SIRT1, a Class III Histone Deacetylase, Regulates LPS-Induced Inflammation in Human Keratinocytes and Mediates the Anti-Inflammatory Effects of Hinokitiol

Skin inflammation is a response of the immune system to infection and injury. In this study, we report that hinokitiol, a tropolone-related natural compound that exhibits antioxidant, anti-inflammatory, and anticancer properties in various cell types, can modulate the inflammatory responses of primary human keratinocytes challenged with lipopolysaccharide (LPS). Hinokitiol treatment inhibited LPS-mediated up-regulation of proinflammatory factors including tumor necrosis factor alpha, IL-6, and prostaglandin E₂ (PGE₂). NF-κB activation and cell migration induced by LPS were blocked in keratinocytes treated with hinokitiol. Sirt1, a class Ⅲ histone deacetylase, was up-regulated by hinokitiol treatment, and the inhibition of Sirt1 activity using a pharmacological inhibitor or genetic silencing blocked hinokitiol-mediated anti-inflammatory effects. Further, hyperactivation of Sirt1 deacetylase using an adenoviral vector also attenuated LPS-induced inflammatory responses. We thus show that hinokitiol can attenuate LPS-mediated proinflammatory signals via Sirt1 histone deacetylase activation in primary human keratinocytes and suggest that hinokitiol may be a potential therapeutic agent in skin inflammatory diseases like psoriasis.