Topical hypochlorite ameliorates NF-κB-mediated skin diseases in mice
Topical hypochlorite ameliorates NF-κB-mediated skin diseases in mice
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DOI：
10.1172/jci70895
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发表时间：
2013-12-01
影响因子：
15.9
通讯作者：
Kim, Seung K.
中科院分区：
文献类型：
--
作者：
Leung, Thomas H.;Zhang, Lillian F.;Kim, Seung K.
核因子-kappaB(NF-kappa B)调节细胞对炎症和衰老的反应，核因子-kappa B信号的改变是多种人类疾病发病的基础。针对这一途径的有效临床治疗方法仍然不可用。在原代培养的人角质形成细胞中，我们发现次氯酸盐(HOC1)可逆地抑制了两个依赖于NF-kappa B的基因CCL2和SOD2的表达。在培养细胞中，HOC通过氧化半胱氨酸残基Cys114和Cys115，抑制了核因子-kappaB激活的关键调节因子--核因子-kappaB激酶抑制因子(Ikk)的活性。在核因子-kappa B报告小鼠中，外用HOC1减少了脂多糖诱导的皮肤中的核因子-kappa B信号。我们进一步评估了局部局部应用于两种核因子-kappa B驱动的表皮疾病的小鼠模型。对于急性放射性皮炎的小鼠，外用HOC1抑制了依赖于核因子-kappa B的基因的表达，降低了疾病的严重性，并防止了皮肤溃疡。在老年小鼠中，局部使用HOC可减弱与年龄相关的p16(INK4a)的产生和DNA修复基因Rad50的表达。此外，经HOCl2处理的老年小鼠的皮肤获得了与幼年动物皮肤相当的表皮厚度和增殖。这些数据表明，外用HOC通过IKK调节减少了核因子-kappaB介导的放射性皮炎和皮肤衰老的表皮病理，并促进了HOC1用于临床目的的探索。
Nuclear factor-kappa B (NF-kappa B) regulates cellular responses to inflammation and aging, and alterations in NF-kappa B signaling underlie the pathogenesis of multiple human diseases. Effective clinical therapeutics targeting this pathway remain unavailable. In primary human keratinocytes, we found that hypochlorite (HOC1) reversibly inhibited the expression of CCL2 and SOD2, two NF-kappa B-dependent genes. In cultured cells, HOC inhibited the activity of inhibitor of NF-kappa B kinase (IKK), a key regulator of NF-kappa B activation, by oxidizing cysteine residues Cys114 and Cys115. In NF-kappa B reporter mice, topical HOC1 reduced LPS-induced NF-kappa B signaling in skin. We further evaluated topical HOC use in two mouse models of NF-kappa B-driven epidermal disease. For mice with acute radiation dermatitis, topical HOC1 inhibited the expression of NF-kappa B-dependent genes, decreased disease severity, and prevented skin ulceration. In aged mice, topical HOC attenuated age-dependent production of p16(INK4a) 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 HOC reduces NF-kappa B-mediated epidermal pathology in radiation dermatitis and skin aging through IKK modulation and motivate the exploration of HOC1 use for clinical aims.