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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
07:49

Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling

Published on: August 3, 2018

TGF-beta1 disrupts endotoxin signaling in microglial cells through Smad3 and MAPK pathways

Yingying Le1, Pablo Iribarren, Wanghua Gong

  • 1Laboratory of Molecular Immunoregulation, Center for Cancer Research, and Basic Research Program, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, Frederick, MD 21702, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|July 9, 2004
PubMed

Insights

Transforming growth factor-beta1 (TGF-beta1) suppresses microglial cell activation by inhibiting formyl peptide receptor 2 (FPR2) expression. This finding suggests TGF-beta1 may protect the central nervous system (CNS) from inflammation.

Area of Science:

  • Neuroimmunology
  • Cellular and Molecular Neuroscience
  • Receptor Biology

Background:

  • Formyl peptide receptor-like 1 (FPRL1) and its mouse homologue formyl peptide receptor 2 (FPR2) are G protein-coupled receptors involved in chemotaxis.
  • Beta-amyloid peptide, a factor in Alzheimer's disease, signals through FPR2.
  • Microglial cells, key players in CNS inflammation, express functional FPR2 upon activation by bacterial lipopolysaccharide (LPS).

Purpose of the Study:

  • To investigate the effect of transforming growth factor-beta1 (TGF-beta1) on the expression and function of FPR2 in LPS-activated microglial cells.
  • To identify potential therapeutic agents for suppressing microglial activation in CNS inflammatory conditions.

Main Methods:

  • Investigated TGF-beta1's effect on mRNA expression and function of FPR2 in LPS-activated murine microglial cells.
  • Utilized Smad3 signaling pathway and p300 transcription coactivator analysis.
  • Examined the activation of MAPKs, NF-kappaB, and FPR2 expression.

Main Results:

  • TGF-beta1 dose-dependently inhibited both mRNA expression and function of FPR2 in LPS-activated microglial cells.
  • The inhibitory effect was mediated by Smad3 and p300.
  • TGF-beta1 activated MAPKs, rendering cells refractory to LPS, and inhibited NF-kappaB activation, ultimately down-regulating FPR2.

Conclusions:

  • TGF-beta1 inhibits microglial activation by suppressing LPS-induced FPR2 up-regulation.
  • The Smad3 and p300 signaling pathways are crucial for TGF-beta1's inhibitory effects.
  • TGF-beta1 may play a protective role in CNS diseases involving microglial activation by proinflammatory stimuli.

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