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Archives of Toxicology

, Volume 93, Issue 8, pp 2307–2320 | Cite as

Keratinocyte-derived IL-36γ plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes

  • Jeong Joo Pyo
  • Sungjin Ahn
  • Sun Hee Jin
  • Seungchan An
  • Eunyoung Lee
  • Jungmin Choi
  • Jeayoung C. Shin
  • Hyunjung Choi
  • Hyoung-June Kim
  • Dalwoong Choi
  • Minsoo NohEmail author
Organ Toxicity and Mechanisms
  • 261 Downloads

Abstract

Chemical leukoderma is an acquired type of vitiligo that can be initiated by various exogenous chemicals such as hydroquinone (HQ), rhododendrol (RD), or 4-tertiary butyl phenol (4-TBP). Despite the importance of epidermal keratinocytes in diverse dermatological conditions, their toxicological role in chemical leukoderma is poorly understood. To elucidate their role in the pathogenesis of chemical leukoderma, genome-scale transcriptional analysis was performed in human epidermal keratinocytes (HEKs) treated with a sub-cytotoxic HQ concentration (10 µM). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-based functional enrichment analysis of HQ-induced differentially expressed genes (DEGs) revealed that HQ significantly upregulated DEGs related to the IL-17 signaling pathway and significantly downregulated DEGs associated with melanogenesis in HEKs. The meta-analysis between the HQ-induced and cytokine-induced transcriptional data (GSE53751) showed that 58 DEGs were commonly upregulated between HQ- and IL-17A-treated HEKs. Notably, the expression of IL36G was significantly increased in HEKs in response to both HQ and IL-17A. IL-36γ (2 µg/ml) directly inhibits melanin biosynthesis in cultured human epidermal melanocytes (HEMs) and downregulates the gene transcription of key enzymes in the melanogenesis pathway including TYR, DCT, and TYRP1. Moreover, IL-36γ autocrinally regulated keratinocyte function to produce the proinflammatory cytokines IL-36γ, IL-6, and CXCL8/IL-8 in a concentration-dependent manner, suggesting that IL-36γ may stimulate the amplification cycle of cutaneous inflammation. In this regard, hydroquinone-induced IL-36γ from human keratinocytes plays a pivotal role in the development of chemical leukoderma by autocrinally or paracrinally modulating the crosstalk between keratinocytes and melanocytes.

Keywords

Chemical leukoderma Hydroquinone Human epidermal keratinocytes (HEKs) IL-36γ Anti-melanogenic activity 

Notes

Acknowledgements

This study was partly supported by the MRC Grant of the National Research Foundation in Korea (NRF-2018R1A5A2024425) and a National Research Foundation of Korea (NRF) Grant (2015R1A2A2A01008408).

Compliance with ethical standards

Conflict of interest

Hyunjung Choi and Hyoung-June Kim are employees of AmorePacific. The other authors have no conflicts of interest.

Supplementary material

204_2019_2506_MOESM1_ESM.docx (367 kb)
Supplementary material 1 (DOCX 367 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.College of PharmacySeoul National UniversitySeoulRepublic of Korea
  2. 2.Natural Products Research Institute, College of PharmacySeoul National UniversitySeoulRepublic of Korea
  3. 3.AmorePacific Corporation R&D CenterYonginRepublic of Korea
  4. 4.Department of Public Health Science, Graduate School and College of Public Health ScienceKorea UniversitySeoulRepublic of Korea

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