Abstract
Objective
α-Lipoic acid (LA) exerts beneficial effects in cardiovascular diseases though its antioxidant and/or anti-inflammatory functions. It is postulated that the anti-inflammatory function of LA results from its antioxidant function. In this study we tested whether inhibition of NF-κB by LA is dependent on its antioxidant function.
Methods
Human umbilical vein endothelial cells (HUVECs) were treated with tumor necrosis factor-α (TNFα) in the presence of various antioxidants, including LA, tiron, apocynin, and tempol. The activation of the nuclear factor-κB (NF-κB) signaling pathway was then analyzed.
Results
LA, but not other tested antioxidants, inhibited TNFα-induced inhibitor-kappaB-α (IκBα) degradation and VCAM-1 and COX2 expression in HUVECs. Although LA activated the phosphatidylinositol-3-kinase (PI3-kinase)/Akt pathway in HUVECs, inhibition of Akt by LY294002 did not affect inhibition of TNFα-induced IκBα degradation by LA. In transient co-transfection assays of a constitutively active mutant of IκB kinase-2 (IKK2), IKK2(EE), and a NF-κB luciferase reporter construct, LA dose-dependently inhibited IKK2(EE)-induced NF-κB activation in addition to inhibiting IKK activity in in vitro assays. Consistent with the effect on luciferase expression, LA inhibited IKK2(EE)-induced cyclo-oxygenase-2 (COX2) expression, suggesting that IKK2 inhibition by LA may be a relevant mechanism that explains its anti-inflammatory effects.
Conclusions
LA inhibits NF-κB activation through antioxidant-independent and probably IKK-dependent mechanisms.
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Acknowledgments
This study was supported by grants from National Institutes of Health (NIH) R01ES013406 and R01ES015146 to Dr. Rajagopalan.
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Responsible Editor: Liwu Li.
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Ying, Z., Kampfrath, T., Sun, Q. et al. Evidence that α-lipoic acid inhibits NF-κB activation independent of its antioxidant function. Inflamm. Res. 60, 219–225 (2011). https://doi.org/10.1007/s00011-010-0256-7
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DOI: https://doi.org/10.1007/s00011-010-0256-7