Updated on 2024/10/04

Information

 

写真a

 
YAMAMURA KAZUHIKO
 
Organization
Kyushu University Hospital Reserch and Clinical Center for Yusho and Dioxin Assistant Professor
Title
Assistant Professor
External link

Awards

  • Best Presentation Award

    2017.12   第46回日本免疫学会   The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction

  • 2016年度九州大学医学博士優秀賞

    2017.3   九州大学  

  • 安江賞

    2015.10   第40回 東海皮膚科漢方研究会   ANTI-ALLERGIC MECHANISMS OF JAPANESE HERBAL MEDICINE, YOKUKANSAN ON MAST CELLS

  • 最優秀口演賞

    2014.7   第17回生医研リトリート  

Papers

  • Editorial: Crosstalk: skin cells and immune cells in inflammatory skin diseases

    Yamamura, K; Kim, HJ; Kim, JE

    FRONTIERS IN IMMUNOLOGY   15   1472313   2024.8   ISSN:1664-3224

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    DOI: 10.3389/fimmu.2024.1472313

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  • Evolution of pathologic B-cell subsets and serum environment-specific sIgEs in patients with atopic dermatitis and controls, from infancy to adulthood

    Czarnowicki, T; David, E; Yamamura, K; Han, J; He, H; Pavel, AB; Glickman, J; Erickson, T; Estrada, Y; Krueger, JG; Rangel, SM; Paller, AS; Guttman-Yassky, E

    ALLERGY   2024.7   ISSN:0105-4538 eISSN:1398-9995

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    Language:English   Publisher:Allergy: European Journal of Allergy and Clinical Immunology  

    Background: While B-cells have historically been implicated in allergy development, a growing body of evidence supports their role in atopic dermatitis (AD). B-cell differentiation across ages in AD, and its relation to disease severity scores, has not been well defined. Objective: To compare the frequency of B-cell subsets in blood of 0–5, 6–11, 12–17, and ≥18 years old patients with AD versus age-matched controls. Methods: Flow cytometry was used to measure B-cell subset frequencies in the blood of 27 infants, 17 children, 11 adolescents, and 31 adults with moderate-to-severe AD and age-matched controls. IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometry panel were used to determine frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgEs) levels were measured using ImmunoCAP®. Results: Adolescents with AD had lower frequencies of major B-cells subsets (p <.03). CD23 expression increased with age and was higher in AD compared to controls across all age groups (p <.04). In AD patients, multiple positive correlations were observed between IL-17-producing T-cells and B-cell subsets, most significantly non-switched memory (NSM) B-cells (r =.41, p =.0005). AD severity positively correlated with a list of B-cell subsets (p <.05). IL-9 levels gradually increased during childhood, reaching a peak in adolescence, paralleling allergen sensitization, particularly in severe AD. Principal component analysis of the aggregated environmental sIgE data showed that while controls across all ages tightly clustered together, adolescents with AD demonstrated distinct clustering patterns relative to controls. Conclusions: Multiple correlations between B-cells and T-cells, as well as disease severity measures, suggest a complex interplay of immune pathways in AD. Unique B-cell signature during adolescence, with concurrent allergen sensitization and IL-9 surge, point to a potentially wider window of opportunity to implement interventions that may prevent the progression of the atopic march.

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  • Difamilast, a Topical Phosphodiesterase 4 Inhibitor, Produces Soluble ST2 via the AHR-NRF2 Axis in Human Keratinocytes

    Tsuji, G; Yumine, A; Kawamura, K; Takemura, M; Kido-Nakahara, M; Yamamura, K; Nakahara, T

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   25 ( 14 )   2024.7   ISSN:1661-6596 eISSN:1422-0067

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    Difamilast, a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective in the treatment of atopic dermatitis (AD), although the mechanism involved remains unclear. Since IL-33 plays an important role in the pathogenesis of AD, we investigated the effect of difamilast on IL-33 activity. Since an in vitro model of cultured normal human epidermal keratinocytes (NHEKs) has been utilized to evaluate the pharmacological potential of adjunctive treatment of AD, we treated NHEKs with difamilast and analyzed the expression of the suppression of tumorigenicity 2 protein (ST2), an IL-33 receptor with transmembrane (ST2L) and soluble (sST2) isoforms. Difamilast treatment increased mRNA and protein levels of sST2, a decoy receptor suppressing IL-33 signal transduction, without affecting ST2L expression. Furthermore, supernatants from difamilast-treated NHEKs inhibited IL-33-induced upregulation of TNF-α, IL-5, and IL-13 in KU812 cells, a basophil cell line sensitive to IL-33. We also found that difamilast activated the aryl hydrocarbon receptor (AHR)–nuclear factor erythroid 2-related factor 2 (NRF2) axis. Additionally, the knockdown of AHR or NRF2 abolished the difamilast-induced sST2 production. These results indicate that difamilast treatment produces sST2 via the AHR–NRF2 axis, contributing to improving AD symptoms by inhibiting IL-33 activity.

    DOI: 10.3390/ijms25147910

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  • A Case of Intractable Lower Leg Ulcer with Idiopathic Multicentric Castleman's Disease

    SUGI Yuta, YAMAMURA Kazuhiko, TAKEI Itsuki, NAKAHARA Makiko, ICHIKI Toshio, MIYAWAKI Kota, YAMAMOTO Hidetaka, YAMAMURA Mika, NAKAHARA Takeshi

    The Nishinihon Journal of Dermatology   86 ( 3 )   233 - 237   2024.6   ISSN:03869784 eISSN:18804047

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    Language:Japanese   Publisher:Western Division of Japanese Dermatological Association  

    <p>47 歳,男性。約 2 年前より左下腿に潰瘍が出現し,拡大傾向であったため約 1 年前に前医を受診した。 外用治療を行われるも難治であり,潰瘍は徐々に拡大したため当科を紹介され受診し,精査加療目的に入院となった。入院時,左下腿の腫脹とほぼ全周にわたる潰瘍に加え,発熱,全身倦怠感,貧血,低栄養を認めた。背景の基礎疾患を検索したところ,血清 IL-6 値の上昇と CT 検査上,左鼠径部から傍大動脈周囲にかけて多発するリンパ節腫大を認めた。左鼠径部リンパ節生検を施行したところ,病理組織学的に硝子血管型 Castleman 病が疑われ,ほかの所見と合わせて特発性多中心性 Castleman 病と診断した。プレドニゾロン(PSL)15 mg/ 日の内服を開始し,発熱と全身倦怠感は改善傾向となった。潰瘍に対しては感染のコントロールを行い,デブリードマンおよび分層植皮術を施行した。2 回の分層植皮術と局所の圧迫,外用治療で潰瘍はほぼ上皮化し,PSL は徐々に減量した。Castleman 病と下腿潰瘍の合併は比較的稀ではあるが,全身症状を伴う難治性の下腿潰瘍に対しては本症を疑う必要があると考えた。</p>

    DOI: 10.2336/nishinihonhifu.86.233

    CiNii Research

  • Gram‐negative anaerobes elicit a robust keratinocytes immune response with potential insights into <scp>HS</scp> pathogenesis

    Samuel C. Williams, Sandra Garcet, Hong Hur, Shunsuke Miura, Juana Gonzalez, Kristina Navrazhina, Mika Yamamura‐Murai, Kazuhiko Yamamura, Xuan Li, John Frew, Vincent A. Fischetti, Uri Sela, James G. Krueger

    Experimental Dermatology   33 ( 5 )   2024.4   ISSN:0906-6705 eISSN:1600-0625

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    Abstract

    Hidradenitis Suppurativa (HS) is a chronic autoinflammatory skin disease with activated keratinocytes, tunnel formation and a complex immune infiltrate in tissue. The HS microbiome is polymicrobial with an abundance of commensal gram‐positive facultative (GPs) Staphylococcus species and gram‐negative anaerobic (GNA) bacteria like Prevotella, Fusobacterium and Porphyromonas with increasing predominance of GNAs with disease severity. We sought to define the keratinocyte response to bacteria commonly isolated from HS lesions to probe pathogenic relationships between HS and the microbiome. Type strains of Prevotella nigrescens, Prevotella melaninogenica, Prevotella intermedia, Prevotella asaccharolytica, Fusobacterium nucleatum, as well as Staphylococcus aureus and the normal skin commensal Staphylococcus epidermidis were heat‐killed and co‐incubated with normal human keratinocytes. RNA was collected and analysed using RNAseq and RT‐qPCR. The supernatant was collected from cell culture for protein quantification. Transcriptomic profiles between HS clinical samples and stimulated keratinocytes were compared. Co‐staining of patient HS frozen sections was used to localize bacteria in lesions. A mouse intradermal injection model was used to investigate early immune recruitment. TLR4 and JAK inhibitors were used to investigate mechanistic avenues of bacterial response inhibition. GNAs, especially F. nucleatum, stimulated vastly higher CXCL8, IL17C, CCL20, IL6, TNF and IL36γ transcription in normal skin keratinocytes than the GPs S. epidermidis and S. aureus. Using RNAseq, we found that F. nucleatum (and Prevotella) strongly induced the IL‐17 pathway in keratinocytes and overlapped with transcriptome profiles of HS patient clinical samples. Bacteria were juxtaposed to activated keratinocytes in vivo, and F. nucleatum strongly recruited murine neutrophil and macrophage migration. Both the TLR4 and pan‐JAK inhibitors reduced cytokine production. Detailed transcriptomic profiling of healthy skin keratinocytes exposed to GNAs prevalent in HS revealed a potent, extensive inflammatory response vastly stronger than GPs. GNAs stimulated HS‐relevant genes, including many genes in the IL‐17 response pathway, and were significantly associated with HS tissue transcriptomes. The close association of activated keratinocytes with bacteria in HS lesions and innate infiltration in murine skin cemented GNA pathogenic potential. These novel mechanistic insights could drive future targeted therapies.

    DOI: 10.1111/exd.15087

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  • The therapeutic AHR-modulating agent Tapinarof regulates semaphorin 3A expression in human keratinocytes via NRF2. International journal

    Gaku Tsuji, Ayako Yumine, Kazuhiko Yamamura, Masaki Takemura, Makiko Kido-Nakahara, Takamichi Ito, Takeshi Nakahara

    The Journal of investigative dermatology   144 ( 3 )   710 - 713.e8   2024.3   ISSN:0022-202X eISSN:1523-1747

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    DOI: 10.1016/j.jid.2023.10.002

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  • Regulatory Mechanism of the IL-33-IL-37 Axis via Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis. International journal

    Gaku Tsuji, Kazuhiko Yamamura, Koji Kawamura, Makiko Kido-Nakahara, Takamichi Ito, Takeshi Nakahara

    International journal of molecular sciences   24 ( 19 )   2023.10   ISSN:1661-6596 eISSN:1422-0067

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    Interleukin (IL)-33 and IL-37 have been identified as novel cytokines involved in various inflammatory diseases. However, their specific roles remain largely unknown. Recent studies have shown that IL-33, which triggers inflammation, and IL-37, which suppresses it, cooperatively regulate the balance between inflammation and anti-inflammation. IL-33 and IL-37 are also deeply involved in the pathogenesis of inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. Furthermore, a signaling pathway by which aryl hydrocarbon receptor (AHR), a receptor for dioxins, regulates the expression of IL-33 and IL-37 has been revealed. Here, we outline recent findings on the mechanisms regulating IL-33 and IL-37 expression in AD and psoriasis. IL-33 expression is partially dependent on mitogen-activated protein kinase (MAPK) activation, and IL-37 has a role in suppressing MAPK in human keratinocytes. Furthermore, IL-33 downregulates skin barrier function proteins including filaggrin and loricrin, thereby downregulating the expression of IL-37, which colocalizes with these proteins. This leads to an imbalance of the IL-33-IL-37 axis, involving increased IL-33 and decreased IL-37, which may be associated with the pathogenesis of AD and psoriasis. Therefore, AHR-mediated regulation of the IL-33-IL-37 axis may lead to new therapeutic strategies for the treatment of AD and psoriasis.

    DOI: 10.3390/ijms241914633

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  • Staphylococcus Aureus and Streptococcus Pyogenes Induce Psoriasis-Related Transcriptomes Augmented by IL-17A and TNF-α. International journal

    Shunsuke Miura, Yohei Ichimura, Uri Sela, Sandra Garcet, Charissa Salud-Gnilo, Xuan Li, Juana Gonzalez, Mika Murai-Yamamura, Kazuhiko Yamamura, Darshna Rambhia, Norma Kunjravia, James G Krueger

    The Journal of investigative dermatology   143 ( 8 )   1613 - 1617   2023.8   ISSN:0022202X

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    DOI: 10.1016/j.jid.2022.12.026

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  • PDE4 inhibition by difamilast regulates filaggrin and loricrin expression via keratinocyte proline-rich protein in human keratinocytes. International journal

    Gaku Tsuji, Akiko Hashimoto-Hachiya, Ayako Yumine, Masaki Takemura, Makiko Kido-Nakahara, Takamichi Ito, Kazuhiko Yamamura, Takeshi Nakahara

    Journal of dermatological science   110 ( 2 )   61 - 68   2023.5   ISSN:0923-1811 eISSN:1873-569X

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Journal of Dermatological Science  

    BACKGROUND: Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is unclear. Since skin barrier dysfunction including reduced expression of filaggrin (FLG) and loricrin (LOR) contributes to AD development, difamilast treatment may be able to improve this dysfunction. PDE4 inhibition increases transcriptional activity of cAMP-responsive element binding protein (CREB). Therefore, we hypothesized that difamilast may affect FLG and LOR expression via CREB in human keratinocytes. OBJECTIVE: To elucidate the mechanism by which difamilast regulates FLG and LOR expression via CREB in human keratinocytes. METHODS: We analyzed normal human epidermal keratinocytes (NHEKs) treated with difamilast. RESULTS: We observed increases of intracellular cAMP levels and CREB phosphorylation in difamilast (5 μM)-treated NHEKs. Next, we found that difamilast treatment increased mRNA and protein levels of FLG and LOR in NHEKs. Since reduced expression of keratinocyte proline-rich protein (KPRP) is reported to be involved in skin barrier dysfunction in AD, we examined KPRP expression in difamilast-treated NHEKs. We found that difamilast treatment increased mRNA and protein levels of KPRP in NHEKs. Furthermore, KPRP knockdown using siRNA transfection abolished the upregulation of FLG and LOR in difamilast-treated NHEKs. Finally, CREB knockdown canceled the upregulation of FLG, LOR, and KPRP in difamilast-treated NHEKs, indicating that PDE4 inhibition by difamilast treatment positively regulates FLG and LOR expression via the CREB-KPRP axis in NHEKs. CONCLUSION: These findings may provide further guidance for therapeutic strategies in the treatment of AD using difamilast.

    DOI: 10.1016/j.jdermsci.2023.04.007

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  • Cathelicidin Antimicrobial Peptide LL37 Induces Toll-Like Receptor 8 and Amplifies IL-36γ and IL-17C in Human Keratinocytes. International journal

    Shunsuke Miura, Sandra Garcet, Xuan Li, Inna Cueto, Charissa Salud-Gnilo, Norma Kunjravia, Kazuhiko Yamamura, Juana Gonzalez, Mika Murai-Yamamura, Darshna Rambhia, James G Krueger

    The Journal of investigative dermatology   143 ( 5 )   832 - 841   2023.5   ISSN:0022202X

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    LL37 is produced by skin injury and bacterial infection and plays an important role in the early stages of psoriasis. In particular, the intracellular receptors toll-like receptors (TLR)3, TLR7, TLR8, and TLR9 are thought to be involved in the pathogenesis of psoriasis in conjunction with LL37, but the interaction between TLR7/8 and LL37 in keratinocytes (KCs) remains unclear. This study aimed to clarify the relationship between LL37 and TLR7/8 in KCs and their involvement in the pathogenetic pathways seen in psoriasis using cultured KCs and skin samples of patients with psoriasis. TLR7/8 was induced by LL37 in KCs. TLR8 but not TLR7 functionally induced many psoriasis-related molecules, whereas IL-17C was not altered by the blockade of TLR7/8. Although costimulation of LL37 with self-RNA/DNA did not show any interaction, LL37 itself would promote psoriasis-related genes. IL-36 receptor antagonistic antibody suppressed IL-17C induced by LL37. In psoriatic epidermis, LL37, TLRs, IL-17C, and IL-36γ expressions were increased and coexpressed with each other. Thus, we concluded that LL37 activates TLR8 in KCs and induces IL-17C through the induction of IL-36γ. Regulation of TLR8 or LL37 in KCs could be a potential therapeutic strategy for psoriatic inflammation.

    DOI: 10.1016/j.jid.2022.10.017

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  • PDE4 inhibition by difamilast regulates filaggrin and loricrin expression via keratinocyte proline-rich protein in human keratinocytes(タイトル和訳中)

    Tsuji Gaku, Hashimoto-Hachiya Akiko, Yumine Ayako, Takemura Masaki, Kido-Nakahara Makiko, Ito Takamichi, Yamamura Kazuhiko, Nakahara Takeshi

    Journal of Dermatological Science   110 ( 2 )   61 - 68   2023.5   ISSN:0923-1811

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  • The role of OX40/OX40L axis in atopic dermatitis

    Yamamura, K; Yamamura, M; Garcet, S; Dahabreh, D; Gonzalez, J; Miura, S; Williams, S; Nakahara, T; Krueger, J; Guttman-Yassky, E

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   143 ( 5 )   S11 - S11   2023.5   ISSN:0022-202X eISSN:1523-1747

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  • Tapinarof, a therapeutic AHR-modulating agent, induces semaphorin 3A production via NRF2 in human keratinocytes: Implications for atopic dermatitis

    Tsuji, G; Takai-Yumine, A; Takemura, M; Yamamura, K; Ito, T; Kido-Nakahara, M; Nakahara, T

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   143 ( 5 )   S189 - S189   2023.5   ISSN:0022-202X eISSN:1523-1747

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  • Novel Therapeutic Targets for the Treatment of Atopic Dermatitis. International journal

    Gaku Tsuji, Kazuhiko Yamamura, Koji Kawamura, Makiko Kido-Nakahara, Takamichi Ito, Takeshi Nakahara

    Biomedicines   11 ( 5 )   2023.4   ISSN:2227-9059 eISSN:2227-9059

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    Atopic dermatitis (AD) is a chronic inflammatory skin disease that significantly impacts quality of life. The pathogenesis of AD is a complex combination of skin barrier dysfunction, type II immune response, and pruritus. Progress in the understanding of the immunological mechanisms of AD has led to the recognition of multiple novel therapeutic targets. For systemic therapy, new biologic agents that target IL-13, IL-22, IL-33, the IL-23/IL-17 axis, and OX40-OX40L are being developed. Binding of type II cytokines to their receptors activates Janus kinase (JAK) and its downstream signal, namely signal transduction and activator of transcription (STAT). JAK inhibitors block the activation of the JAK-STAT pathway, thereby blocking the signaling pathways mediated by type II cytokines. In addition to oral JAK inhibitors, histamine H4 receptor antagonists are under investigation as small-molecule compounds. For topical therapy, JAK inhibitors, aryl hydrocarbon receptor modulators, and phosphodiesterase-4 inhibitors are being approved. Microbiome modulation is also being examined for the treatment of AD. This review outlines current and future directions for novel therapies of AD that are currently being investigated in clinical trials, focusing on their mechanisms of action and efficacy. This supports the accumulation of data on advanced treatments for AD in the new era of precision medicine.

    DOI: 10.3390/biomedicines11051303

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  • Identification of a functional DOCK8 gene polymorphism associated with atopic dermatitis. International journal

    Kazufumi Kunimura, Kazuhiko Yamamura, Takeshi Nakahara, Makiko Kido-Nakahara, Takehito Uruno, Yoshinori Fukui

    Allergy   77 ( 12 )   3670 - 3672   2022.12   ISSN:0105-4538 eISSN:1398-9995

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    DOI: 10.1111/all.15429

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  • The Dawn of a New Era in Atopic Dermatitis Treatment. International journal

    Kazuhiko Yamamura, Takeshi Nakahara

    Journal of clinical medicine   11 ( 20 )   2022.10   ISSN:2077-0383 eISSN:2077-0383

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Journal of Clinical Medicine  

    Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, and the condition is typified by barrier dysfunction and immune dysregulation. Recent studies have characterized various phenotypes and endotypes of AD and elucidated the mechanism. Numerous topical and systemic narrow targeting therapies for AD have been developed according to these findings. Topical medications, including Janus kinase (JAK) inhibitors, phosphodiesterase 4 inhibitors, and the aryl hydrocarbon receptor agonist tapinarof, are effective and safe for AD compared to topical corticosteroids. Oral JAK inhibitors and monoclonal antibodies targeting interleukin (IL)-4, IL-13, IL-31, IL-33, OX40, thymic stromal lymphopoietin, and sphingosine 1-phosphate signaling have displayed outstanding efficacy against moderate-to-severe AD. We are currently in a new era of AD treatment.

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  • Concordance in judgment of clinical borders of basal cell carcinomas in Japanese patients: A preliminary study of JCOG2005 (J-BASE-MARGIN)

    Kamimura, A; Nakamura, Y; Takenouchi, T; Matsushita, S; Omodaka, T; Yamamura, K; Uchi, H; Yoshikawa, S; Yanagisawa, H; Ito, T; Kiyohara, Y; Nakamura, Y; Aoki, M; Ishizuki, S; Oashi, K; Miyagawa, T; Maeda, T; Ogata, D; Hatta, N; Ohe, S; Isei, T; Takahashi, A; Umeda, Y; Yamaguchi, B; Ishikawa, M; Horimoto, K; Fujsawa, Y; Uehara, J; Shibayama, Y; Kiniwa, Y; Kawahara, Y; Matsuya, T; Uhara, H; Kato, J; Nakamura, Y; Murakami, T; Namikawa, K; Yoshino, K; Funakoshi, T; Takatsuka, S; Matsui, Y; Sasaki, J; Koga, H; Yokota, K; Komori, T; Fukushima, S; Yamazaki, N

    JOURNAL OF DERMATOLOGY   49 ( 9 )   837 - 844   2022.9   ISSN:0385-2407 eISSN:1346-8138

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  • Confirmatory trial of narrower side margin excision for head and neck basal cell carcinoma in the Japanese (East Asian) population: JCOG2005 (J-BASE-MARGIN).

    Nakamura, Y; Sano, Y; Kataoka, T; Shibata, T; Fukuda, H; Matsushita, S; Fujisawa, Y; Takenouchi, T; Omodaka, T; Yamamura, K; Aoki, M; Uchi, H; Tsutsui, K; Yoshikawa, S; Ogata, D; Yanagisawa, H; Omatsu, J; Ito, T; Namikawa, K; Yamazaki, N

    JOURNAL OF CLINICAL ONCOLOGY   40 ( 16 )   2022.6   ISSN:0732-183X eISSN:1527-7755

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  • TH 2 cytokines and Staphylococcus aureus cooperatively induce atopic dermatitis-like transcriptomes. International journal

    Mika Murai-Yamamura, Sandra Garcet, Kazuhiko Yamamura, Juana Gonzalez, Shunsuke Miura, Xuan Li, Hong Hur, Emma Guttman-Yassky, James G Krueger

    Allergy   76 ( 11 )   3534 - 3537   2021.11

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    DOI: 10.1111/all.15035

  • IL-36 and IL-17A Cooperatively Induce a Psoriasis-Like Gene Expression Response in Human Keratinocytes. International journal

    Shunsuke Miura, Sandra Garcet, Charissa Salud-Gnilo, Juana Gonzalez, Xuan Li, Mika Murai-Yamamura, Kazuhiko Yamamura, Darshna Rambhia, Norma Kunjravia, Emma Guttman-Yassky, James G Krueger

    The Journal of investigative dermatology   141 ( 8 )   2086 - 2090   2021.8

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    DOI: 10.1016/j.jid.2021.01.019

  • OVOL2-Mediated ZEB1 Downregulation May Prevent Promotion of Actinic Keratosis to Cutaneous Squamous Cell Carcinoma. International journal

    Maho Murata, Takamichi Ito, Yuka Tanaka, Kazuhiko Yamamura, Kazuhisa Furue, Masutaka Furue

    Journal of clinical medicine   9 ( 3 )   2020.2

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    Progression of actinic keratosis (AK) to cutaneous squamous cell carcinoma (cSCC) is rare. Most cases of AK remain as intraepidermal lesions, owing to the suppression of the epithelial-to-mesenchymal transition (EMT). Ovo-like transcriptional repressor 1 (OVOL1) and ovo-like zinc finger 2 (OVOL2) are important modulators of EMT in some tumors, but their roles in skin tumors remain elusive. This study elucidated the roles of OVOL1/2 in AK and cSCC using 30 AK/30 cSCC clinical samples, and an A431 human SCC cell line using immunohistochemistry and molecular biological approaches. Immunohistochemically, OVOL1/2 were upregulated in AK and downregulated in cSCC. Meanwhile, EMT-related factors, vimentin and zinc finger E-box binding homeobox 1 (ZEB1) were downregulated in AK and upregulated in cSCC. Moreover, ZEB1 expression was higher in tumors in which OVOL2 expression was low. Thus, we observed an inverse association between OVOL2 and ZEB1 expression in AK and cSCC. Although knockdown of OVOL1 or OVOL2 increased the mRNA and protein levels of ZEB1, only OVOL2 knockdown increased the invasive ability of A431. In conclusion, OVOL2 inhibits ZEB1 expression and may inhibit the promotion of AK into cSCC. OVOL2/ZEB1 axis may be a potential target for preventing the development of cSCC.

    DOI: 10.3390/jcm9030618

  • Selective role of neurokinin B in IL-31-induced itch response in mice. International journal

    Daiji Sakata, Takehito Uruno, Keisuke Matsubara, Tsugunobu Andoh, Kazuhiko Yamamura, Yuki Magoshi, Kazufumi Kunimura, Yasuhisa Kamikaseda, Masutaka Furue, Yoshinori Fukui

    The Journal of allergy and clinical immunology   144 ( 4 )   1130 - 1133   2019.10

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    DOI: 10.1016/j.jaci.2019.06.031

  • Serum squamous cell carcinoma antigen (SCCA)-2 correlates with clinical severity of pediatric atopic dermatitis in Ishigaki cohort. International journal

    Satoshi Takeuchi, Norihiro Furusyo, Junya Ono, Yoshinori Azuma, Masaki Takemura, Hitokazu Esaki, Kazuhiko Yamamura, Yasutaka Mitamura, Gaku Tsuji, Mari Kiyomatsu-Oda, Jun Hayashi, Kenji Izuhara, Masutaka Furue

    Journal of dermatological science   95 ( 2 )   70 - 75   2019.8

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    BACKGROUND: We sometimes encounter difficulties in assessing the severity of pediatric atopic dermatitis (AD) using currently available biomarkers such as thymus and activation-regulated chemokine (TARC) due to the higher baseline values in non-AD children. Recent case control studies have indicated the usefulness of squamous cell carcinoma antigens (SCCAs) in pediatric and adult AD. Notably, SCCAs are induced by IL-4 and IL-13, vital Th2 cytokines that play important roles in AD etiology. OBJECTIVES: Relatively low prevalence and mild disease severity of pediatric AD are observed in our Ishigaki cohort presumably due to the moisturising subtropical climate, which could conversely mean possible higher allergic potential of non-AD subjects towards AD. Thus, the purpose of this study was to further investigate the feasibility of using SCCAs together with TARC and periostin as biomarkers for pediatric AD even in the Ishigaki cohort. METHODS: We enrolled 1459 nursery school children and identified 96 as having AD through 2009-2011. As statistical analyses, we performed Student's t-test, correlation analysis, and receiver and operating characteristic (ROC) analysis. RESULTS: Serum SCCA1, SCCA2, periostin and TARC levels were all significantly increased in AD compared with those in non-AD, but only serum SCCA2 showed a significant increase in AD when assessed in each age group or in subgroup analysis. Among the biomarkers tested, serum SCCA2 also showed the best correlations with clinical AD severity and TARC and showed the best diagnosability for AD in ROC analysis. CONCLUSIONS: SCCA2 is a potent biomarker for pediatric AD in the Ishigaki cohort.

    DOI: 10.1016/j.jdermsci.2019.07.005

  • Cyto/chemokine profile of in vitro scratched keratinocyte model: Implications of significant upregulation of CCL20, CXCL8 and IL36G in Koebner phenomenon. International journal

    Kazuhisa Furue, Takamichi Ito, Yuka Tanaka, Ayako Yumine, Akiko Hashimoto-Hachiya, Masaki Takemura, Maho Murata, Kazuhiko Yamamura, Gaku Tsuji, Masutaka Furue

    Journal of dermatological science   94 ( 1 )   244 - 251   2019.4

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    BACKGROUND: Scratch injury induces Koebner phenomenon in psoriasis. Smoking is also a risk factor for psoriasis. Keratinocytes can produce various psoriasis-related molecules including TNF, IL1 A, IL1B, IL6, IL12B, IL17C, IL23 A, IL36 A, IL36B, IL36 G, CXCL1, CXCL2, CXCL8, CXCL9, CXCL10, CCL20, IFNB, and CAMP. However, the scratch-induced molecular profiling remains elusive. OBJECTIVE: To profile the induction pattern of above-mentioned psoriasis-related and keratinocyte-derived molecules by scratch injury in the presence or absence of anti-psoriatic drugs or benzo[a]pyrene, a major environmental pollutant of tobacco smoke. METHODS: Confluent normal human keratinocytes were scratched and molecules were assayed by qRT-PCR, ELISA and Western blotting with or without drugs and benzo[a]pyrene. RESULTS: Among the 18 molecules, the scratch injury on a confluent keratinocyte sheet significantly and selectively upregulated the mRNA expression of four cyto/chemokines, CXCL8, CCL20, IL36G, and TNF, in a scratch-line-number-dependent manner under either low- or high-calcium condition. However, significant protein secretion was only demonstrated for CXCL8 and CCL20. The IL36 G protein was not secreted, but its intracellular level was significantly upregulated by scratch injury, whereas neither the secretion nor the intracellular level of TNF protein was affected by scratch injury. Dexamethasone, but not maxacalcitol nor the phosphodiesterase 4 inhibitor apremilast, partially inhibited the CXCL8 and CCL20 secretion. Benzo[a]pyrene significantly and synergistically enhanced the scratch-induced CCL20 secretion that may explain why smoking is a risk factor for psoriasis. CONCLUSION: CCL20 and to a less extent CXCL8 may play a key role in triggering the Koebner phenomenon after scratch injury to keratinocytes.

    DOI: 10.1016/j.jdermsci.2019.04.002

  • Tryptophan photo-product FICZ upregulates AHR/MEK/ERK-mediated MMP1 expression: Implications in anti-fibrotic phototherapy. International journal

    Mika Murai, Kazuhiko Yamamura, Akiko Hashimoto-Hachiya, Gaku Tsuji, Masutaka Furue, Chikage Mitoma

    Journal of dermatological science   91 ( 1 )   97 - 103   2018.7

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    BACKGROUND: Scleroderma is caused by aberrant transforming growth factor-ß signaling. The degradation of extracellular matrix proteins is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Ultraviolet (UV) radiation has been a therapy for scleroderma. 6-Formylindolo[3,2-b]carbazole (FICZ), an endogenous aryl hydrocarbon receptor (AHR) ligand, is a tryptophan metabolite generated by UV exposure. Nonetheless, whether FICZ regulates MMPs and TIMPs has not been investigated. OBJECTIVE: To elucidate the regulatory roles of FICZ in the expression of MMPs and TIMPs in normal human dermal fibroblasts (NHDFs). METHODS: Quantitative real-time polymerase chain reaction was performed to determine the expression of MMPs or TIMPs in the NHDFs treated with FICZ or UVB. The MMPs levels were measured by enzyme-linked immunosorbent assay. The actions of FICZ on MMPs were analyzed using AHR-knockdown NHDFs or selective inhibitors of mitogen-activated protein kinases (MAPKs). Microtubule-associated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) phosphorylation was examined by western blotting. RESULTS: UVB increased the mRNA and protein levels of MMP1 and MMP3 in NHDFs, while FICZ upregulated those of MMP1, but not MMP3. The effects of FICZ on TIMPs were negligible. FICZ increased MMP1 expression in an AHR-dependent manner. The FICZ-induced MMP1 upregulation was ameliorated with MEK/ERK inhibitors, whereas the effects of UVB were canceled with c-Jun N-terminal kinase (JNK) and p38-MAPK as well as MEK/ERK inhibitors. FICZ-induced ERK phosphorylation is dependent on AHR. CONCLUSION: FICZ contributes to the UV-mediated anti-fibrotic effects via the AHR/MEK/ERK signal pathway in NHDFs. FICZ is a potential therapeutic agent for scleroderma.

    DOI: 10.1016/j.jdermsci.2018.04.010

  • Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye. International journal

    Tetsuya Sakurai, Takehito Uruno, Yuki Sugiura, Takaaki Tatsuguchi, Kazuhiko Yamamura, Miho Ushijima, Yuko Hattori, Mutsuko Kukimoto-Niino, Chiemi Mishima-Tsumagari, Mayuki Watanabe, Makoto Suematsu, Yoshinori Fukui

    Science signaling   11 ( 541 )   2018.7

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    Although immune responses are essential to protect the body from infection, they can also harm tissues. Certain tissues and organs, including the eye, constitute specialized microenvironments that locally inhibit immune reactivity. Dedicator of cytokinesis protein 2 (DOCK2) is a Rac-specific guanine nucleotide exchange factor (GEF) that is predominantly found in hematopoietic cells. DOCK2 plays a key role in immune surveillance because it is essential for the activation and migration of leukocytes. DOCK2 mutations cause severe immunodeficiency in humans. We found that DOCK2-mediated Rac activation and leukocyte migration were effectively inhibited by cholesterol sulfate (CS), but not by cholesterol or other sulfated steroids. CS bound to the catalytic domain of DOCK2 and suppressed its GEF activity. Mass spectrometric quantification revealed that CS was most abundantly produced in the Harderian gland, which provides the lipids that form the oily layer of the tear film. Sulfation of cholesterol is mediated by the sulfotransferases SULT2B1b and, to a lesser extent, SULT2B1a, which are produced from the same gene through alternative splicing. By genetically inactivating Sult2b1, we showed that the lack of CS in mice augmented ultraviolet- and antigen-induced ocular surface inflammation, which was suppressed by administration of eye drops containing CS. Thus, CS is a naturally occurring DOCK2 inhibitor and contributes to the generation of the immunosuppressive microenvironment in the eye.

    DOI: 10.1126/scisignal.aao4874

  • Highlighting Interleukin-36 Signalling in Plaque Psoriasis and Pustular Psoriasis. International journal

    Kazuhisa Furue, Kazuhiko Yamamura, Gaku Tsuji, Chikage Mitoma, Hiroshi Uchi, Takeshi Nakahara, Makiko Kido-Nakahara, Takafumi Kadono, Masutaka Furue

    Acta dermato-venereologica   98 ( 1 )   5 - 13   2018.1

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    Plaque psoriasis and pustular psoriasis are overlapping, but distinct, disorders. The therapeutic response to biologics supports the pivotal role of the tumour necrosis alpha (TNF-?)/ interleukin (IL)-23/IL-17/IL-22 axis in the pathogenesis of these disorders. Recently, functional activation of the IL-36 receptor (IL-36R) was discovered to be another driving force in the pathogenesis of psoriasis. This was first highlighted by the discovery that a loss-of-function mutation of the IL-36R antagonist (IL-36Ra) causes pustular psoriasis. Although the TNF-?/IL-23/IL-17/IL-22 axis and the functional activation of IL-36R are fundamentally involved in plaque psoriasis and pustular psoriasis, respectively, the 2 pathways are closely related and mutually reinforced, resulting in full-blown clinical manifestations. This review summarizes current topics on how IL-36 agonists (IL-36?, IL-36?, IL-36?) signal IL-36R, the pathological expression of IL-36 agonists and IL-36Ra in plaque and pustular psoriatic lesions, and the cross-talk between the TNF-?/IL-23/IL-17/IL-22 axis and the functional activation of IL-36R in the epidermal milieu.

    DOI: 10.2340/00015555-2808

  • The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction. International journal

    Kazuhiko Yamamura, Takehito Uruno, Akira Shiraishi, Yoshihiko Tanaka, Miho Ushijima, Takeshi Nakahara, Mayuki Watanabe, Makiko Kido-Nakahara, Ikuya Tsuge, Masutaka Furue, Yoshinori Fukui

    Nature communications   8   13946 - 13946   2017.1

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    Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.

    DOI: 10.1038/ncomms13946

  • Levels of immunoglobulin E specific to the major food allergen and chemokine (C-C motif) ligand (CCL)17/thymus and activation regulated chemokine and CCL22/macrophage-derived chemokine in infantile atopic dermatitis on Ishigaki Island. International journal

    Hitokazu Esaki, Satoshi Takeuchi, Norihiro Furusyo, Kazuhiko Yamamura, Sayaka Hayashida, Gaku Tsuji, Masaki Takemura, Jun Hayashi, Masutaka Furue

    The Journal of dermatology   43 ( 11 )   1278 - 1282   2016.11

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    Atopic dermatitis (AD) is a multifactorial T-helper (Th)2-mediated skin disease frequently associated with elevated serum immunoglobulin (Ig)E and food allergy is also a Th2- and IgE-mediated adverse immunological reaction. Our previous study indicated the relation of egg allergy history and disease severity of AD. Thus, the purpose of the study was to investigate the levels of IgE specific to major food allergens (egg, milk, wheat) and Th2 chemokines (chemokine [C-C motif] ligand [CCL]17/thymus and activation regulated chemokine [TARC] and CCL22/macrophage-derived chemokine [MDC]) and the relationship between them. A total of 743 nursery school children were enrolled. Dermatologist-based physical examination and a questionnaire survey were also conducted. Significantly increased levels of disease severity markers (CCL17/TARC and CCL22/MDC) were confirmed in children with AD. The levels of CCL22/MDC in all of the children were markedly high compared with those reported in adults. IgE specific to egg white, ovomucoid, wheat and mite antigen were significantly higher in the AD group than in the non-AD group. Among them, IgE specific to egg allergens were well associated with disease severity markers, and IgE specific to ovomucoid seemed particularly well correlated with the presence of egg allergy history. In conclusion, the markedly high level of CCL22/MDC in children as compared with those reported in adults may partly explain the AD-prone nature of children and their spontaneous remission afterwards. Mild but significant correlation of IgE specific to egg allergens and Th2 chemokines may explain correlation of disease severity and comorbidity of egg allergy in our previous study.

    DOI: 10.1111/1346-8138.13360

  • Incidence, serum IgE and TARC/CCL17 levels in atopic dermatitis associated with other allergic diseases: an update from the Ishigaki cohort. International journal

    Satoshi Takeuchi, Hitokazu Esaki, Norihiro Furusyo, Sayaka Hayashida, Kazuhiko Yamamura, Gaku Tsuji, Masaki Takemura, Jun Hayashi, Masutaka Furue

    Acta dermato-venereologica   95 ( 4 )   480 - 4   2015.4

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    Population cohort studies are important for understanding the current status of the target disease and its relation to comorbidity, gender, age, or environmental factors. To better understand atopic dermatitis (AD) and its related diseases, we initiated in 2001 a population cohort study of nursery school children from Ishigaki Island, Okinawa, Japan. The cohort study comprised a dermatologist-based physical examination, questionnaire administration, and blood sample analysis. The mean prevalence of AD was 6.3&#37;. Questionnaire-based bronchial asthma and egg allergy in the children and paternal and sibling AD were statistically significant risk factors for AD. Boys with AD had a high incidence of asthma that was coexistent with a high serum total immunoglobulin E level. Also a high incidence of egg allergy was associated with greater AD severity as assessed by TARC/CCL17.

    DOI: 10.2340/00015555-1989

  • Anti-allergic mechanisms of Japanese herbal medicine, yokukansan on mast cells. International journal

    Kazuhiko Yamamura, Shiori Kato, Takahiro A Kato, Yoshito Mizoguchi, Akira Monji, Shigenobu Kanba, Masutaka Furue, Satoshi Takeuchi

    The Journal of dermatology   41 ( 9 )   808 - 14   2014.9

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    We previously reported that the addition of orally administered yokukansan (YKS), a traditional Japanese herbal medicine, to the standard regimen using histamine H1-receptor inhibitors was effective in controlling refractory chronic urticaria, but the mechanism remained unknown. YKS has also been reported to be effective on inhibiting the development of atopic dermatitis-like skin lesions in NC/Nga mice. As known, the release of various chemical mediators including histamine from degranulated mast cells is strongly related to the mechanism of these diseases. Thus the purpose of this study was to examine the mechanisms behind the medicinal effects of YKS on mast cells using an in vitro system and rat basophil leukemia (RBL-2H3) cells. The degree of degranulation was measured by β-hexosaminidase secretion assay and intracellular calcium influx assay. ELISA for cytokines (TNF-α and IL-4) was also conducted using cell culture media. Furthermore, we investigated the effects of YKS on the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokine production (IL-8) in human dermal microvascular endothelial cells using gene-transcriptional- and immunohisotoligical analysis. We found that YKS inhibited secretion of β-hexosaminidase, intracellular calcium increase, production of TNF-α and ICAM-1 expression, and that several YKS ingredients may be the key effectors. In conclusion, YKS may suppress several mast cell functions such as degranulation and calcium increase that eventually inhibits the release of proinflammatory cytokines. Furthermore, YKS suppresses ICAM-1 expression on human microvascular endothelial cells. These findings may promote our understanding of the beneficial effects of YKS on mast cell-associated allergic diseases.

    DOI: 10.1111/1346-8138.12578

  • DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation. International journal

    Kana Ogawa, Yoshihiko Tanaka, Takehito Uruno, Xuefeng Duan, Yosuke Harada, Fumiyuki Sanematsu, Kazuhiko Yamamura, Masao Terasawa, Akihiko Nishikimi, Jean-François Côté, Yoshinori Fukui

    The Journal of experimental medicine   211 ( 7 )   1407 - 19   2014.6

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    Mast cells play a key role in the induction of anaphylaxis, a life-threatening IgE-dependent allergic reaction, by secreting chemical mediators that are stored in secretory granules. Degranulation of mast cells is triggered by aggregation of the high-affinity IgE receptor, FcεRI, and involves dynamic rearrangement of microtubules. Although much is known about proximal signals downstream of FcεRI, the distal signaling events controlling microtubule dynamics remain elusive. Here we report that DOCK5, an atypical guanine nucleotide exchange factor (GEF) for Rac, is essential for mast cell degranulation. As such, we found that DOCK5-deficient mice exhibit resistance to systemic and cutaneous anaphylaxis. The Rac GEF activity of DOCK5 is surprisingly not required for mast cell degranulation. Instead, DOCK5 associated with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3β. When DOCK5-Nck2-Akt interactions were disrupted, microtubule formation and degranulation response were severely impaired. Our results thus identify DOCK5 as a key signaling adaptor that orchestrates remodeling of the microtubule network essential for mast cell degranulation.

    DOI: 10.1084/jem.20131926

  • Decrease of reactive oxygen species and reciprocal increase of nitric oxide in human dermal endothelial cells by Bidens pilosa extract: a possible explanation of its beneficial effect on livedo vasculopathy. International journal

    Futoshi Kohda, Masakazu Takahara, Akiko Hachiya, Kenjiro Takei, Gaku Tsuji, Kazuhiko Yamamura, Masutaka Furue

    Journal of dermatological science   72 ( 1 )   75 - 7   2013.10

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    DOI: 10.1016/j.jdermsci.2013.05.008

  • Subcutaneous calcification of the lower legs in a patient with mixed connective tissue disease. International journal

    Kazuhiko Yamamura, Masakazu Takahara, Kana Masunaga, Takuya Sawabe, Masaki Kitano, Toshihiko Mashino, Masutaka Furue

    The Journal of dermatology   38 ( 8 )   791 - 3   2011.8

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    A 56-year-old woman who had been treated for mixed connective tissue disease (MCTD) noticed a skin ulcer on the lower leg. There was no history of trauma. X-rays of the lower legs showed extensive calcification in the soft tissue. Biopsied tissue from the ulcer showed marked calcium deposition with necrosis. Laboratory findings revealed normal serum calcium and phosphate levels and normal parathyroid function. On the basis of these findings, we diagnosed skin ulcer due to subcutaneous dystrophic calcification associated with MCTD. The ulcer was gradually reduced in size and epithelialized by treatment with local debridement and antibiotics.

    DOI: 10.1111/j.1346-8138.2010.01177.x

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Presentations

Research Projects

  • アトピー性皮膚炎における新規そう痒惹起物質の同定とその感知機構の解明

    Grant number:23K15285  2023 - 2025

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (A)

    山村 和彦

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    Authorship:Principal investigator  Grant type:Scientific research funding

    本研究では、ヒト感覚神経細胞をこれまで報告のあったアトピー性皮膚炎患者血球細胞で発現が変化しているサイトカイン/生理活性脂質で刺激し、解析することで、アトピー性皮膚炎痒みに関わりのある新規そう痒惹起物質の同定、及びその産生制御機構とシグナル伝達経路の解明、新たな創薬標的の導出を目的とする。

    CiNii Research

  • iPS細胞由来ヒト感覚神経を用いたアトピー性皮膚炎における痒みのメカニズムの探求

    Grant number:22K20686  2022 - 2023

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Research Activity start-up

    山村 和彦

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    Authorship:Principal investigator  Grant type:Scientific research funding

    アトピー性皮膚炎は国民の7-15%が罹患し、多くの患者さんが激しい痒みに悩まされています。これまでヒトの痒みに関連する研究は、ヒト末梢神経が入手困難だったこともあり、ほとんどなされてきませんでした。本研究は、近年開発されたヒトiPS細胞由来の末梢感覚神経を用いることで、アトピー性皮膚炎に特徴的な痒みを引き起こすメカニズムとそれに重要な物質を特定することを目的にしています。

    CiNii Research

  • 炎症性皮膚疾患のThサブセット偏移を制御する生理活性脂質の同定と疾患モデルの創出

    2020 - 2022

    Japan Society for the Promotion of Science  Postdoctoral Fellowships for Research Abroad

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    Authorship:Principal investigator  Grant type:Joint research

  • アトピー性皮膚炎における新しい共刺激分子の特徴と役割

    2018 - 2019

    アステラス病態代謝研究会

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    Authorship:Principal investigator  Grant type:Contract research

Travel Abroad

  • 2018.11 - 2022.3

    Staying countory name 1:United States   Staying institution name 1:The Rockefeller University (USA), Laboratory for Investigative Dermatology