion-induced inflammation. 国際誌査読有り

Ryo Onodera, Sanki Asakawa, Ryosuke Segawa, Natsumi Mizuno, Kouetsu Ogasawara, Masahiro Hiratsuka, Noriyasu Hirasawa

Scientific reports　8　(1)　2911-2911　2018年2月13日

DOI： 10.1038/s41598-018-21014-8 　

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Nickel ions (Ni2+) are eluted from various metallic materials, such as medical devices implanted in human tissues. Previous studies have shown that Ni2+ enters inflammatory cells inducing inflammation. However, the regulation of Ni2+ uptake in cells has not yet been reported in detail. In the present study, we investigated the effects of various divalent cations on Ni2+ uptake and Ni2+-induced interleukin (IL)-8 production in the human monocytic cell line, THP-1. We demonstrated that ZnCl2, MnCl2, and CoCl2 inhibited the Ni2+ uptake, while CuCl2, FeCl2, MgCl2, and divalent metal transporter (DMT)-1 inhibitor, Chlorazol Black, did not. Furthermore, ZnCl2 inhibited Ni2+-induced IL-8 production, correlating with the inhibition of Ni2+ uptake. These results suggested that Ni2+ uptake occurred through Zn2+, Mn2+, and Co2+-sensitive transporters and that the inhibition of Ni2+ uptake resulted in the inhibition of IL-8 production. Furthermore, using an Ni wire-implanted mouse model, we found that Ni wire-induced expression of mouse macrophage inflammatory protein-2 (MIP-2) and cyclooxygenase-2 (COX-2) mRNA in the skin tissue surrounding the wire were enhanced by low Zn conditions. These results suggested that the physiological concentration of Zn2+ modulates Ni2+ uptake by inflammatory cells, and a Zn deficient state might increase sensitivity to Ni.
Induction of thymic stromal lymphopoietin by a steroid alkaloid derivative in mouse keratinocytes. 国際誌査読有り

Yan Weng, Natsumi Mizuno, Jiangxu Dong, Ryosuke Segawa, Takayuki Yonezawa, Byung Yoon Cha, Je-Tae Woo, Takahiro Moriya, Masahiro Hiratsuka, Noriyasu Hirasawa

International immunopharmacology　55　28-37　2018年2月

DOI： 10.1016/j.intimp.2017.11.045 　

ISSN：1567-5769

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Thymic stromal lymphopoietin (TSLP) plays critical roles in inducing and exacerbating allergic diseases. Chemical compounds that induce TSLP production can enhance sensitization to antigens and exacerbate allergic inflammation. Hence, identifying such chemicals will be important to prevent an increase in allergic diseases. In the present study, we found, for the first time, that a steroid alkaloid derivative, code no. 02F04, concentration and time dependently induced mRNA expression and production of TSLP in a mouse keratinocyte cell line, PAM212. In particular, the activity of 02F04 was selective to TSLP. As an analogue of the liver X receptor (LXR) endogenous ligand, 02F04 rapidly increased ATP-binding cassette transporter A1 (ABCA1) expression by regulating the nuclear receptor of LXR. However, instead of being inhibited by the LXR antagonist, 02F04-induced TSLP production was delayed and markedly suppressed by inhibitors of phospholipase C (PLC), pan-protein kinase C (PKC), PKCδ, Rho-associated protein kinase (ROCK), extracellular signal-regulated kinase (ERK) 1/2, and IκΒ kinase 2 (IKK2). Treatment with 02F04 caused the formation of F-actin filaments surrounding the nucleus of PAM212 cells, which then disappeared following addition of ROCK inhibitor. 02F04 also induced phosphorylation of ERK1/2 from 2h after treatment, with a maximum at 24h, and increased nuclear factor-κB (NF-κB) promoter activity by 1.3-fold. Taken together, these results indicate that 02F04-induced TSLP production is regulated via distinct signal transduction pathways, including PLC, PKC, ROCK, ERK1/2, and NF-κB but not nuclear receptors. 02F04, with a unique skeletal structure in inducing TSLP production, can represent a potential new tool for investigating the role of TSLP in allergic diseases.
Induced histamine regulates Ni elution from an implanted Ni wire in mice by downregulating neutrophil migration 査読有り

Yu Kishimoto, Sanki Asakawa, Taiki Sato, Takayuki Takano, Takahisa Nakajyo, Natsumi Mizuno, Ryosuke Segawa, Takeo Yoshikawa, Masahiro Hiratsuka, Kazuhiko Yanai, Hiroshi Ohtsu, Noriyasu Hirasawa

EXPERIMENTAL DERMATOLOGY　26　(10)　868-874　2017年10月

DOI： 10.1111/exd.13315 　

ISSN：0906-6705

eISSN：1600-0625
Pentanoic acid induces thymic stromal lymphopoietin production through G(q/11) and Rho-associated protein kinase signaling pathway in keratinocytes 国際誌査読有り

Natsumi Mizuno, Koudai Abe, Yukari Morishita, Saori Yamashita, Ryosuke Segawa, Jiangxu Dong, Takahiro Moriya, Masahiro Hiratsuka, Noriyasu Hirasawa

INTERNATIONAL IMMUNOPHARMACOLOGY　50　216-223　2017年9月

DOI： 10.1016/j.intimp.2017.06.024 　

ISSN：1567-5769

eISSN：1878-1705
LPS priming in early life decreases antigen uptake of dendritic cells via NO production 国際誌査読有り

Natsumi Mizuno, Yusuke Sasaki, Ryosuke Segawa, Sanki Asakawa, Masahiro Hiratsuka, Noriyasu Hirasawa

IMMUNOBIOLOGY　223　(1)　25-31　2017年1月

DOI： 10.1016/j.imbio.2017.10.018 　

ISSN：0171-2985
Lipopolysaccharide-Activated Leukocytes Enhance Thymic Stromal Lymphopoietin Production in a Mouse Air-Pouch-Type Inflammation Model 査読有り

Ryosuke Segawa, Natsumi Mizuno, Takahiro Hatayama, Dong Jiangxu, Masahiro Hiratsuka, Yasuo Endo, Noriyasu Hirasawa

INFLAMMATION　39　(4)　1527-1537　2016年8月

DOI： 10.1007/s10753-016-0388-1 　

ISSN：0360-3997

eISSN：1573-2576
Inhibitory effects of nicotine derived from cigarette smoke on thymic stromal lymphopoietin production in epidermal keratinocytes 査読有り

Jiangxu Dong, Ryosuke Segawa, Natsumi Mizuno, Masahiro Hiratsuka, Noriyasu Hirasawa

CELLULAR IMMUNOLOGY　302　19-25　2016年4月

DOI： 10.1016/j.cellimm.2016.01.001 　

ISSN：0008-8749

eISSN：1090-2163
Exacerbation of Allergic Diseases by Chemicals: Role of TSLP 査読有り

Ryosuke Segawa, Noriyasu Hirasawa

JOURNAL OF PHARMACOLOGICAL SCIENCES　124　(3)　301-306　2014年3月

DOI： 10.1254/jphs.13R16CP 　

ISSN：1347-8613

eISSN：1347-8648
Identification of a cell line producing high levels of TSLP: Advantages for screening of anti-allergic drugs 査読有り

Ryosuke Segawa, Saori Yamashita, Natsumi Mizuno, Mika Shiraki, Takahiro Hatayama, Nozomi Satou, Masahiro Hiratsuka, Michihiro Hide, Noriyasu Hirasawa

JOURNAL OF IMMUNOLOGICAL METHODS　402　(1-2)　9-14　2014年1月

DOI： 10.1016/j.jim.2013.10.012 　

ISSN：0022-1759

eISSN：1872-7905
Induction of Thymic Stromal Lymphopoietin Production by Nonanoic Acid and Exacerbation of Allergic Inflammation in Mice 査読有り

Saori Yamashita, Ryosuke Segawa, Nozomi Satou, Masahiro Hiratsuka, Warren J. Leonard, Noriyasu Hirasawa

ALLERGOLOGY INTERNATIONAL　62　(4)　463-471　2013年12月

DOI： 10.2332/allergolint.13-OA-0552 　

ISSN：1323-8930

eISSN：1440-1592
P3-3 マウスアレルギー性空気嚢型炎症モデルにおけるTSLP産生の解析(P3 動物モデル,ポスター,第60回日本アレルギー学会秋季学術大会)

瀬川良佑, 平澤典保

アレルギー　59　(9)　1429-1429　2010年
出版者・発行元：一般社団法人日本アレルギー学会
DOI： 10.15036/arerugi.59.1429_3

︎全件表示 ︎最初の5件までを表示

MISC 1

日-10-O40-25 東北大学薬学研究科4年制博士課程におけるスーパージェネラリスト・ファーマシスト養成教育の試み : 医学部臨床修練への参加(薬学教育(実務実習・その他)、卒後研修・研修制度,一般演題(口頭)40,再興、再考、創ろう最高の医療の未来)

瀬川良佑, 高橋亜希, 平塚真弘, 眞野成康, 富岡佳久, 佐藤博, 平澤典保

日本医療薬学会年会講演要旨集　23　245-245　2013年8月28日
出版者・発行元：日本医療薬学会

共同研究・競争的資金等の研究課題 2

BET タンパク質機能阻害による皮膚免疫活性化への影響の解明

瀬川良佑

2023年4月1日～ 2025年3月31日
低酸素シグナルによるエピジェネティック変化を介した TSLP 発現抑制機構の解析

瀬川良佑

2021年4月1日～ 2023年3月31日

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皮膚の特に表皮細胞から産生される Thymic stromal lymphopoietin (TSLP) はアトピー性皮膚炎の発症・増悪化に大きく寄与しており、アトピー性皮膚炎の治療標的として着目されている。本研究は低酸素応答誘導剤の一つである Prolyl hydroxylase domain 阻害薬（PHD 阻害薬）が TSLP 産生を抑制するという現象に着目し、その抑制機構の詳細を解明することを目的としている。本研究により明らかとなる抑制機構は新たなアトピー性皮膚炎の治療戦略構築や病態理解につながる。特に低酸素シグナルのエピジェネティックな転写制御機構への影響に着目し、PHD 阻害薬による TSLP 発現抑制に対して種々のエピジェネティック制御因子阻害剤の効果を検討した。結果としてヒストン脱アセチル化酵素阻害剤により TSLP 発現抑制作用が減弱すること、DNAメチル化転移酵素阻害剤により TSLP 発現抑制作用が増強することを見出した。今後、各エピジェネティック制御因子のノックダウン法も組み合わせて、関与するエピジェネティック制御因子の同定を行う。また低酸素シグナル活性化に重要な転写因子の一つである HIF1α のノックダウンにより PHD 阻害薬による TSLP 発現抑制作用が打ち消されることから、本抑制機序に対する転写因子 HIF1α の寄与を示すことができた。今後は HIF1α による TSLP 発現抑制機構について、HIF1α の TSLP promoter 上での結合部位や、ヒストン修飾の変化に着目して解析を進めていく。さらに、 PHD 阻害剤による TSLP 発現抑制作用が細菌由来の炎症性シグナルを模倣するTLR2 活性化剤による TSLP 発現誘導に選択的に生じることを見出した。このことから今後は、TLR2 活性化による TSLP 産生シグナルに着目し、PHD 阻害薬による TSLP 発現抑制機構を明らかにしていく。