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 December 2, 2013; First published November 15, 2013
Citation Information: J Clin Invest. 2013;123(12):5361-5370. https://doi.org/10.1172/JCI70895.
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Categories: 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 4

HOCl attenuates acute radiation dermatitis.

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HOCl attenuates acute radiation dermatitis. (A) Relative percentage of N...
(A) Relative percentage of NF-κB reporter gene activation in the skin of LPS-stimulated NF-κB reporter mice treated topically with and without HOCl (n = 3 in each group). *P < 0.01. Four-week-old mice received 6 Gy irradiation daily for 10 days on their back skin. Prior to each dose of radiation, mice were treated with H2O or HOCl (n = 5–7 for each treatment group). (B) Images taken of the back skin on days 14, 20, and 30 after the start of irradiation. Representative images are selected from each group. (C) Score based on RTOG criteria for radiation-induced dermatitis in mice treated with H2O or HOCl. *P < 0.001 comparing treatment groups across 14-, 20,- and 30-day time points. P < 0.01 for individual 14-, 20-, and 30-day time points. (D) H&E staining of epidermis from indicated mice on day 14. White dashed line indicates basement membrane; red arrows indicate skin appendages. Scale bar: 20 μm. Representative images selected from each group. (E) Relative mRNA levels of Ccl2, Cxcl10, Il6, Mnsod, and Nfkbia in back skin isolated from irradiated mice treated with H2O or HOCl on day 14 (n = 4–6 for each treatment group). Control obtained from untreated mouse back skin. *P < 0.05 for all genes. Data are presented as the average ± SEM.