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The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling

Olga Ananieva1, Joanne Darragh, Claus Johansen

  • 1Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

Nature Immunology
|August 12, 2008
PubMed

Insights

Mitogen-activated protein kinase-activated protein kinase 1 (MSK1) and MSK2 limit inflammatory cytokine production. These kinases are crucial for negative feedback in Toll-like receptor-driven inflammation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Mitogen-activated protein kinases (MAPKs) like p38 and Erk1/2 are key signaling molecules.
  • MSK1 and MSK2 are kinases activated downstream of p38 and Erk1/2.
  • Toll-like receptor (TLR) signaling initiates inflammatory responses.

Purpose of the Study:

  • To investigate the role of MSK1 and MSK2 in regulating inflammatory responses.
  • To elucidate the molecular mechanisms by which MSK1 and MSK2 control cytokine production.
  • To determine the in vivo significance of MSK1 and MSK2 in inflammatory models.

Main Methods:

  • Primary macrophage stimulation with lipopolysaccharide (LPS).
  • Analysis of gene transcription, including DUSP1 and IL-10.
  • Assessment of transcription factor binding to gene promoters.
  • In vivo studies using MSK1 and MSK2 deficient mice in endotoxic shock and contact eczema models.

Main Results:

  • MSK1 and MSK2 are essential for limiting pro-inflammatory cytokine production following LPS stimulation.
  • MSK1 and MSK2 induce transcription of DUSP1 and IL-10, acting as negative feedback regulators.
  • MSK1/MSK2 deficiency impairs CREB and ATF1 binding to IL-10 and DUSP1 gene promoters.
  • MSK1/MSK2 deficient mice exhibit heightened sensitivity to LPS-induced endotoxic shock and prolonged inflammation.

Conclusions:

  • MSK1 and MSK2 are critical negative feedback components in TLR-driven inflammatory pathways.
  • These kinases play a vital role in controlling the magnitude and duration of inflammatory responses.
  • Targeting MSK1/MSK2 could offer therapeutic strategies for inflammatory diseases.

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