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 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.
Department of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany. cwruck@ukaachen.de
Christoph Jan
CJ
Wruck
Konrad
K
Streetz
Goran
G
Pavic
Mario E
ME
Götz
Mersedeh
M
Tohidnezhad
Lars-Ove
LO
Brandenburg
Deike
D
Varoga
Oliver
O
Eickelberg
Thomas
T
Herdegen
Christian
C
Trautwein
Kaimin
K
Cha
Yuet Wai
YW
Kan
Thomas
T
Pufe
D000818:Animals; D000975:Antioxidants; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D017354:Point Mutation; D020218:Response Elements; D014158:Transcription, Genetic
D000975:Antioxidants; C508600:IL6 protein, human; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse