Persistent release of IL-1s from skin causes systemic Inflammatory diseases

• Project/Area Number: 26461690
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Mie University
• Principal Investigator: Yamanaka Keiichi 三重大学, 医学系研究科, 教授 (70314135)
• Co-Investigator(Kenkyū-buntansha): 水谷 仁 三重大学, 医学系研究科, リサーチアソシエイト (30115737)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: アトピー性皮膚炎 / 尋常性乾癬 / サイトカイン / 動脈硬化症 / 全身性アミロイドーシス / 慢性皮膚疾患 / 心血管病変 / 脂質代謝異常 / 全身性炎症 / 皮膚炎 / 乾癬 / IL-1 / 慢性炎症

Outline of Final Research Achievements

The skin is an immune organ that produces large amount of proinflammatory cytokines including IL-1. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. We here showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloidsis in multiple organs in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by the administration of anti-IL-1α and IL-1β antibodies.

Research Products

• [Journal Article] Restrictive interleukin-10 induction by an innocuous Parainfluenza virus vector ameliorates nasal allergy. (2017)
  • Author(s): Yamanaka K, Nakanishi T, Isono K, Hasegawa C, Inada Y, Mizutani K, Matsushima Y, Okada K, Mabuchi T, Kondo M, Yamagiwa A, Kakeda M, Habe K, Nosaka T, Gabazza EC, Yamazaki H, Mizutani H, Kawano M.
  • Journal Title: J Allergy Clin Immunol Volume: 139 Issue: 2 Pages: 682-686
  • DOI: 10.1016/j.jaci.2016.05.044
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Skin inflammation leads immunoglobulin G aggregation and deposition in multiple organs (2017)
  • Author(s): Yamanaka K, Okada K, Nakanishi T, Mizutani K, Matsushima Y, Kondo M, Habe K, Mizutani H, Seo N
  • Journal Title: J Dermatol Sci. Volume: 88 Issue: 1 Pages: 146-148
  • DOI: 10.1016/j.jdermsci.2017.05.013
  • Peer Reviewed
• [Journal Article] Neutrophils are not the dominant interleukin-17 producer in psoriasis. (2017)
  • Author(s): Yamanaka, K., A. Yamagiwa, T. Akeda, M. Kondo, M. Kakeda, K. Habe, S. Imafuku, S. Sano and H. Mizutani
  • Journal Title: J Dermatol Volume: 印刷中 Issue: 7 Pages: 170-171
  • DOI: 10.1111/1346-8138.13807
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Is the Anti-NXP-2(ANTI-MJ) antibody a marker antibody for dysphagia in dermatomyositis? - report of three cases (2017)
  • Author(s): Kakeda M, Yamanaka K, Muro Y, Mizuntani H
  • Journal Title: EMJ Dermatology Volume: 5 Pages: 57-58
  • Peer Reviewed
• [Journal Article] Compound heterozygotes for filaggrin gene mutations do not always show severe atopic dermatitis. (2017)
  • Author(s): Sekiya, A., M. Kono, H. Tsujiuchi, T. Kobayashi, T. Nomura, M. Kitakawa, N. Suzuki, K. Yamanaka, H. Sueki, W. H. McLean, H. Shimizu and M. Akiyama
  • Journal Title: J EUR ACAD DERMATOL Volume: 31 Issue: 1 Pages: 158-162
  • DOI: 10.1111/jdv.13871
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A new biomarker for psoriasis. (2016)
  • Author(s): Yamanaka, K. and H. Mizutani
  • Journal Title: BRIT J DERMATOL Volume: 174 Issue: 6 Pages: 1191-1192
  • DOI: 10.1111/bjd.14746
  • Peer Reviewed
• [Journal Article] Olopatadine, a non-sedating H1 antihistamine, decreases the nocturnal scratching without affecting sleep quality in atopic dermatitis. (2015)
  • Author(s): Yamanaka K, Motomura E, Noro Y, Umeda K, Morikawa T, Umeda-Togami K, Omoto Y, Isoda K, Kondo M, Tsuda K, Okuda M, Gabazza EC, Mizutani H.
  • Journal Title: Exp Dermatol. Volume: 24 Issue: 3 Pages: 227-229
  • DOI: 10.1111/exd.12630
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] "Inflammatory skin march": IL-1-mediated skin inflammation, atopic dermatitis, and psoriasis to cardiovascular events. (2015)
  • Author(s): Yamanaka K, Mizutani H.
  • Journal Title: J Allergy Clin Immunol. Volume: 136 Issue: 3 Pages: 823-824
  • DOI: 10.1016/j.jaci.2015.06.009
  • Peer Reviewed
• [Journal Article] Immunological parameters in prophylactic sublingual immunotherapy in asymptomatic subjects sensitized to Japanese cedar pollen (2015)
  • Author(s): Yamanaka K, Shah SA, Sakaida H, Yamagiwa A, Masuda S, Mizutani H, Takeuchi K.
  • Journal Title: Allergology International Volume: 64 Issue: 1 Pages: 54-59
  • DOI: 10.1016/j.alit.2014.07.001
  • NAID: 130004873123
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] Novel acoustic evaluation system for scratching behavior in itching dermatitis: Rapid and accurate analysis for nocturnal scratching of atopic dermatitis patients. (2014)
  • Author(s): Noro Y, Omoto Y, Umeda K, Tanaka F, Shiratsuka Y, Yamada T, Isoda K, Matsubara K, Yamanaka K, Gabazza EC, Nishikawa M, Mizutani H.
  • Journal Title: J Dermatol. Volume: 41 Issue: 3 Pages: 233-238
  • DOI: 10.1111/1346-8138.12405
  • Peer Reviewed
• [Journal Article] Continuous high-dose antigen exposure preferentially induces IL-10, but intermittent antigen exposure induces IL-4. (2014)
  • Author(s): Yamanaka K, Nakanishi T, Watanabe J, Kondo M, Yamagiwa A, Gabazza EC, Mizutani H.
  • Journal Title: Exp Dermatol. Volume: 23 Issue: 1 Pages: 63-65
  • DOI: 10.1111/exd.12295
  • Peer Reviewed
• [Journal Article] Biologic therapy improves psoriasis by decreasing the activity of monocytes and neutrophils. (2014)
  • Author(s): Yamanaka K, Umezawa Y, Yamagiwa A, Saeki H, Kondo M, Gabazza EC, Nakagawa H, Mizutani H.
  • Journal Title: J Dermatol Volume: 41 Issue: 8 Pages: 679-85
  • DOI: 10.1111/1346-8138.12560
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Persistent release of IL-1s from skin is associated with systemic cardio-vascular disease, emaciation and systemic amyloidosis: the potential of anti-IL-1 therapy for systemic inflammatory diseases. (2014)
  • Author(s): Yamanaka K, Nakanishi T, Saito H, Maruyama J, Isoda K, Yokochi A, Imanaka-Yoshida K, Tsuda K, Kakeda M, Okamoto R, Fujita S, Iwakura Y, Suzuki N, Ito M, Maruyama K, Gabazza EC, Yoshida T, Shimaoka M, Mizutani H.
  • Journal Title: PLoS One. Volume: 9 Issue: 8 Pages: 104479-104479
  • DOI: 10.1371/journal.pone.0104479
  • Peer Reviewed / Open Access
• [Presentation] Rapid changes in the red meat and α-Gal specific IgE-RAST level in the clinical course of a case with red meat allergy and Haemaphysalis longicornis bite (2017)
  • Author(s): Kondo M, Nakagawa T, Yamanaka K, Mizutani H
  • Organizer: 76th Annual Meeting of the Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Neutrophil is not the dominant IL-17 producer in psoriasis (2017)
  • Author(s): Yamanaka K, Yamagiwa A, Akeda T, Kondo M, Kakeda M, Habe K, Mizutani H
  • Organizer: 76th Annual Meeting of the Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Is the anti-NXP-2(ANTI-MJ) antibody a marker antibody for dysphagia in dermatomyositis? -report of three cases (2017)
  • Author(s): Kakeda M, Yamanaka K, Tsuda K, Matsushima Y, Gyobu M, Yokoyama T, Habe K, Muro Y, Mizutani H
  • Organizer: The 26th European Academy of Dermatology and Venereology Congress
  • Int'l Joint Research
• [Presentation] Skin inflammation leads immunoglobulin G aggregation and deposition in multiple organs (2017)
  • Author(s): Matsushima Y, Okada K, Mizutani K, Kondo M, Habe K, Yamanaka K
  • Organizer: 47th Annual ESDR Meeting
  • Int'l Joint Research
• [Presentation] Is neutrophil the dominant IL-17 producer in psoriasis? (2017)
  • Author(s): Mizutani K, Matsushima Y, Okada K, Yamagiwa A, Akeda T, Kondo M, Kakeda M, Habe K, Yamanaka K
  • Organizer: 47th Annual ESDR Meeting
  • Int'l Joint Research
• [Presentation] What is the optimal treatment goal for psoriasis patients with safety and satisfaction? (2016)
  • Author(s): K Yamanaka
  • Organizer: The 41st Annual Meeting of The Japanese Society for Investigative Dermatology
  • Place of Presentation: 仙台国際センター（宮城県、仙台市）
  • Year and Date: 2016-12-09
  • Invited
• [Presentation] 高度炎症状態としての乾癬を考える (2016)
  • Author(s): 山中恵一
  • Organizer: 第68回日本皮膚科学会西部支部学術大会
  • Place of Presentation: 市民センター （鳥取県、米子市）
  • Year and Date: 2016-11-19
  • Invited
• [Presentation] 乾癬の病態を考慮した、IL-17 阻害薬の位置づけ (2016)
  • Author(s): 山中恵一
  • Organizer: 第68回日本皮膚科学会西部支部学術大会
  • Place of Presentation: 市民センター （鳥取県、米子市）
  • Year and Date: 2016-11-19
  • Invited
• [Presentation] 尋常性乾癬治療において外用薬を効果的に使用するために (2016)
  • Author(s): 山中恵一
  • Organizer: 第46回日本皮膚アレルギー・接触皮膚炎学会総会学術大会
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2016-11-05
  • Invited
• [Presentation] 乾癬の成因や病態における IL-17A の重要性 (2016)
  • Author(s): 山中恵一
  • Organizer: 第67回日本皮膚科学会中部支部学術大会
  • Place of Presentation: 大阪国際会議場（大阪府、大阪市）
  • Year and Date: 2016-10-22
  • Invited
• [Presentation] Anti-NXP-2(MJ)antibody-positive dermatomyositis developing severe dysphagia and immune thrombocytopenic purpura with generalized subcutaneous edema:a case report (2016)
  • Author(s): Kakeda M, Omoto Y, Gyobu M, Habe K, Yamanaka K, Muro Y and M. H
  • Organizer: 25th European Academy of Dermatology and Venereology Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-09-28
• [Presentation] The Concept of Inflammatory Skin March (2016)
  • Author(s): K.Yamanaka
  • Organizer: Asian Summit for Psoriasis2016
  • Place of Presentation: Seoul, South Korea
  • Year and Date: 2016-09-24
  • Int'l Joint Research / Invited
• [Presentation] IL-17産生細胞・単球 (2016)
  • Author(s): 山中恵一
  • Organizer: 第31回日本乾癬学会学術大会
  • Place of Presentation: 県民センター(栃木県、宇都宮市)
  • Year and Date: 2016-09-02
  • Invited
• [Presentation] Biologics時代における乾癬治療～患者背景を考えた薬剤の使い分け～ (2016)
  • Author(s): 山中恵一
  • Organizer: 第31回日本乾癬学会学術大会
  • Place of Presentation: 県民センター(栃木県、宇都宮市)
  • Year and Date: 2016-09-02
  • Invited
• [Presentation] 皮膚からわかることAD、乾癬モデル (2016)
  • Author(s): 山中恵一
  • Organizer: 第16回日本抗加齢医学会総会
  • Place of Presentation: 横浜国際会議場（神奈川県、横浜市）
  • Year and Date: 2016-06-11
  • Invited
• [Presentation] 乾癬 アトピー性皮膚炎などによる紅皮症 (2016)
  • Author(s): 山中恵一
  • Organizer: 第115回日本皮膚科学会総会
  • Place of Presentation: 京都国際会館（京都府、京都市）
  • Year and Date: 2016-06-03
  • Invited
• [Presentation] 乾癬における外用剤の作用機序・患者が望む外用療法 (2016)
  • Author(s): 山中恵一
  • Organizer: 第115回日本皮膚科学会総会
  • Place of Presentation: 京都国際会館（京都府、京都市）
  • Year and Date: 2016-06-03
  • Invited
• [Presentation] 慢性皮膚炎症と内臓病変について (2016)
  • Author(s): 山中恵一
  • Organizer: 第278回日本皮膚科学会東海地方会
  • Place of Presentation: プライムセントラルタワー（愛知県、名古屋市）
  • Invited
• [Presentation] アレルギーに関する研究成果を診療に生かす (2015)
  • Author(s): 山中恵一
  • Organizer: 第31回日本臨床皮膚科医会総会・臨床学術大会
  • Place of Presentation: オホーツク・文化交流センター (北海道・網走)
  • Year and Date: 2015-06-20
  • Invited
• [Presentation] 教育講演13 膿疱性乾癬の病態と治療 what's new? (2015)
  • Author(s): 山中恵一
  • Organizer: 第114回日本皮膚科学会総会:
  • Place of Presentation: 横浜国際平和会議場 (神奈川県・横浜)
  • Year and Date: 2015-05-29
  • Invited
• [Presentation] 教育講演24 乾癬における生物学的製剤による治療 update (2015)
  • Author(s): 山中恵一
  • Organizer: 第114回日本皮膚科学会総会:
  • Place of Presentation: 横浜国際平和会議場 (神奈川県・横浜)
  • Year and Date: 2015-05-29
  • Invited
• [Presentation] シンポジウム16 成人の悪化因子の現状と難治化の原因 (2015)
  • Author(s): 山中恵一
  • Organizer: 第64回日本アルルギー学会学術大会
  • Place of Presentation: 横浜国際平和会議場 (神奈川県・横浜)
  • Year and Date: 2015-05-26
  • Invited
• [Presentation] The Era of biologic therapy in psoriatic disease, the step we need to take from Derm’s perspective on PsA (2015)
  • Author(s): Keiichi Yamanaka
  • Organizer: Taiwan Psoriasis Speaker tour
  • Place of Presentation: Taipei (Taiwan)
  • Year and Date: 2015-04-15
  • Int'l Joint Research / Invited
• [Presentation] Persistent release of IL-1s from skin is associated with systemic cardio-vascular disease, emaciation and systemic amyloidosis (2014)
  • Author(s): K. Yamanaka, T. Nakanishi, M. Kakeda, H. Mizutani
  • Organizer: JSID meeting
  • Place of Presentation: Suita, Osaka, Japan
  • Year and Date: 2014-12-12 – 2014-12-14
• [Presentation] Why Should we Stop Scratching? (2014)
  • Author(s): K. Yamanaka
  • Organizer: World Allergy Organization (WAO) International Scientific Conference
  • Place of Presentation: Rio de Janeiro, Brazil
  • Year and Date: 2014-12-06 – 2014-12-09
  • Invited
• [Presentation] What do the evidences tell us about the efficacy of topical treatment? (2014)
  • Author(s): K. Yamanaka
  • Organizer: The 3rd Eastern Asia Dermatology Congress
  • Place of Presentation: Jeju, Korea
  • Year and Date: 2014-05-21 – 2014-05-23
  • Invited