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Extracellular signal-regulated kinase 5 promotes acute cellular and systemic inflammation

Kevin Wilhelmsen1, Fengyun Xu2, Katherine Farrar3

  • 1Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94143, USA. wilhelmsenk@anesthesia.ucsf.edu.

Science Signaling
|August 27, 2015
PubMed

Insights

Mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5) promotes inflammation in critical illness. Inhibiting ERK5 reduces inflammatory responses and protects against death, suggesting ERK5 as a therapeutic target.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Medicine

Background:

  • Inflammatory critical illness involves acute inflammation and organ injury, often triggered by infections or tissue damage.
  • The role of mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5) in inflammation is debated, with some suggesting anti-inflammatory effects.
  • Previous research indicated ERK5 mediates pro-inflammatory responses in human cells via Toll-like receptor 2 (TLR2) stimulation.

Purpose of the Study:

  • To investigate the role of ERK5 in mediating pro-inflammatory responses in human cells and its potential as a therapeutic target in inflammatory critical illness.
  • To determine if inhibiting ERK5 or its upstream kinase MEK5 impacts inflammatory pathways and outcomes in preclinical models.

Main Methods:

  • Inhibition of ERK5 and MEK5 kinase activity and reduction of their protein levels in primary human vascular endothelial cells and monocytes.
  • Stimulation of cells with microbial Toll-like receptor (TLR) agonists, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α).
  • Administration of MEK5 or ERK5 inhibitors to mice subjected to TLR ligand challenge, Staphylococcus aureus infection, sterile lung ischemia-reperfusion injury, and endotoxemia.

Main Results:

  • ERK5 was found to promote inflammation induced by various microbial TLR agonists and pro-inflammatory cytokines (IL-1β, TNF-α) in human cells.
  • Inhibition of MEK5 or ERK5 significantly reduced plasma pro-inflammatory cytokine levels in mice subjected to different inflammatory challenges.
  • Pharmacological inhibition of ERK5 conferred protection against mortality in mice with endotoxemia.

Conclusions:

  • ERK5 plays a pro-inflammatory role in human endothelial cells and monocytes, contrary to some previous reports.
  • ERK5 and its upstream kinase MEK5 are potential therapeutic targets for managing inflammatory critical illness.
  • Targeting ERK5 may offer a novel strategy for treating diverse conditions associated with systemic inflammation and organ injury.

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