バリア破綻による皮膚炎発症の機序:表皮セラミド欠損マウスを用いた解析

2011 Fiscal Year Annual Research Report

• Project/Area Number: 21591436
• Research Institution: Kochi University
• Principal Investigator: 佐野 栄紀 高知大学, 教育研究部・医療学系, 教授 (80273621)
• Co-Investigator(Kenkyū-buntansha): 中島 喜美子 高知大学, 教育研究部・医療学系, 講師 (20403892) ; 山本 真有子 高知大学, 教育研究部・医療学系, 助教 (20423478)
• Keywords: 乾癬 / 表皮セラミド / IL-17 / IL-23 / 表皮バリア / Th17 / γδT細胞

Research Abstract

アトピー性皮膚炎および乾癬の皮疹では表皮セラミドの減少が知られている。また乾癬においては最近セラミドの生合成に関わる酵素、serine palmityoiltransferase (SPT)の活性が低下していることが報告された。応募者らは表皮特異的SPT遺伝子破壊マウスK5.sptlc2-/-を用いた研究を行ってきた。このマウスは生後2週目よりバリア機能が破綻し、それに伴って皮膚炎を発症する。そこにランゲルハンス細胞の活性化が誘導されTh17,γδT細胞が所属リンパ節において増加する事実、および皮疹部のサイトカインの解析結果を1昨年度および昨年度報告した。最近、乾癬においてはIL-17産生性γδT細胞の関与が報告されている。従って、このマウスに生じる皮膚病変のみならず免疫学的変調も乾癬と類似するものと考えた。本年度の研究実績の概要を以下に述べる。1)このノックアウトマウスにおける皮疹部および所属リンパ節で増加するIL-17産生性γδT細胞(γδ-17)はVγ5が陰性であることより、表皮由来γδT細胞由来ではないことが明らかになった。2)このマウス皮疹部ではIL-12/23p40およびIL-23p19の遺伝子発現の上昇が見られたが、IL-12p35は正常マウスのレベルと変わらなかった。また皮疹部ではIL-23を産生するCD11c陽性細胞(樹状細胞)が多数浸潤している。3)IL-17産生性γδT細胞はIL-22も産生していることがFACS解析により明らかになった。4)このマウス皮疹の表皮細胞はStat3が活性化していることが免疫組織学的に証明された。5)このマウスに抗IL-12/23p40抗体を投与することによって皮膚に浸潤するγδT細胞の数が減少し、皮疹も軽快する。以上より、表皮セラミド減少に伴うγδ-17の誘導機構および皮疹発症の関与が明らかになり、乾癬モデルとなりうることが示された。

Research Products

• [Journal Article] Stat3 as a therapeutic target for the treatment of psoriasis. A clinical feasibility study with STA-21, a Stat3 Inhibitor (2011)
  • Author(s): Miyoshi K, Takaishi M, Nakajima K, Ikeda M, Kanda T, Tarutani M, Iiyama T, Asao N, Digiovanni J, Sano S
  • Journal Title: Journal of Investigative Dermatology Volume: 131 Pages: 108-117
  • Peer Reviewed
• [Journal Article] Diminished regulatory T cells in cutaneous lesions of thymoma-associated multi-organ autoimmunity : A newly described paraneoplastic autoimmune disorder with fatal clinical course (2011)
  • Author(s): Hanafusa T, Azukizawa H, Kitaba S, Murota H, Umegaki N, Terao M, Sano S, Nakagiri T, Okumura M, Katayama I
  • Journal Title: Clinical & Experimental Immunology Volume: 164 Pages: 164-170
  • Peer Reviewed
• [Journal Article] 18FDG PET/CT is a powerful tool for detecting subclinical arthritis in patients with psoriatic arthritis and/or psoriasis vulgaris (2011)
  • Author(s): Takata T, Taniguchi Y, Ohnishi T, Kohsaki S, Nogami M, Nakajima H, Kumon Y, Terada Y, Ogawa Y,Tarutani M, Sano S
  • Journal Title: Journal of Dermatological Science Volume: 64 Pages: 144-147
  • Peer Reviewed
• [Journal Article] Safety and effectiveness of a new enzyme-targeting radiosensitization treatment (KORTUC II) for intratumoral injection for low-LET radioresistant tumors (2011)
  • Author(s): Ogawa Y, Kubota K, Ue H, Tadokoro M, Matsui R, Yamanishi T, Hamada N, Kariya S, Nishioka A, Nakajima H, Tarutani M, Sano S
  • Journal Title: International Journal of Oncology Volume: 39 Pages: 553-560
  • Peer Reviewed
• [Journal Article] Kinetics of circulating Th17 cytokines and adipokines in psoriasis patients (2011)
  • Author(s): Nakajima H, Nakajima K, Tarutani M, Morishige R, Sano S
  • Journal Title: Archives of Dermatological Research Volume: 303 Pages: 451-455
  • Peer Reviewed
• [Journal Article] Altered lipid profiles in the stratum comeum of Sjogren-Larsson Syndrome (2011)
  • Author(s): Nakajima K, Sano S, Uchida Y, Akiyama M, Morita Y, Shimizu H
  • Journal Title: Journal of Dermatological Science Volume: 303 Pages: 451-455
  • Peer Reviewed
• [Journal Article] Presence of Merkel cell polyomavirus in Japanese cutaneous squamous cell carcinoma (2011)
  • Author(s): Murakami M, Imajoh M, Ikawa T, Nakajima H, Kamioka M, Nemoto Y, Ujihara T, Uchiyama J, Matsuzaki S, Sano S, Daibata M
  • Journal Title: Journal of Clinical Virology Volume: 50 Pages: 37-41
  • Peer Reviewed
• [Journal Article] Ramsay-Hunt syndrome (2011)
  • Author(s): Taguchi T, Ueda S, Kudo T, Nakajima H, Nishioka R, Sano S, Terada Y
  • Journal Title: Journal of Infection Volume: 62 Pages: 180-181
  • Peer Reviewed
• [Journal Article] Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model (2011)
  • Author(s): Nakajima K, Kanda T, Takaishi M, Shiga T, Miyoshi K, Nakajima H, Kamijima R, Tarutani M, Benson JM, Elloso MM, Gutshall LL, Naso MF, Iwakura Y, DiGiovanni J, Sano S
  • Journal Title: Journal of Immunology Volume: 186 Pages: 4481-4489
  • Peer Reviewed
• [Journal Article] Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis (2011)
  • Author(s): Swindell WR, Johnston A, Carbajal S, Han G, Wohn C, Lu J, Xing X, Nair RP, Voorhees JJ, Elder JT, Wang XJ, Sano S, Prens EP, Digiovanni J, Pittelkow MR, Ward NL, Gudjonsson JE
  • Journal Title: PLosOne Volume: 6;e18266 Pages: 1-20
  • Peer Reviewed
• [Presentation] Induction of mesenchymal-epithelial transition in fibroblast-like spindle cancer cells by reprogramming factors (2011)
  • Author(s): Takaishi M, Takeda J, Sano S
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-12-13
• [Presentation] Epicutaneous treatment with TLR7 agonist leads to lupus glomerulonephritis in wild-type mice (2011)
  • Author(s): Sano S, Yokogawa M, Takaishi M, Nakajima K, Kataoka S
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] Novel imaging mass spectrometry to visualize essential epidermal barrier ceramides required for mammalian survival (2011)
  • Author(s): Uchida Y, Goto-Inoue N, Hayasaka T, Zaima N, Nakajima K, Sano S, Holleran WM, Setou M
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] Inhibitory effect of a cathepsin K inhibitor on the development of psoriasis-like lesions (2011)
  • Author(s): Hirai T, Kanda T, Nakajima K, Yamamoto M, Sano S
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] Development of psoriasis-like lesions in a mouse model by IL-23-dependent but IL-22-independent signaling (2011)
  • Author(s): Takaishi M, Nakajima K, Ouyang W, Sano S
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] Psoriasis-like skin lesion induced by Raf-MAPK signaling requires Stat3 activation (2011)
  • Author(s): Tarutani M, Miyoshi K, Takaishi M, Sano S
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] Anti-tumor effect of imiquimod on UVB-induced SCC is mediated through Th1/Th17 cells (2011)
  • Author(s): Yokogawa M, Shiga T, Nakajima K, Takaishi M, Tarutani M, DiGiovanni J, Sano S
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] Topical tacrolimus treatment does not facilitate UV-induced carcinogenesis in a mouse model (2011)
  • Author(s): Shiga T, Kawamura K, Kamijima R, Yokogawa M, Tarutani M, Sano S
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] Sebaceous glands as the primary target of EGFR-inhibitor in the development of papulopustular eruption (2011)
  • Author(s): Takata T, Tarutani M, Sano S
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] T cell subcet of tumor-infiltrating lymphocytes predict prognosis of patients with cutaneous angiosarcoma (2011)
  • Author(s): Fujii H, Arakawa A, Kitoh A, Matsumura T, Konishi K, Sano S, Miyachi Y, Tanioka M
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] A novel link between Th17 cutokines and adipokines in psoriasis (2011)
  • Author(s): Nakajima H, Nakajima K, Tarutani M, Morishige R, Sano S
  • Organizer: The 36th annual meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-12-09
• [Presentation] IL-23 is essential, but IL-22 is dispensable for the development of psoriasis-like lesions in K5.Stat3C mice (2011)
  • Author(s): Takaishi M, Nakajima K, Wenjun Ouyang, Sano S
  • Organizer: 41st Annual ESDR Meeting
  • Place of Presentation: Barcelona International Convention Centre (Spain)
  • Year and Date: 2011-09-07
• [Presentation] Inhibitory Effect of a Cathepsin K Inhibitor on the Development of Psoriasis-Like Lesions in a Mouse Model (2011)
  • Author(s): Hirai T, Kanda T, Nakajima K, Yamamoto M, Sano S
  • Organizer: 41st Annual ESDR Meeting
  • Place of Presentation: Barcelona International Convention Centre (Spain)
  • Year and Date: 2011-09-07
• [Presentation] Increased expression of endothelin-1 in cultured keratinocyte by combined treatments with narrow-band ultraviolet B irradation and tacalcitol (2011)
  • Author(s): Takata T, Tarutani M, Sano S
  • Organizer: 22nd World Congress of Dermatology
  • Place of Presentation: COEX Convention and Exhibition Center (Seoul, Korea)
  • Year and Date: 2011-05-24
• [Presentation] A case of nevoid basal cell carcinomasyndrome (2011)
  • Author(s): Kudo T, Shiga T, Nakajima H, Tarutani M, Sano S
  • Organizer: 22nd World Congress of Dermatology
  • Place of Presentation: COEX Convention and Exhibition Center (Seoul, Korea)
  • Year and Date: 2011-05-24
• [Presentation] Pityriasis rubra pilaris treated with maxacalcitol and narrow-band uvbirradiation (2011)
  • Author(s): Okino T, Kitagawa C, Nakajima H, Tarutani M, Sano S
  • Organizer: 22nd World Congress of Dermatology
  • Place of Presentation: COEX Convention and Exhibition Center (Seoul, Korea)
  • Year and Date: 2011-05-24
• [Presentation] Mouse Model for Psoriatic Arthritis (2011)
  • Author(s): Sano S
  • Organizer: 22nd World Congress of Dermatology
  • Place of Presentation: COEX Convention and Exhibition Center (Seoul, Korea)(招待講演)
  • Year and Date: 2011-05-24
• [Presentation] Reprogramming genes for induced pluripotent stem cells (iPSCs) reversed changes. associated with epithelial-to-mesenchymal transition of skin cancer cells (2011)
  • Author(s): Takaishi M, Yamamoto M, Yokogawa M, Takeda J, Sano S
  • Organizer: The 71th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: JW Marriott Desert Ridge Resort and Spa (Phenix, U.S.A)
  • Year and Date: 2011-05-04
• [Presentation] Psoriasis-like skin lesion induced by Raf-MAPK signaling requires Stat3 activation (2011)
  • Author(s): Tarutani M, Miyoshi K, Takaishi M, Sano S
  • Organizer: The 71th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: JW Marriott Desert Ridge Resort and Spa (Phenix, U.S.A)
  • Year and Date: 2011-05-04
• [Presentation] Primary ceramide deficiency in keratinocytes leads to gene alterations linked to dermatitis (2011)
  • Author(s): Nakajima K, Terao M, Azukizawa H, Katayama I, Takeda J, Sano S
  • Organizer: The 71th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: JW Marriott Desert Ridge Resort and Spa (Phenix, U.S.A)
  • Year and Date: 2011-05-04
• [Presentation] Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis (2011)
  • Author(s): Swindell WR, Johnston A, Carbajal S, Han G, Wohn C, Lu J, Xing X, Nair R P, Voorhees J J, Elder JT, Wang X-J, Sano S, Prens EP, DiGiovanni J, Pittelkow MR, Ward NL, Gudjonsson JE
  • Organizer: The 71th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: JW Marriott Desert Ridge Resort and Spa (Phenix, U.S.A)
  • Year and Date: 2011-05-04
• [Presentation] Cytokine aberrations in a mouse model of psoriatic arthritis (2011)
  • Author(s): Yamamoto M, Sano S
  • Organizer: The 71th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: JW Marriott Desert Ridge Resort and Spa (Phenix, U.S.A)
  • Year and Date: 2011-05-04
• [Presentation] Topical tacrolimus treatment does not facilitate UV-induced carcinogenesis in a mouse model (2011)
  • Author(s): Shiga T, Yokogawa M, Tarutani M, Sano S
  • Organizer: The 71th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: JW Marriott Desert Ridge Resort and Spa (Phenix, U.S.A)
  • Year and Date: 2011-05-04