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TNF-alpha, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages

Federica Alciato1, Pier Paolo Sainaghi, Daniele Sola

  • 1Clinical Immunology, Department of Clinical and Experimental Medicine, Università del Piemonte Orientale A. Avogadro, Novara, Italy.

Journal of Leukocyte Biology
|January 28, 2010
PubMed

Insights

Growth arrest-specific 6 (GAS6) protein inhibits pro-inflammatory cytokine secretion from macrophages. This immune modulation involves the Mer receptor and an anti-inflammatory pathway activating PI3K/Akt/GSK3 beta and inhibiting NF-kappaB.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Growth arrest-specific 6 (GAS6) is implicated in immune modulation.
  • Monocytes and macrophages are key cells involved in GAS6-mediated immune effects.
  • Understanding GAS6's role in regulating cytokine secretion is crucial for immune response studies.

Purpose of the Study:

  • To investigate the effect of GAS6 on cytokine secretion by monocytes/macrophages.
  • To elucidate the molecular pathways underlying GAS6-mediated immune modulation.

Main Methods:

  • Stimulation of U937 cells and primary monocytes/macrophages with LPS.
  • Assessment of cytokine secretion (TNF-alpha, IL-6).
  • Analysis of GAS6 receptor expression (Mer, Axl, Tyro3) and activation via immunoblotting.
  • Investigation of downstream signaling pathways (PI3K/Akt, GSK3 beta, NF-kappaB).

Main Results:

  • GAS6 significantly inhibited TNF-alpha and IL-6 secretion in LPS-stimulated cells.
  • The Mer receptor, but not Axl or Tyro3, was identified as the functional GAS6 receptor on differentiated U937 cells.
  • GAS6 stimulation led to Mer activation, increased Akt phosphorylation, GSK3 beta phosphorylation, and inhibited NF-kappaB nuclear translocation.

Conclusions:

  • GAS6 protein exerts anti-inflammatory effects by modulating macrophage cytokine secretion.
  • The observed immune modulation is mediated through the Mer receptor.
  • GAS6 triggers an anti-inflammatory pathway involving PI3K/Akt/GSK3 beta signaling, leading to the inhibition of NF-kappaB activation.

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