The anti-inflammatory and antioxidative effects of nicotinamide, a vitamin B(3) derivative, are elicited by FoxO3 in human gestational tissues: implications for preterm birth.

The inflammatory process plays a pivotal role during the pathogenesis of human labour, both at term and at preterm. Nicotinamide, a vitamin B(3) derivative, exerts anti-inflammatory and antioxidative properties in several cell types by interaction with various intracellular signalling proteins via modulating the activity of various transcription factors, including activation of the O subfamily of Forkhead/winged helix transcription factors (FoxO) and inhibition of nuclear factor-κB (NF-κB). The aim of this study was to determine the effect of nicotinamide on the expression of pro-labour and mediators in human placenta. The effects of nicotinamide were evaluated, over 24 h, by treating placenta with 0, 25 and 50 mM nicotinamide in the absence or presence of 10 μg/ml lipopolysaccharide (LPS). Nicotinamide treatment resulted in a significant reduction of basal and/or LPS-stimulated release and gene expression of the pro-inflammatory cytokines TNF-α, IL-6 and the chemokine IL-8, and the release of the prostaglandins PGE(2) and PGF(2)α and cyclooxygenase (COX)-2 mRNA expression. Additionally, nicotinamide treatment of human placenta resulted in attenuation of basal and LPS-induced oxidative stress, reducing 8-isoprostane release and increasing gene expression of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT). There was no effect of nicotinamide on NF-κB activation. The anti-inflammatory and antioxidant actions of nicotinamide were abolished by knockdown of FoxO3 using siRNA. In conclusion, nicotinamide exerts anti-inflammatory and antioxidative effects in human placenta, in part, via activation of FoxO3. Further studies should be undertaken to define a possible implication of vitamin B(3) derivatives in the management of preterm labour and delivery. Crown