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

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 mu M). 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-36 gamma (2 mu g/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-36 gamma autocrinally regulated keratinocyte function to produce the proinflammatory cytokines IL-36 gamma, IL-6, and CXCL8/IL-8 in a concentration-dependent manner, suggesting that IL-36 gamma may stimulate the amplification cycle of cutaneous inflammation. In this regard, hydroquinone-induced IL-36 gamma from human keratinocytes plays a pivotal role in the development of chemical leukoderma by autocrinally or paracrinally modulating the crosstalk between keratinocytes and melanocytes.