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Topical hypochlorite ameliorates NF-κB–mediated skin diseases in mice
Thomas H. Leung, … , Susan J. Knox, Seung K. Kim
Thomas H. Leung, … , Susan J. Knox, Seung K. Kim
Published November 15, 2013
Citation Information: J Clin Invest. 2013;123(12):5361-5370. https://doi.org/10.1172/JCI70895.
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Research Article Genetics

Topical hypochlorite ameliorates NF-κB–mediated skin diseases in mice

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Abstract

Nuclear factor-κB (NF-κB) regulates cellular responses to inflammation and aging, and alterations in NF-κB signaling underlie the pathogenesis of multiple human diseases. Effective clinical therapeutics targeting this pathway remain unavailable. In primary human keratinocytes, we found that hypochlorite (HOCl) reversibly inhibited the expression of CCL2 and SOD2, two NF-κB–dependent genes. In cultured cells, HOCl inhibited the activity of inhibitor of NF-κB kinase (IKK), a key regulator of NF-κB activation, by oxidizing cysteine residues Cys114 and Cys115. In NF-κB reporter mice, topical HOCl reduced LPS-induced NF-κB signaling in skin. We further evaluated topical HOCl use in two mouse models of NF-κB–driven epidermal disease. For mice with acute radiation dermatitis, topical HOCl inhibited the expression of NF-κB–dependent genes, decreased disease severity, and prevented skin ulceration. In aged mice, topical HOCl attenuated age-dependent production of p16INK4a and expression of the DNA repair gene Rad50. Additionally, skin of aged HOCl-treated mice acquired enhanced epidermal thickness and proliferation, comparable to skin in juvenile animals. These data suggest that topical HOCl reduces NF-κB–mediated epidermal pathology in radiation dermatitis and skin aging through IKK modulation and motivate the exploration of HOCl use for clinical aims.

Authors

Thomas H. Leung, Lillian F. Zhang, Jing Wang, Shoucheng Ning, Susan J. Knox, Seung K. Kim

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Figure 5

HOCl treatment induces epidermal hyperplasia and cell proliferation while maintaining normal skin architecture.

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HOCl treatment induces epidermal hyperplasia and cell proliferation whil...
Data from 2-day-old mice (2 d) and 18-month-old mice treated topically with H2O (18 mo) or HOCl (18 mo + HOCl) for 14 days (n = 11 for each 18-month-old treatment group; n = 3 for 2-day-old mice). (A) H&E staining of epidermis from indicated mice. (B) Average epidermal thickness (number of cell layers) for each treatment group. Skin thickness from the 18-month-old plus HOCl group was determined 1 week and 2 weeks after cessation of HOCl (n = 3 for the HOCl treatment groups 1 week and 2 weeks after cessation of treatment). *P = 0.001. (C) Ki-67 immunostaining (green) on paraffin-embedded sections of 18-month-old mouse skin with and without HOCl treatment. (D) Percentage of basal keratinocytes expressing Ki-67. (E) Keratin 14 (K14), keratin 10 (K10), and loricrin immunostaining (green), and (F) keratin 17 (K17) immunostaining (green) on paraffin-embedded sections of skin from the 18-month-old plus HOCl treatment group. Expected staining in the lower portion of the hair follicle and hair infundibulum is denoted with white arrowheads. White dashed line in E indicates basement membrane. Nuclei in panels C, E, and F were counterstained with DAPI (blue). Original magnification, ×20 (A, C, E and F). Representative images were selected from each group. (B and D) Conditions with and without HOCl are denoted by black and gray bars, respectively. Data are presented as the average ± SEM.
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