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The proximal interferon-stimulated response elements are essential for interferon responsiveness: a promoter analysis

T Ronni1, S Matikainen, A Lehtonen

  • 1Department of Virology, National Public Health Institute, Helsinki, Finland.

Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research
|October 22, 1998
PubMed

Insights

Human MxA protein confers resistance to RNA viruses. Its gene expression in macrophages is rapidly induced by low doses of Interferon-alpha (IFN-alpha), independent of protein synthesis, highlighting key regulatory elements.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • The human MxA protein is a key mediator of cellular resistance against various RNA viruses, including influenza.
  • MxA gene expression is typically regulated by type I interferons (IFNs) and can be directly induced by viral infection in certain cell types.

Purpose of the Study:

  • To investigate the regulation of MxA gene expression in human macrophages.
  • To identify the specific regulatory elements and signaling pathways involved in MxA induction by interferons.

Main Methods:

  • Quantitative analysis of MxA mRNA levels in human macrophages following stimulation with different doses of IFN-alpha and IFN-gamma.
  • Assessment of the role of Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-alpha) in MxA induction.
  • Analysis of the MxA promoter region using techniques such as Electrophoretic Mobility Shift Assay (EMSA) and DNase I footprinting to identify transcription factor binding sites.

Main Results:

  • MxA mRNA levels in human macrophages are significantly upregulated by very low doses of IFN-alpha in a dose-dependent manner.
  • IFN-gamma also induced MxA expression, but to a much weaker extent.
  • The induction of MxA by IFNs was rapid and did not require de novo protein synthesis.
  • IL-6 and TNF-alpha did not affect MxA mRNA levels, even in combination with IFNs.
  • The MxA promoter contains two functional IFN-stimulated response elements (ISRE) crucial for IFN-alpha-induced transcription, which bind the IFN-stimulated gene factor 3 complex.
  • The transcription factor Spl binds to a specific region of the MxA promoter, potentially interacting with the basal transcriptional machinery.

Conclusions:

  • The study elucidates the intricate transcriptional regulation of the MxA gene in human macrophages, emphasizing the critical role of IFN-alpha.
  • The findings identify specific ISRE sites and the transcription factor Spl as key players in mediating MxA induction, providing insights into antiviral defense mechanisms.

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