Nrf2 Induces Interleukin-6 (IL-6) Expression via an Antioxidant Response Element within the IL-6 Promoter

Christoph Jan Wruck,Konrad Streetz,Goran Pavic,Mario E Götz,Mersedeh Tohidnezhad,Lars-Ove Brandenburg,Deike Varoga,Oliver Eickelberg,Thomas Herdegen,Christian Trautwein,Kaimin Cha,Yuet Wai Kan,Thomas Pufe

doi:10.1074/jbc.m110.162008

Abstract

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 knock-out 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 IL6 expression in a cholestatic hepatitis mouse model. Our findings suggest a possible role of IL-6 in oxidative stress defense and also give indication about an important function for Nrf2 in the regulation of hematopoietic and inflammatory processes.

Highlights

Because of its diverse biological function and simultaneous description in different studies, IL-6 was initially assigned several names
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
Some TREs are found to be embedded within an ARE, such as in the promoter region of human NAD(P)H:quinine oxidoreductase-1 (NQO1), rat and mouse glutathione S-transferase (GST) Ya subunit, and rat GST-P (5)

Summary

Introduction

Because of its diverse biological function and simultaneous description in different studies, IL-6 was initially assigned several names. 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. Using Nrf2 knock-out mice we demonstrate that Nrf2 is a potent activator of IL-6 gene transcription in vivo. Nrf2-dependent IL-6 mRNA and Protein Synthesis—In vitro and in vivo studies were performed to investigate the effect of common Nrf2 activators on the hepatic expression of IL-6.

Results

Conclusion