Dual-specificity phosphatase 5 acts as an anti-inflammatory regulator by inhibiting the ERK and NF-kappa B signaling pathways
- Authors
- Seo, Huiyun; Cho, Young-Chang; Ju, Anna; Lee, Sewoong; Park, Byoung Chul; Park, Sung Goo; Kim, Jeong-Hoon; Kim, Kwonseop; Cho, Sayeon
- Issue Date
- Dec-2017
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- SCIENTIFIC REPORTS, v.7, no.1
- Journal Title
- SCIENTIFIC REPORTS
- Volume
- 7
- Number
- 1
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/3503
- DOI
- 10.1038/s41598-017-17591-9
- ISSN
- 2045-2322
- Abstract
- Although dual-specificity phosphatase 5 (DUSP5), which inactivates extracellular signal-regulated kinase (ERK), suppresses tumors in several types of cancer, its functional roles remain largely unknown. Here, we show that DUSP5 is induced during lipopolysaccharide (LPS)-mediated inflammation and inhibits nuclear factor-kappa B (NF-kappa B) activity. DUSP5 mRNA and protein expression increased transiently in LPS-stimulated RAW 264.7 cells and then returned to basal levels. DUSP5 overexpression in RAW 264.7 cells suppressed the production of pro-inflammatory tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), whereas knockdown of DUSP5 increased their expression. Investigation of two major inflammatory signaling pathways, mitogen-activated protein kinase (MAPK) and NF-kappa B, using activator protein-1 (AP-1) and NF-kappa B reporter plasmids, respectively, showed that NF-kappa B transcription activity was downregulated by DUSP5 in a phosphatase activity-independent manner whereas AP-1 activity was inhibited by DUSP5 phosphatase activity towards ERK,. Further investigation showed that DUSP5 directly interacts with transforming growth factor beta-activated kinase 1 (TAK1) and inhibitor of.B (I kappa B) kinases (IKKs) but not with I kappa Ba. DUSP5 binding to IKKs interfered with the association of TAK1 with IKKs, suggesting that DUSP5 might act as a competitive inhibitor of TAK1-IKKs association. Therefore, we propose that DUSP5 negatively regulates ERK and NF-kappa B in a phosphatase activitydependent and -independent manner, respectively.
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