MMPP Attenuates the Inflammatory Response by Suppressing ROS and Proinflammatory Cytokine and Chemokine Production in TNF-α/IFN-γ-Stimulated Human Keratinocytes

Abstract

Keratinocytes play a significant role in regulating skin immune homeostasis, and their dysregulation is central to chronic inflammatory disorders such as atopic dermatitis and psoriasis. Inflammatory mediators such as tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) can disrupt this balance, inducing abnormal cytokine and chemokine expression that promotes immune cell infiltration and chronic inflammation in the skin. While (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB) has shown anti-inflammatory effects, its clinical potential is limited due to poor stability and lack of drug-like properties. To overcome these limitations, (E)-2-Methoxy-4-(3-(4-methoxyphenyl)prop-1- en-1-yl)phenol (MMPP), a stable BHPB analog, was synthesized as a potential therapeutic candidate. This study examined the antioxidant and anti-inflammatory effects of MMPP in TNF-α/IFN-γstimulated human HaCaT keratinocytes, assessing its impact on reactive oxygen species (ROS) production and proinflammatory signaling pathways. MMPP significantly reduced ROS levels and inhibited proinflammatory cytokine and chemokine expression by interacting with IKKα/β and suppressing the main downstream IκBα and NF-κB, with additional effects on MAPK, AP-1, and STAT1 pathways. These findings highlight the promise of MMPP as a stable, drug-like agent with therapeutic potential for skin inflammation and oxidative stress by modulating keratinocytemediated immune responses.