The role of IL-33 in the dysfunction of skin barrier

• Project/Area Number: 16K10172
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Jichi Medical University
• Principal Investigator: Komine Mayumi 自治医科大学, 医学部, 教授 (00282632)
• Research Collaborator: Jin Meijuan ; Tsuda Hidetoshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: IL-33 / 有棘層 / トランスジェニックマウス / 表皮細胞 / 炎症 / 皮膚炎 / ＩＬ－３３ / 皮膚バリア機能

Outline of Final Research Achievements

Transgenic mice　expressing　IL-33　in　the　suprabasal　layer　of　epidermal　keratinocytes　were　generated,　by utilizing involucrin promoter. Transgenic mice grew slower and small, and died in 4th week. Skin, lung, lymph node and spleen was harvested in 3rd week, and histologically, immunohistochemically studied. RNA was extracted from each sample, which was subjected to DNA microarray. IL-33Tg mice showed very strong inflammation in hands and feet, with extensive inflammatory cells in the joints. The results of microarray is now being analyzed.

Academic Significance and Societal Importance of the Research Achievements

IL-33はTh2タイプのサイトカインとして広く認識されているが、それ以外の働きについては不明な点が多い。IL-33は炎症性皮膚疾患では有棘層に強く発現するため、有棘層に発現するIL-33の役割を解明することにより、皮膚疾患の病態解明につながる。今回の結果は、有棘層に発現するIL-33が、外力の影響を受けやすい手足に非常に強い炎症を惹起することを示しており、乾癬などの炎症性皮膚疾患における有棘層ケラチノサイトのIL-33発現が、乾癬の病態に関与している可能性が示唆された。この結果は、炎症性皮膚疾患の治療開発において新たなステップとなる可能性がある。

Research Products

• [Journal Article] Interleukin-33 is expressed in the lesional epidermis in herpes virus infection but not in verruca vulgaris. (2018)
  • Author(s): Jin M., Komine M., Tsuda H., Oshio T., Ohtsuki M.
  • Journal Title: J Dermatol Volume: 45 Issue: 7 Pages: 855-857
  • DOI: 10.1111/1346-8138.14334
  • Peer Reviewed
• [Journal Article] Methotrexate, but not narrowband ultraviolet B radiation, suppresses interleukin-33 mRNA levels in psoriatic plaques and protein levels in serum of patients with psoriasis (2018)
  • Author(s): Meephansan Jitlada、Subpayasarn Urairack、Ponnikorn Saranyoo、Chakkavittumrong Panlop、Juntongjin Premjit、Komine Mayumi、Ohtsuki Mamitaro、Poovorawan Yong
  • Journal Title: The Journal of Dermatology Volume: 45 Issue: 3 Pages: 322-325
  • DOI: 10.1111/1346-8138.14009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Differential expression of alarmins: IL-33 as a candidate marker for early diagnosis of toxic epidermal necrolysis. (2018)
  • Author(s): Adachi A., Komine M., Tsuda H., Nakajima S., Kabashima K., Ohtsuki M.
  • Journal Title: J Allergy Clin Immunol Pract. Volume: 7 Issue: 1 Pages: 325-327
  • DOI: 10.1016/j.jaip.2018.05.037
  • Peer Reviewed
• [Journal Article] Real-world use of apremilast for patients with psoriasis in Japan (2018)
  • Author(s): Kishimoto Megumi、Komine Mayumi、Hioki Tomoyuki、Kamiya Koji、Sugai Junichi、Ohtsuki Mamitaro
  • Journal Title: The Journal of Dermatology Volume: 45 Issue: 11 Pages: 1345-1348
  • DOI: 10.1111/1346-8138.14617
  • Peer Reviewed
• [Journal Article] Involvement of M2 macrophages in the pathomechanisms of multicentric reticulohistiocytosis. (2017)
  • Author(s): Kamiya K, Komine M, Murata S, Ohtsuki M.
  • Journal Title: Journal of Dermatology Volume: 56 Issue: 8
  • DOI: 10.1111/ijd.13661
  • Peer Reviewed
• [Journal Article] Apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of Japanese patients with moderate to severe plaque psoriasis: Efficacy, safety and tolerability results from a phase 2b randomized controlled trial. (2017)
  • Author(s): Ohtsuki M, Okubo Y, Komine M, Imafuku S, Day RM, Chen P, Petric R, Maroli A, Nemoto O.
  • Journal Title: Journal of Dermatology Volume: 44 Issue: 8 Pages: 873884-873884
  • DOI: 10.1111/1346-8138.13829
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Diagnosis of pseudoxanthoma elasticum in a 4-year-old boy (2017)
  • Author(s): Maki N., Komine M., Tsuda H., Fujita Y., Fujita E., Murata S., Demitsu T., Utani A., Ohtsuki M.
  • Journal Title: J Dertmatol Volume: 印刷中 Issue: 2 Pages: 244-236
  • DOI: 10.1111/1346-8138.13805
  • Peer Reviewed
• [Journal Article] Identification of promoter region of human IL-33 responsive to induction by IFNγ (2017)
  • Author(s): Tsuda H., Komine M., Tominaga S., Ohtsuki M.
  • Journal Title: J Dermatol Sci Volume: 85 Issue: 2 Pages: 137-140
  • DOI: 10.1016/j.jdermsci.2016.11.002
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nuclear ezpression of IL-33 in epidermal keratinocytes promotes wound healing in mice (2017)
  • Author(s): Oshio T., Komine M., Tsuda H., Tominaga S., Saito H., Nakae S., Ohtsuki M.
  • Journal Title: J Dermatol Sci Volume: 85 Issue: 2 Pages: 106-114
  • DOI: 10.1016/j.jdermsci.2016.10.008
  • Peer Reviewed
• [Journal Article] Adalimumab administration after infliximab therapy is a successful treatment strategy for generalized pustular psoriasis. (2017)
  • Author(s): Matsumoto A, Komine M, Karakawa M, Kishimoto M, Ohtsuki M.
  • Journal Title: Journal of Dermatology Volume: - Issue: 2 Pages: 202-204
  • DOI: 10.1111/1346-8138.13632
  • Peer Reviewed
• [Journal Article] Effects of maxacalcitol ointment on skin lesions in patients with psoriasis receiving treatment with adalimumab. (2016)
  • Author(s): Karakawa M, Komine M, Kishimoto M, Maki N, Matsumoto A, Sugai J, Ohtsuki M
  • Journal Title: Journal of Dermatology Volume: 43 Issue: 11 Pages: 1354-1357
  • DOI: 10.1111/1346-8138.13515
  • Peer Reviewed
• [Presentation] Poly I:CはTLR3-IRF3を介して IL-33をプロモーターレベルで誘導する (2018)
  • Author(s): 小宮根真弓、金 美娟、津田英利、大槻マミ太郎
  • Organizer: 日本炎症・再生医学会
• [Presentation] 表皮細胞に対するアプレミラストの作用についての検討 (2018)
  • Author(s): 金 美娟、小宮根真弓、津田英利、大槻マミ太郎
  • Organizer: 山梨地方会
• [Presentation] IL-33 determines the type of inflammation in psoriasis mice model (2018)
  • Author(s): Hidetoshi Tsuda, Mayumi Komine, Tomoyuki Hioki, Susumu Nakae, Mamitaro Ohtsuki
  • Organizer: Inflammatory Skin Disease Summit
  • Int'l Joint Research
• [Presentation] 表皮角化細胞へのTNFα刺激はIL-33の発現を抑制する (2018)
  • Author(s): 津田英利、小宮根真弓、大槻マミ太郎
  • Organizer: 分子皮膚科フォーラム
• [Presentation] The double-stranded RNA induces IL-33 promoter activation through TLR3-IRF3 pathway, depending on EGF receptor activation in normal human epidermal keratinocytes (2017)
  • Author(s): Jin M, Komine M, Tsuda H, Tominaga S, Ohtsuki M.
  • Organizer: 76th Annual Meeting of Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Toll-like receptor 3 activation results in IL-33 promoter activation through IRF3 transcription factor depending on EGF receptor activation in normal human epidermal keratinocytes. (2017)
  • Author(s): Jin M, Komine M, Tsuda H, Ohtsuki M.
  • Organizer: 42nd Annual Meeting of Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Nuclear IL-33 knock down by siRNA impairs cell division and cell motility of normal human epidermal keratinocytes (2017)
  • Author(s): Tsuda H, Komine M, Ohtsuki M.
  • Organizer: 76th Annual Meeting of Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Loss of IL-33 alters cytokine profile in imiquimod-induced psoriasis model (2017)
  • Author(s): Tsuda H, Komine M, Ohtsuki M.
  • Organizer: 42nd Annual Meeting of Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] STAT3 activation causes IL-33 expression in normal human epidermal keratinocyte (2017)
  • Author(s): Tsuda H, Komine M, Ohtsuki M.
  • Organizer: 47th Annual Meeting of European Society for Dermatological Research
  • Int'l Joint Research
• [Presentation] Analysis of Oncostatin M signaling in Hemangiosarcoma Cell Line and Regulation of IL-33 Expression (2016)
  • Author(s): Hidetoshi Tsuda, Mayumi Komine, Meijuan Jin, Naomi Nakano, Shin-ichi Tominaga, Mikio Masuzawa, Mamitaro Ohtsuki
  • Organizer: 41th Annual Meeting of 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
  • Int'l Joint Research
• [Presentation] Double-stranded RNA induces IL-33 expression through activation of EGFR, ERK, p38 and TBK-1 in normal epidermal keratinocytes. (2016)
  • Author(s): Meijuan Jin, Mayumi Komine, Hidetoshi Tsuda, Shin-ichi Tominaga, Mamitaro Ohtsuki
  • Organizer: 41th Annual Meeting of 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
  • Int'l Joint Research
• [Presentation] The loss of nuclear IL-33 affects cell division of normal human keratinocyte (2016)
  • Author(s): Hidetoshi Tsuda, Mayumi Komine, Shin-ichi Tominaga, Mamitaro Ohtsuki
  • Organizer: 46th Annual Meeting of European Society for Dermatological Research
  • Place of Presentation: Munchen, Germany
  • Year and Date: 2016-09-07
  • Int'l Joint Research
• [Presentation] Double-stranded RNA induces IL-33 expression through activation of EGFR, ERK, and p38 in normal human epidermal keratinocytes. (2016)
  • Author(s): Meijuan Jin, Mayumi Komine, Hidetoshi Tsuda, Mamitaro Ohtsuki
  • Organizer: 46th Annual Meeting of European Society for Dermatological Research
  • Place of Presentation: Munchen, Germany
  • Year and Date: 2016-09-07
  • Int'l Joint Research
• [Presentation] IL-33 is expressed in lesional skin of herpes virus infection,but not of verruca vulgaris. (2016)
  • Author(s): Meijuan Jin, Mayumi Komine, Hidetoshi Tsuda, Shin-ichi Tominaga, Mamitaro Ohtsuki
  • Organizer: 75th Annual Meeting of Society for Investigative Dermatology
  • Place of Presentation: Scottsdale, USA
  • Year and Date: 2016-05-11
  • Int'l Joint Research
• [Book] Psoriasis (2017)
  • Author(s): Jitlada Meephansan, Urairack Subpayasarn, Mayumi Komine, and Mamitaro Ohtsuki
  • Publisher: Intech