Biomol Ther  
IL-1 Receptor Antagonist Reduced Chemical-Induced Keratinocyte Apoptosis through Antagonism to IL-1α/IL-1β
Hyejin Lee1, Kyung Ah Cheong1, Ji-Young Kim1, Nan-Hyung Kim1, Minsoo Noh2 and Ai-Young Lee1,*
1Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine, Goyang 10326,
2Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
E-mail: leeay@duih.org
Tel: +82-31-961-7250, Fax: +82-31-961-7695
Received: August 21, 2017; Revised: October 12, 2017; Accepted: October 17, 2017; Published online: January 9, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Extracellular interleukin 1 alpha (IL-1α) released from keratinocytes is one of the endpoints for in vitro assessments of skin irritancy. Although cells dying via primary skin irritation undergo apoptosis as well as necrosis, IL-1α is not released in apoptotic cells. On the other hand, active secretion has been identified in interleukin-1 receptor antagonist (IL-1ra), which was discovered to be a common, upregulated, differentially-expressed gene in a microarray analysis performed with keratinocytes treated using cytotoxic doses of chemicals. This study examined whether and how IL-1ra, particularly extracellularly released IL-1ra, was involved in chemically-induced keratinocyte cytotoxicity and skin irritation. Primary cultured normal adult skin keratinocytes were treated with cytotoxic doses of chemicals (hydroquinone, retinoic acid, sodium lauryl sulfate, or urshiol) with or without recombinant IL-1ra treatment. Mouse skin was administered irritant concentrations of hydroquinone or retinoic acid. IL-1ra (mRNA and/or intracellular/extracellularly released protein) levels increased in the chemically treated cultured keratinocytes with IL-1α and IL-1β mRNAs and in the chemically exposed epidermis of the mouse skin. Recombinant IL-1ra treatment significantly reduced the chemically-induced apoptotic death and intracellular/extracellularly released IL-1α and IL-1β in keratinocytes. Collectively, extracellular IL-1ra released from keratinocytes could be a compensatory mechanism to reduce the chemically-induced keratinocyte apoptosis by antagonism to IL-1α and IL-1β, suggesting potential applications to predict skin irritation.
Keywords: IL-1ra, Keratinocyte apoptosis, Skin irritation


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