Lymphatic dysfunction involvement in psoriasis like skin inflammation, atopic dermatitis, and skin infection

• Project/Area Number: 16K19708
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: The University of Tokyo
• Principal Investigator: Yamada Daisuke 東京大学, 医学部附属病院, 助教 (90770826)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: リンパ浮腫 / イミキモド誘発乾癬様皮膚炎 / 自然発癌 / サイトカイン蛋白の貯留 / イミキモド / 乾癬 / 有棘細胞癌 / 蛋白貯留 / リンパ流 / 化学発癌 / 腫瘍径 / STAT3 / 表皮肥厚 / アトピー性皮膚炎 / 感染症

Outline of Final Research Achievements

In mice with lymphatic dysfunction, imiquimod-induced psoriasis like inflammation was deteriorated. In addition, larger and more aggressive tumors were formed in TPA- and DMBA-induced skin tumorigenesis model in mice with lymphatic dysfunction. Inconsistent with such results, mRNA expression levels of proinflammatory and prooncogenic cytokines in lesional skin after imiquimod or DMBA administration were comparable between mice with lymphatic dysfunction and wild type mice. On the other hand, we found that protein expression levels of proinflammatory and prooncogenic cytokines in lesional skin after imiquimod or DMBA administration were increased in mice with lymphatic dysfunction. We also revealed that phosphorylation of STAT3 induced by various cytokines was upregulated in epidermal keratinocytes of mice with lymphatic dysfunction. These results suggest that lymphatic dysfunction caused cytokine protein accumulation, resulting in exacerbation of inflammation and carcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

リンパ浮腫が皮膚の炎症や幾つかの腫瘍の発生母地になることは知られていたが、その機序ははっきりとしていなかった。今回、研究代表者は、リンパ浮腫が局所における起炎症性、発がん性サイトカインの蛋白貯留を引き起こし、結果として、皮膚の炎症、腫瘍の発生につながることを見出した。貯留したサイトカインの分解などの治療がリンパ浮腫における長期的な皮膚炎、腫瘍の発生を予防できる可能性があり、リンパ浮腫の新規治療として、検討することができるようになったと思われる。

Research Products

• [Journal Article] Osteogenic melanoma of the right fifth toe. (2019)
  • Author(s): Hayashi Y, Masui Y, Miyagawa T, Yamada D, Miyagaki T, Ikegami M, Kobayashi H, Shinozaki-Ushiku A, Takekoshi T, Sato S
  • Journal Title: Journal of Dermatology Volume: 未収載 Issue: 7
  • DOI: 10.1111/1346-8138.14822
  • Peer Reviewed
• [Journal Article] Trousseau syndrome associated with cutaneous squamous cell carcinoma. (2018)
  • Author(s): Kurniadi I, Yamada D, Wirya AY, Norimatsu Y, Kuzumi A, Ogaki J, Takahashi N, Sato S
  • Journal Title: Journal of Dermatology Volume: 45 Issue: 8
  • DOI: 10.1111/1346-8138.14265
  • Peer Reviewed
• [Journal Article] A Subcutaneous Tumour on the Posterior Neck: A Quiz. (2018)
  • Author(s): Omatsu J, Saigusa R, Miyagawa T, Numajiri H, Akamata K, Masui Y, Yamada D, Sato S
  • Journal Title: Acta Dermato-Venereologica Volume: 98 Issue: 8 Pages: 817-819
  • DOI: 10.2340/00015555-2972
  • Peer Reviewed
• [Journal Article] Dermatofibrosarcoma Protuberans Presenting as a Large Atrophic Plaque on the Chest. (2018)
  • Author(s): Saigusa R, Miyagawa T, Toyama S, Omatsu J, Miyagaki T, Masui Y, Yamada D, Sato S
  • Journal Title: Acta Dermato-Venereologica Volume: 98 Issue: 1 Pages: 155-156
  • DOI: 10.2340/00015555-2800
  • Peer Reviewed
• [Journal Article] Multiple-opposing rotation flaps for the scalp defect including hair whorl. (2017)
  • Author(s): Miyagawa T, Kadono T, Saigusa R, Numajiri H, Omatsu J, Funamizu K, Yamada D, Masui Y, Asano Y, Sato S
  • Journal Title: Journal of Dermatology Volume: 44 Issue: 11
  • DOI: 10.1111/1346-8138.13952
  • Peer Reviewed
• [Journal Article] Nivolumab-induced vitiligo successfully treated with narrowband UVB phototherapy. (2017)
  • Author(s): Miyagawa T, Kadono T, Masui Y, Yamada D, Saigusa R, Numajiri H, Omatsu J, Asano Y, Sato S
  • Journal Title: European Journal of Dermatology Volume: 27 Issue: 6 Pages: 656-658
  • DOI: 10.1684/ejd.2017.3096
  • Peer Reviewed
• [Journal Article] Lymphangiosarcoma of the hip arising in a congenital non-irradiated lymphangioma. (2017)
  • Author(s): Miyagawa T, Kadono T, Saigusa R, Yamada D, Masui Y, Fujita H, Asano Y, Sato S
  • Journal Title: Journal of the German Society of Dermatology Volume: 15 Issue: 12 Pages: 1235-1237
  • DOI: 10.1111/ddg.13356
  • Peer Reviewed
• [Journal Article] Spontaneous regression of melanoma-letting us reaffirm the significance of immunotherapy. (2017)
  • Author(s): Miyagawa T, Kadono T, Yamada D, Sato S.
  • Journal Title: Jpn J Clin Oncol Volume: 印刷中 Issue: 5 Pages: 469-470
  • DOI: 10.1093/jjco/hyx035
  • Peer Reviewed
• [Journal Article] Pazopanib induced a partial response in a patient with metastatic fibrosarcomatous dermatofibrosarcoma protuberans without genetic translocations resistant to mesna, doxorubicin, ifosfamide and dacarbazine chemotherapy and gemcitabine-docetaxel chemotherapy. (2017)
  • Author(s): Miyagawa T, Kadono T, Kimura T, Saigusa R, Yoshizaki A, Miyagaki T, Yamada D, Masui Y, Fujita H, Sato S.
  • Journal Title: J Dermatol Volume: 44 Issue: 3
  • DOI: 10.1111/1346-8138.13717
  • Peer Reviewed