Dual-specificity phosphatase 5 acts as an anti-inflammatory regulator by inhibiting the ERK and NF-κB signaling pathways
| Autor: | Sayeon Cho, Byoung Chul Park, Anna Ju, Sewoong Lee, Huiyun Seo, Young-Chang Cho, Sung Goo Park, Kwonseop Kim, Jeong Hoon Kim |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Phosphatase Anti-Inflammatory Agents lcsh:Medicine Article Mice 03 medical and health sciences Dual-specificity phosphatase Animals Humans Phosphorylation lcsh:Science Extracellular Signal-Regulated MAP Kinases Protein kinase A Inflammation Multidisciplinary 030102 biochemistry & molecular biology biology Chemistry Kinase lcsh:R NF-kappa B Cell biology IκBα HEK293 Cells RAW 264.7 Cells 030104 developmental biology biology.protein Dual-Specificity Phosphatases lcsh:Q Inflammation Mediators Signal transduction Signal Transduction |
| Zdroj: | Scientific Reports SCIENTIFIC REPORTS(7) Scientific Reports, Vol 7, Iss 1, Pp 1-12 (2017) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-17591-9 |
| Popis: | 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-κB (NF-κB) 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-α) 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-κB, using activator protein-1 (AP-1) and NF-κB reporter plasmids, respectively, showed that NF-κB 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 κB (IκB) kinases (IKKs) but not with IκBα. 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-κB in a phosphatase activity-dependent and -independent manner, respectively. |
| Databáze: | OpenAIRE |
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