Kinase inhibitors abrogate IFN-gamma-induced class II transactivator and class II MHC gene expression in astroglioma

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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

N J Van Wagoner1, G M O'Keefe, E N Benveniste

  • 1Department of Cell Biology, University of Alabama at Birmingham, 35294-0005, USA.

Journal of Neuroimmunology
|June 18, 1998
PubMed

Insights

Interferon-gamma (IFN-γ) requires both serine/threonine and tyrosine kinase activity for class II MHC gene expression. These kinases are essential for inducing CIITA mRNA, which drives class II MHC expression in astroglioma cells.

Area of Science:

  • Immunology
  • Molecular Biology
  • Neuroscience

Background:

  • Interferon-gamma (IFN-γ) induces class II Major Histocompatibility Complex (MHC) expression.
  • Class II MHC expression is critical for antigen presentation.
  • The class II transactivator (CIITA) is essential for IFN-γ-induced class II MHC gene transcription.

Purpose of the Study:

  • To investigate the role of serine/threonine (ser/thr) and tyrosine (tyr) kinase activity in IFN-γ-induced class II MHC expression.
  • To determine if these kinase activities are necessary for IFN-γ-induced CIITA expression in human astroglioma cell lines.

Main Methods:

  • Utilized human astroglioma cell lines (CRT and CH235).
  • Administered ser/thr kinase inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, and tyr kinase inhibitors.
  • Assessed class II MHC mRNA and protein expression.
  • Evaluated CIITA mRNA expression.
  • Used cells constitutively expressing CIITA (2fTGH.CIITA) as a control.

Main Results:

  • General ser/thr kinase inhibitors, MAPK inhibitors, and tyr kinase inhibitors dose-dependently reduced IFN-γ-induced class II MHC mRNA and protein expression.
  • These inhibitors abrogated IFN-γ-induced CIITA mRNA expression in astroglioma cells.
  • Cells with constitutive CIITA expression showed no reduction in CIITA or class II MHC mRNA with kinase inhibitors.

Conclusions:

  • Ser/thr kinase activity, potentially involving MAPK, and tyr kinase activity are required for IFN-γ-induced CIITA mRNA expression.
  • CIITA induction by IFN-γ necessitates both ser/thr and tyr kinase signaling pathways.
  • These kinase activities are upstream of CIITA and essential for subsequent class II MHC gene expression.

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