Mechanism of Dose-Dependent Regulation of UBE1L by Polyphenols in Human Bronchial Epithelial Cells.

Ubiquitin activating enzyme E1-like (UBE1L) is the activating enzyme for ISG15ylation (ISG15, interferon stimulated gene 15). UBE1L is thought to be a candidate tumor suppressor gene and has positive activity against stress responses such as viral infections. Both type I interferon and retinoic acid are known to induce UBE1L expression. However, the molecular mechanism of UBE1L regulation is unclear. Here, the effect of several chemopreventive polyphenols on UBE1L expression in human bronchial epithelial cells (Beas-2B) was investigated. Lower concentrations of curcumin, (-)-epigallocatechin-3-gallate (EGCG) and resveratrol upregulated UBE1L, while high concentrations of curcumin, EGCG and resveratrol downregulated UBE1L levels. Interestingly, curcumin, EGCG and resveratrol diminished intracellular reactive oxygen species (ROS) at lower concentrations but generated ROS at higher concentrations. The antioxidant N-acetylcysteine (NAC) increased UBE1L protein levels, while pro-oxidants such as hydrogen peroxide and tert-butyl hydroperoxide (tBHP) decreased UBE1L protein levels, indicating that the intracellular redox status is associated with UBE1L expression. Kinase inhibitors were used to examine the contribution of mitogen-activated protein kinase (MAPK) activity to the polyphenol-regulated UBE1L. Only the inhibition of c-Jun N-terminal kinase (JNK) significantly reduced UBE1L expression. Knockdown of nuclear factor erythroid-2 related factor-2 (Nrf2) caused a concomitant decrease in UBE1L protein levels. It is concluded from the above mentioned results that JNK/Nrf2 signal pathway is involved in the regulation of UBE1L via intracellular ROS status when cells came in contact with polyphenols.