Extracellular signal-regulated kinase 5 promotes acute cellular and systemic inflammation
| Autor: | Wilhelmsen, Kevin, Xu, Fengyun, Farrar, Katherine, Tran, Alphonso, Khakpour, Samira, Sundar, Shirin, Prakash, Arun, Wang, Jinhua, Gray, Nathanael S, Hellman, Judith |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Tumor Necrosis Factor-alpha Inflammatory and immune system Interleukin-1beta Monocytes Toll-Like Receptor 2 Systemic Inflammatory Response Syndrome Mice Emerging Infectious Diseases Infectious Diseases Human Umbilical Vein Endothelial Cells Animals Humans 2.1 Biological and endogenous factors Biochemistry and Cell Biology Aetiology Mitogen-Activated Protein Kinase 7 |
| Zdroj: | Science signaling, vol 8, iss 391 |
| 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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