Nicotinamide mononucleotide and nicotinamide riboside attenuate cytokine production in human keratinocytes via suppression of p38 Pathway

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by impaired epidermal barrier function and immune dysregulation. Current therapies are largely symptomatic and frequently associated with adverse effects, underscoring the need for safer and more effective treatment strategies. Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are precursors of nicotinamide adenine dinucleotide (NAD⁺) and have been reported to regulate inflammatory signaling and cellular metabolism. This study investigated the anti-inflammatory effects of NMN and NR in an in vitro model of AD. METHODS AND RESULTS: Human keratinocyte HaCaT cells were stimulated with TNF-α and IFN-γ to mimic AD-associated inflammation and pretreated with NMN or NR. Quantitative PCR analysis demonstrated that NMN significantly and dose-dependently reduced mRNA expression of IL-1β, macrophage-derived chemokine (MDC/CCL22), CCL5 (RANTES), CCL17 (TARC), IL8, and thymic stromal lymphopoietin (TSLP). NR similarly suppressed these inflammatory mediators except IL-1β, which was not significantly reduced. Western blot analysis showed that both NMN and NR inhibited phosphorylation of p38 MAPK, whereas phosphorylation levels of Akt, ERK, NF-κB, and JNK were not significantly altered. Neither compound affected cell viability. CONCLUSIONS: NMN and NR attenuate pro-inflammatory gene expression in cytokine-stimulated keratinocytes, primarily through inhibition of p38 MAPK signaling. NMN demonstrated broader anti-inflammatory effects than NR. These findings identify NAD⁺ precursors, particularly NMN, as potential therapeutic candidates for AD by targeting keratinocyte-mediated inflammation.

Atopic dermatitis; Keratinocytes; NAD⁺; Nicotinamide mononucleotide; Nicotinamide riboside chloride; p38 MAPK.