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Pro-inflammatory cytokine release in keratinocytes is mediated through the MAPK signal-integrating kinases

Rasmus Boye Kjellerup1, Knud Kragballe, Lars Iversen

  • 1Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.

Experimental Dermatology
|December 18, 2007
PubMed

Insights

Mitogen-activated protein kinases (MAPKs) regulate cytokine expression. This study shows MAPK signal-integrating kinase 1 (Mnk1) inhibition reduces pro-inflammatory cytokine release in human skin cells, suggesting a role in inflammatory skin diseases.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Immunology

Background:

  • Mitogen-activated protein kinases (MAPKs) are crucial regulators of cytokine expression.
  • MAPK signal-integrating kinase 1 (Mnk1) is activated by p38 MAPK and ERK1/2 pathways.
  • Mnk1 phosphorylates eukaryotic initiation factor 4E (eIF4E), influencing protein synthesis.

Purpose of the Study:

  • To investigate the role of Mnk1 and eIF4E phosphorylation in cytokine expression in human keratinocytes.
  • To determine if Mnk1 inhibition affects the release of pro-inflammatory cytokines.
  • To explore the potential involvement of Mnk1 in inflammatory skin conditions.

Main Methods:

  • Primary human keratinocytes were stimulated with anisomycin or IL-1beta.
  • Phosphorylation of Mnk1 and eIF4E was assessed.
  • The effect of Mnk inhibitor CGP57380 on eIF4E phosphorylation and cytokine release was evaluated.
  • Cytokine protein levels (TNF-alpha, IL-1beta, IL-6) were measured.

Main Results:

  • Anisomycin and IL-1beta induced time-dependent phosphorylation of Mnk1 and eIF4E in keratinocytes.
  • The Mnk inhibitor CGP57380 blocked eIF4E phosphorylation.
  • Inhibition of eIF4E phosphorylation significantly reduced anisomycin-induced release of TNF-alpha, IL-1beta, and IL-6.
  • IL-1beta-induced TNF-alpha release was also diminished by blocking eIF4E phosphorylation.

Conclusions:

  • Mnk1 and eIF4E phosphorylation play a significant role in regulating pro-inflammatory cytokine production in human keratinocytes.
  • Mnk1 inhibition effectively reduces cytokine release, highlighting its potential as a therapeutic target.
  • These findings suggest that Mnk1 contributes to the cytokine expression observed in inflammatory skin diseases.

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