title: Extracellular signal-regulated kinase 5 promotes acute cellular and systemic inflammation.
abstract: 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.
authors: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94143, USA. wilhelmsenk@anesthesia.ucsf.edu.
authors: Kevin
authors: K
authors: Wilhelmsen
authors: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Fengyun
authors: F
authors: Xu
authors: Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Katherine
authors: K
authors: Farrar
authors: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Alphonso
authors: A
authors: Tran
authors: Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Samira
authors: S
authors: Khakpour
authors: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Shirin
authors: S
authors: Sundar
authors: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Arun
authors: A
authors: Prakash
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Jinhua
authors: J
authors: Wang
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Nathanael S
authors: NS
authors: Gray
authors: Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94143, USA. Division of Critical Care Medicine and Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Judith
authors: J
authors: Hellman
mesh_terms: D000818:Animals; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology* / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology; D008297:Male; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000276:immunology*; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7