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Repression of class II major histocompatibility complex genes by cyclic AMP is mediated by conserved promoter

L B Ivashkiv1, L H Glimcher

  • 1Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115.

The Journal of Experimental Medicine
|December 1, 1991
PubMed

Insights

Elevated cyclic AMP (cAMP) inhibits class II major histocompatibility complex (MHC) antigen expression by targeting specific DNA elements in the MHC genes. This reveals a dual role for these DNA sequences in regulating gene expression.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) induce class II major histocompatibility complex (MHC) antigen expression.
  • Elevated intracellular cyclic adenosine monophosphate (cAMP) levels, induced by agents like prostaglandins, inhibit this MHC antigen induction.
  • The precise mechanism by which cAMP suppresses MHC class II expression remains to be fully elucidated.

Purpose of the Study:

  • To investigate the molecular mechanism underlying cAMP-mediated downregulation of class II MHC gene expression.
  • To analyze the impact of elevated cAMP on cell surface expression, mRNA levels, and promoter activity of murine A alpha and E beta class II MHC genes.

Main Methods:

  • Analysis of cell surface expression, mRNA levels, and promoter activity of A alpha and E beta class II MHC genes.
  • Utilized reporter gene assays with specific promoter sequences (151 bp of A alpha, 192 bp of E beta).
  • Performed mutational analysis on the A alpha promoter to identify key DNA regulatory elements.

Main Results:

  • Elevated cAMP caused a coordinated repression of both basal and cytokine-induced A alpha and E beta expression.
  • Specific promoter regions (151 bp A alpha, 192 bp E beta) were sufficient to confer cAMP-mediated repression.
  • The conserved S and X1 DNA elements in the A alpha promoter were identified as crucial mediators of cAMP downregulation, also essential for cytokine induction.

Conclusions:

  • Identified specific DNA elements (S and X1) that mediate the repression of class II MHC genes by cAMP.
  • Demonstrated that the same DNA sequences can mediate both positive (cytokine induction) and negative (cAMP repression) regulation of class II MHC expression.
  • Provides a deeper understanding of the complex regulatory network controlling immune responses at the molecular level.

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