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A cell-type-specific requirement for IFN regulatory factor 5 (IRF5) in Fas-induced apoptosis

Arnaud Couzinet1, Kaoru Tamura, Hui-Min Chen

  • 1Departments of Immunology and Molecular Pathology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|February 13, 2008
PubMed

Insights

Interferon regulatory factor 5 (IRF5) promotes cell death through the Fas receptor in specific cells like hepatocytes. IRF5 is crucial for Fas-induced apoptosis, preceding caspase activation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Apoptosis is a regulated cell death process vital for development and disease.
  • Interferon regulatory factor 5 (IRF5) is known for innate immunity and DNA damage-induced apoptosis.
  • The role of IRF5 in death receptor signaling remained largely uncharacterized.

Purpose of the Study:

  • To investigate the cell-type-specific function of IRF5 in Fas-mediated apoptosis.
  • To elucidate the molecular stage at which IRF5 acts within the Fas signaling pathway.

Main Methods:

  • Utilized gene-deficient mice (Irf5 knockout) to assess apoptosis.
  • Administered Fas-activating monoclonal antibodies in vivo.
  • Examined apoptosis in various cell types including hepatocytes, dendritic cells, thymocytes, and embryonic fibroblasts.
  • Assessed the activation of caspase 8 and c-Jun N-terminal kinase (JNK).

Main Results:

  • Mice lacking Irf5 were resistant to Fas-induced hepatic apoptosis and lethality.
  • IRF5 acts upstream of caspase 8 and JNK activation in Fas signaling.
  • IRF5 is essential for apoptosis in hepatocytes and CpG-activated dendritic cells.
  • IRF5 is not required for Fas-induced apoptosis in thymocytes and embryonic fibroblasts in vitro.

Conclusions:

  • IRF5 exhibits a cell-type-specific role in promoting apoptosis via the Fas death receptor.
  • IRF5 is a critical regulator in specific Fas-mediated apoptotic pathways, particularly in the liver.
  • These findings reveal a novel function of IRF5 in the intricate regulation of death receptor signaling.

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