Exp Mol Med.
2013 Jul;45(7):e32.
Reactive oxygen species regulate context-dependent inhibition of NFAT5 target genes
- Affiliations
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- 1Research Institute of Immunobiology, Catholic Research Institute of Medical Science, Seoul, Korea. wan725@catholic.ac.kr
- 2School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Korea.
- 3Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, St Vincent's Hospital, Seoul, Korea.
- 4WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, South Korea. euyi@snu.ac.kr
Abstract
- The activation of nuclear factor of activated T cells 5 (NFAT5), a well-known osmoprotective factor, can be induced by isotonic stimuli, such as activated Toll-like receptors (TLRs). It is unclear, however, how NFAT5 discriminates between isotonic and hypertonic stimuli. In this study we identified a novel context-dependent suppression of NFAT5 target gene expression in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS) or a high salt (NaCl) concentration. Although LPS and NaCl both used NFAT5 as a core transcription factor, these stimuli mutually inhibited distinct sets of NFAT5 targets within the cells. Although reactive oxygen species (ROS) are essential for this inhibition, the source of ROS differed depending on the context: mitochondria for high salt and xanthine oxidase for TLRs. Specifically, the high salt-induced suppression of interleukin-6 (IL-6) production was mediated through the ROS-induced inhibition of NFAT5 binding to the IL-6 promoter. The context-dependent inhibition of NFAT5 target gene expression was also confirmed in mouse spleen and kidney tissues that were cotreated with LPS and high salt. Taken together, our data suggest that ROS function as molecular sensors to discriminate between TLR ligation and osmotic stimuli in RAW 264.7 macrophages, directing NFAT5 activity toward proinflammatory or hypertonic responses in a context-dependent manner.
MeSH Terms
-
Animals
*Gene Expression Regulation/drug effects
Interleukin-6/biosynthesis/genetics
Lipopolysaccharides/pharmacology
Macrophages/drug effects/metabolism
Male
Mannitol/pharmacology
Mice
Mice, Inbred BALB C
NF-kappa B/metabolism
Promoter Regions, Genetic/genetics
Protein Binding/drug effects/genetics
Reactive Oxygen Species/*metabolism
Rotenone/pharmacology
Sodium Chloride/pharmacology
Toll-Like Receptors
Transcription Factors/genetics/*metabolism
Interleukin-6
Lipopolysaccharides
NF-kappa B
Reactive Oxygen Species
Toll-Like Receptors
Transcription Factors
Rotenone
Mannitol
Sodium Chloride
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