Nrf2 induces interleukin-6 (IL-6) expression via an antioxidant response element within the IL-6 promoter

IL-6 gene expression is controlled by a promoter-region containing multiple regulatory elements such as NF-κB, NF-IL6, CRE, GRE and TRE. In this study, we demonstrated that TRE, found within the IL-6 promoter, is embedded in a functional antioxidant response element (ARE) matching an entire ARE consensus sequence. Further, point mutations of the ARE consensus sequence in the IL-6 promoter construct selectively eliminate ARE but not TRE activity. Nrf2 is a redox-sensitive transcription factor which provides cytoprotection against electrophilic and oxidative stress and is the most potent activator of ARE-dependent transcription. Using Nrf2 knockout mice we demonstrate that Nrf2 is a potent activator of IL-6 gene transcription in vivo. Moreover, we show evidence that Nrf2 is the transcription factor that activates IL-6 expression in a cholestatic hepatitis mouse model. Our findings suggest a possible role of IL-6 in oxidative stress defence and also give indication about an important function for Nrf2 in the regulation of hematopoietic and inflammatory processes.