Extracellular signal–regulated kinase 5 promotes acute cellular and systemic inflammation
| Autor: | Judith Hellman, Arun Prakash, Samira Khakpour, Kevin Wilhelmsen, Jinhua Wang, Katherine Farrar, Shirin V. Sundar, Alphonso Tran, Fengyun Xu, Nathanael S. Gray |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
Male Interleukin-1beta Inflammation Biology Systemic inflammation Biochemistry Article Monocytes Proinflammatory cytokine Mice medicine Human Umbilical Vein Endothelial Cells Animals Humans Protein kinase A Molecular Biology Mitogen-Activated Protein Kinase 7 Innate immune system Tumor Necrosis Factor-alpha Cell Biology Systemic Inflammatory Response Syndrome Toll-Like Receptor 2 TLR2 Immunology Tumor necrosis factor alpha medicine.symptom |
| Popis: | Inflammatory critical illness is a syndrome that is characterized by acute inflammation and organ injury, and it is triggered by infections and noninfectious tissue injury, both of which activate innate immune receptors and pathways. Although reports suggest an anti-inflammatory role for the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5), we previously found that ERK5 mediates proinflammatory responses in primary human cells in response to stimulation of Toll-like receptor 2 (TLR2). We inhibited the kinase activities and reduced the abundances of ERK5 and MEK5, a MAPK kinase directly upstream of ERK5, in primary human vascular endothelial cells and monocytes, and found that ERK5 promoted inflammation induced by a broad range of microbial TLR agonists and by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Furthermore, we found that inhibitors of MEK5 or ERK5 reduced the plasma concentrations of proinflammatory cytokines in mice challenged with TLR ligands or heat-killed Staphylococcus aureus, as well as in mice that underwent sterile lung ischemia-reperfusion injury. Finally, we found that inhibition of ERK5 protected endotoxemic mice from death. Together, our studies support a proinflammatory role for ERK5 in primary human endothelial cells and monocytes, and suggest that ERK5 is a potential therapeutic target in diverse disorders that cause inflammatory critical illness. |
| Databáze: | OpenAIRE |
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