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cis-Urocanic Acid Initiates Gene Transcription in Primary Human Keratinocytes¹

Kazuyo Kaneko^*, Ulrike Smetana-Just^*, Mary Matsui, Antony R. Young^*, Susan John, Mary Norval and Susan L. Walker^2,*

^* Photobiology Group, St. John’s Institute of Dermatology and Immunobiology Department, Division of Immunology, Guy’s, King’s and St. Thomas’ School of Medicine, King’s College London, London, United Kingdom; Clinique Laboratories, Melville, NY 11747; and Biomedical Sciences, University of Edinburgh Medical School, Edinburgh, United Kingdom

It is well established that solar UV radiation (UVR) suppresses cutaneous cell-mediated immunity in humans. trans-Urocanic acid (trans-UCA) is a major UVR-absorbing skin molecule that undergoes a photoisomerization to its cis-isomer following UVR exposure. Animal studies have demonstrated that cis-UCA plays a role in UVR-induced immune suppression, but the molecular mechanisms of action of cis-UCA are not fully understood. In this study, we examined changes in gene expression and synthesis of cytokines and PGE₂ following UCA treatment of primary human keratinocytes. A limited microarray analysis of keratinocytes from two donors indicated that 400 genes were induced by solar-simulated radiation (SSR), 16 of which were also up-regulated by cis-UCA. In contrast, trans-UCA had little or no effect on gene expression. The genes up-regulated by both cis-UCA and SSR were associated with apoptosis, cell growth arrest, cytokines, and oxidative stress. Further studies using primary keratinocytes from four new donors showed that PG-endoperoxide synthase-2 was dramatically induced by cis-UCA, resulting in an enhanced secretion of PGE₂ into the cell culture supernatant. cis-UCA also increased cytokine protein production such as that of TNF-, IL-6, and IL-8 in a dose-dependent manner. SSR had the same effect as cis-UCA, but trans-UCA had no effect. In addition, activation of NF-B and lipid peroxidation were induced by cis-UCA and SSR, but not trans-UCA, suggesting possible upstream events of the gene expression changes. The data suggest that the induction of immune suppression by cis-UCA may involve the initiation of gene transcription of immunomodulatory mediators in primary human keratinocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by St. John’s Institute of Dermatology and Clinique Laboratories, Melville, NY.

² Address correspondence and reprint requests to Dr. Susan L Walker, Photobiology Group, St. John’s Institute of Dermatology, 9th Floor of Guy’s Tower, Guy’s Hospital, London SE1 9RT, United Kingdom. E-mail address: susan.walker{at}kcl.ac.uk

³ Abbreviations used in this paper: UVR, UV radiation; CHS, contact hypersensitivity; J, joule; MED, minimal erythema dose; PTGS2, prostaglandin-endoperoxide synthase 2; SSR, solar simulated radiation; UCA, urocanic acid.