MKP-1 negatively regulates LPS-mediated IL-1β production through p38 activation and HIF-1α expression
| Autor: | Pershang Farshi, Harvinder Talwar, Lobelia Samavati, Yusen Liu, Christian Bauerfeld, Mohamad Bouhamdan |
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| Rok vydání: | 2017 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine MAPK/ERK pathway p38 mitogen-activated protein kinases Interleukin-1beta Echinomycin p38 Mitogen-Activated Protein Kinases Article Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Animals Phosphorylation Interleukin 6 Transcription factor Anthracenes Regulation of gene expression biology Interleukin-6 Kinase Macrophages JNK Mitogen-Activated Protein Kinases Dual Specificity Phosphatase 1 Cell Biology Hypoxia-Inducible Factor 1 alpha Subunit Cell biology 030104 developmental biology Gene Expression Regulation Mitogen-activated protein kinase biology.protein Reactive Oxygen Species 030217 neurology & neurosurgery |
| Zdroj: | Cellular Signalling. 34:1-10 |
| ISSN: | 0898-6568 |
| DOI: | 10.1016/j.cellsig.2017.02.018 |
| Popis: | Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine that plays a major role in inflammatory diseases as well as cancer. The inflammatory response after Toll-like receptor (TLR) 4 activation is tightly regulated through phosphorylation of MAP kinases, including p38 and JNK pathways. The activation of MAP kinases is negatively regulated by MAPK phosphatases (MKPs). MKP-1 preferentially dephosphorylates p38 and JNK. IL-1β is regulated through the activation of MAPK, including p38 as well as several transcription factors. The oxygen-sensitive transcription factor HIF-1α is a known transcription factor for several inflammatory cytokines including IL-1β and IL-6. Here, we report that MKP-1 regulates HIF-1α expression in response to LPS. MKP-1 deficient bone marrow derived macrophages (BMDMs) exhibited increased reactive oxygen species (ROS) production and higher HIF-1α expression. In contrast, the expression of all three isoforms of prolyl hydroxylases (PHDs), which are important in destabilizing HIF-1α through hydroxylation, were significantly decreased in MKP-1 deficient BMDMs. LPS challenge of MKP-1 deficient BMDMs led to a substantial increase in IL-1β production. An inhibitor of HIF-1α significantly decreased LPS mediated IL-1β production both at the transcript and protein levels. Similarly, inhibition of p38 MAP kinase reduced LPS mediated pro-IL-1β and HIF-1α protein levels as well as ROS production in MKP-1 deficient BMDMs. These findings demonstrate a regulatory function for MKP-1 in modulating IL-1β expression through p38 activation, ROS production and HIF-1α expression. |
| Databáze: | OpenAIRE |
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