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

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 1

HOCl reversibly inhibits TNF-α–stimulated NF-κB–dependent gene expression in primary human keratinocytes.

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HOCl reversibly inhibits TNF-α–stimulated NF-κB–dependent gene expressio...
(A) Relative mRNA levels of CCL2 and SOD2 in TNF-α–stimulated human keratinocytes with (dotted line) and without (solid line) HOCl pretreatment. (B) Cell viability assessed by trypan blue after HOCl treatment. (C) Relative mRNA levels of CCL2 and SOD2 in human keratinocytes pretreated with H2O or HOCl; 24 hours later, cells were stimulated with TNF-α for 2 hours. Control represents untreated keratinocytes. Data are presented as the average ± SEM. Conditions with and without HOCl treatment are denoted by black and gray bars, respectively.