Cutting edge: apoptosis-regulating signal kinase 1 is required for reactive oxygen species-mediated activation of IFN regulatory factor 3 by lipopolysaccharide.
IFN regulatory factor (IRF) 3 participates in the transcriptional induction of IFN-alpha, IFN-beta, and a subset of IFN-stimulated genes (ISGs) as a result of viral infection. In addition, bacterial cell wall components such as LPS activate IRF3 in a p38-dependent manner. In this study we show that IRF3-mediated ISG induction by LPS requires the production of reactive oxygen species (ROS) by the NADPH-dependent oxidase NOX4. Furthermore, we present evidence that LPS-mediated ROS production leads to activation of apoptosis-regulating-signal kinase (ASK) 1, a MAPK kinase kinase family member capable of activating the MAP kinase 6/p38 axis. ASK1 kinase activity proved essential for IRF3-mediated ISG induction by LPS. Thus, our results presented here suggest a novel role for ROS and ASK1 in the innate immune response as signaling intermediates in the IRF3 activation pathway.
Chiang
Edward
E
Division of Biological Sciences and University of California San Diego Cancer Center, University of California-San Diego, La Jolla, CA 92093, USA.
Dang
Oanh
O
Anderson
Keith
K
Matsuzawa
Atsushi
A
Ichijo
Hidenori
H
David
Michael
M