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ERK and p38 MAPK signaling pathways negatively regulate CIITA gene expression in dendritic cells and macrophages

Yongxue Yao1, Qi Xu, Myung-Ja Kwon

  • 1Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, 950 West Walnut Street R2-302, Indianapolis, IN 46202, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|June 21, 2006
PubMed

Insights

Mitogen-activated protein kinase (MAPK) signals regulate CIITA expression in dendritic cells and macrophages. MAPK and phosphatase activity are crucial for controlling CIITA and MHC class II expression.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The CIITA protein is essential for MHC class II gene expression.
  • Signaling pathways controlling CIITA expression are not fully understood.

Purpose of the Study:

  • To investigate the role of MAPK signaling in regulating CIITA expression in dendritic cells (DC) and macrophages.
  • To elucidate the mechanisms by which MAPK pathways influence CIITA and MHC class II expression.

Main Methods:

  • Utilized mouse bone marrow-derived dendritic cells and macrophages.
  • Employed lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) stimulation.
  • Used pharmacological inhibitors for specific MAPK pathways (MEK, p38, JNK).
  • Assessed gene expression of CIITA, MHC class II, IFN regulatory factor-1, and MHC class I.
  • Investigated the impact of MAPK phosphatase-1 (MKP-1) overexpression and deficiency.
  • Analyzed histone acetylation of the CIITA promoter.

Main Results:

  • MAPK signals regulate both constitutive and IFN-gamma-inducible CIITA expression in DC and macrophages.
  • LPS inhibited CIITA expression in DC, an effect reversed by MyD88 deficiency or MEK/p38 inhibitors.
  • In macrophages, LPS inhibited IFN-gamma-induced CIITA and MHC class II expression.
  • MAPK inhibitors rescued LPS-mediated inhibition and enhanced IFN-gamma induction of CIITA.
  • Overexpression of MKP-1 enhanced CIITA induction, while its absence attenuated expression.
  • ERK and p38 signaling reduced CIITA expression partly via decreased histone acetylation.

Conclusions:

  • MAPK signaling pathways are critical regulators of CIITA expression in both dendritic cells and macrophages.
  • Both MAPK and phosphatase activity play significant roles in modulating CIITA and MHC class II expression.
  • Understanding these pathways provides insights into immune cell regulation and antigen presentation.

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