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Cytokine-induced monocyte MMP-1 is negatively regulated by GSK-3 through a p38 MAPK-mediated decrease in ERK1/2 MAPK

Yahong Zhang1, Larry M Wahl2

  • 1National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.

Journal of Leukocyte Biology
|February 26, 2015
PubMed

Insights

Glycogen synthase kinase-3 (GSK-3) negatively regulates monocyte production of matrix metalloproteinase-1 (MMP-1). Inhibiting GSK-3 enhances MMP-1, revealing a novel pathway involving protein kinase C (PKC) and mitogen-activated protein kinases (MAPKs).

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Monocytes/macrophages produce matrix metalloproteinases (MMPs), enzymes implicated in connective tissue destruction during chronic inflammation.
  • Understanding the signal transduction pathways regulating MMP production is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the role of Glycogen synthase kinase-3 (GSK-3) in regulating cytokine-induced MMP-1 production by monocytes.
  • To elucidate the specific signaling pathways, including mitogen-activated protein kinases (MAPKs) and protein kinase C (PKC), involved in this process.

Main Methods:

  • Monocytes were treated with tumor necrosis factor-alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence or absence of GSK-3 inhibitors (SB216763, GSK-3β siRNA), PKC inhibitors (Gö6976), AKT inhibitors (AKT VIII), and MAPK inhibitors (PD98059, SB203580).
  • Production of MMP-1 was quantified.
  • Phosphorylation levels of GSK-3, p38 MAPK, and ERK1/2 MAPK were assessed.

Main Results:

  • Inhibition of GSK-3 significantly enhanced TNF-α- and GM-CSF-induced MMP-1 production.
  • Cytokine-induced GSK-3 phosphorylation and subsequent MMP-1 production were mediated primarily by a PKC pathway.
  • GSK-3 inhibition led to decreased p38 MAPK phosphorylation and increased ERK1/2 MAPK phosphorylation, with ERK1/2 activation being essential for enhanced MMP-1 production.
  • Conversely, p38 MAPK inhibition mimicked GSK-3 inhibition effects on ERK1/2 activation and MMP-1 production.

Conclusions:

  • GSK-3 acts as a negative regulator of cytokine-induced MMP-1 production in monocytes.
  • The PKC-GSK-3-MAPK signaling axis, specifically the interplay between p38 MAPK and ERK1/2, dictates the level of MMP-1 production.
  • Targeting GSK-3 or modulating downstream MAPK pathways may offer therapeutic strategies for inflammatory conditions characterized by excessive connective tissue degradation.
Keywords:
connective tissueinflammationsignal transduction

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