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Cells resistant to interferon are defective in activation of a promoter-binding factor
D S Kessler1, R Pine, L M Pfeffer
1Laboratory of Molecular Cell Biology, Rockefeller University, New York, NY 10021.
Abstract:
Human cultured cell lines deficient in their ability to respond to type I interferon (IFN) fail to interrupt cellular proliferation or to induce an antiviral state following exposure to IFN alpha. Comparison of non-responsive Daudi and HeLa cell lines with IFN-responsive partner cell lines and examination of non-responsive Raji cells showed that the defective cell lines expressed type I IFN receptors of typical number and affinity and bound IFN equivalently compared to the normal cells. However, transcriptional induction of interferon-stimulated genes (ISGs) was greatly reduced and delayed in these cell lines, leading to reduced accumulation of ISG mRNA. Furthermore, the rapid activation of IFN-stimulated promoter binding factors whose appearance correlates with ISG transcriptional induction, did not occur in non-responsive cells. Thus, the primary defect of these cells leading to an impaired physiological response to IFN appears to be an inability to activate promoter-binding factors necessary to trigger ISG transcription, an obligate early step in antiviral and antiproliferative physiology.
Insights
Human cells unable to respond to type I interferon (IFN) show defects in activating interferon-stimulated genes (ISGs). This inability to trigger ISG transcription prevents antiviral and antiproliferative responses, impacting cellular immunity.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Type I interferons (IFNs) are crucial for innate immunity, mediating antiviral and antiproliferative responses.
- Defective IFN signaling can impair immune function and increase susceptibility to infections.
Purpose of the Study:
- To investigate the molecular basis of cellular unresponsiveness to type I interferon (IFN) in human cell lines.
- To identify the specific defect preventing the induction of interferon-stimulated genes (ISGs) and subsequent physiological responses.
Main Methods:
- Comparative analysis of IFN-responsive and non-responsive human cell lines (Daudi, HeLa, Raji).
- Assessment of type I IFN receptor expression, IFN binding affinity, and IFN-stimulated promoter binding factor activation.
- Quantification of interferon-stimulated gene (ISG) mRNA accumulation.
Main Results:
- Non-responsive cell lines possessed functional type I IFN receptors and equivalent IFN binding.
- Transcriptional induction of ISGs and ISG mRNA accumulation were significantly reduced and delayed.
- Key interferon-stimulated promoter binding factors failed to activate rapidly in non-responsive cells.
Conclusions:
- The primary defect in these cells is an impaired ability to activate promoter-binding factors essential for ISG transcription.
- This defect in ISG induction underlies the failure to mount antiviral and antiproliferative responses to type I IFN.
- Understanding this pathway is critical for comprehending cellular immunity and developing therapeutic strategies.