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CREB and AP-1 activation regulates MKP-1 induction by LPS or M-CSF and their kinetics correlate with macrophage

Cristina Casals-Casas1, Eva Alvarez, Maria Serra

  • 1Institute for Research in Biomedicine, University of Barcelona, Spain.

European Journal of Immunology
|July 9, 2009
PubMed

Insights

MAPK phosphatase-1 (MKP-1) regulates innate immunity by inactivating ERK1/2 in macrophages. Its gene expression is controlled by a specific promoter region, requiring CRE/AP-1 binding for activation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • MAPK phosphatase-1 (MKP-1) is a key regulator in innate immunity.
  • MKP-1 deactivates ERK1/2, influencing macrophage proliferation and activation.
  • Understanding MKP-1 regulation is crucial for immune response modulation.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling MKP-1 gene expression in macrophages.
  • To identify the specific promoter regions and transcription factors involved in MKP-1 induction.
  • To investigate the distinct kinetics of MKP-1 induction by different stimuli.

Main Methods:

  • Gene expression analysis in macrophages.
  • Site-directed mutagenesis of the MKP-1 proximal promoter.
  • Gel shift assays and chromatin immunoprecipitation (ChIP) to study protein-DNA interactions.

Main Results:

  • Macrophage proliferation and activation induce MKP-1 via proximal promoter sequences (-380 to -180 bp).
  • The CRE/AP-1 element within this region is essential for LPS- or M-CSF-induced MKP-1 gene activation.
  • c-Jun and CREB were identified as binding factors to the CRE/AP-1 box.
  • Distinct induction kinetics by M-CSF and LPS correlate with JNK, c-jun, and Raf-1 signaling pathways.

Conclusions:

  • The proximal promoter region containing the CRE/AP-1 site is critical for MKP-1 gene induction in macrophages.
  • Specific transcription factors, c-Jun and CREB, mediate MKP-1 expression.
  • Signal transduction pathways differentially regulate MKP-1 kinetics, impacting macrophage function.

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