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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 12 Pg. 5361-70 (Dec 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 24231355 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• CCL2 protein, human
• Cdkn2a protein, mouse
• Chemokine CCL2
• Cyclin-Dependent Kinase Inhibitor p16
• DNA-Binding Proteins
• NF-kappa B
• Oxidants
• Tumor Necrosis Factor-alpha
• Hypochlorous Acid
• Superoxide Dismutase
• superoxide dismutase 2
• I-kappa B Kinase
• Acid Anhydride Hydrolases
• Rad50 protein, mouse
• Cysteine

Topics

• ATP-Binding Cassette Transporters (biosynthesis, genetics)
• Acid Anhydride Hydrolases
• Administration, Cutaneous
• Amino Acid Substitution
• Animals
• Cells, Cultured
• Chemokine CCL2 (biosynthesis, genetics)
• Cyclin-Dependent Kinase Inhibitor p16 (biosynthesis, genetics)
• Cysteine (drug effects)
• DNA Repair (drug effects)
• DNA-Binding Proteins
• Drug Evaluation, Preclinical
• Female
• Gene Expression Regulation (drug effects)
• Genes, Reporter
• Humans
• Hypochlorous Acid (administration & dosage, therapeutic use)
• I-kappa B Kinase (antagonists & inhibitors)
• Keratinocytes (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• NF-kappa B (genetics, physiology)
• Oxidants (administration & dosage, therapeutic use)
• Oxidation-Reduction
• Radiodermatitis (drug therapy, pathology)
• Skin Aging (drug effects)
• Skin Diseases (drug therapy, genetics, metabolism, pathology)
• Skin Ulcer (prevention & control)
• Superoxide Dismutase (biosynthesis, genetics)
• Transcription, Genetic (drug effects)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, pharmacology)