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Constitutive Interferon Attenuates RIPK1/3-Mediated Cytokine Translation

Hayley I Muendlein1, Joseph Sarhan2, Beiyun C Liu3

  • 1Graduate Program in Genetics, Tufts Graduate School of Biomedical Sciences, Boston, MA 02111, USA.

Cell Reports
|January 23, 2020
PubMed

Insights

Receptor-interacting protein kinase 1 and 3 (RIPK1/3) kinase activity drives cytokine production. Constitutive type I interferon (IFN) signaling suppresses this inflammation by inhibiting translation initiation, independent of cell death.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Receptor-interacting protein kinase 1 and 3 (RIPK1/3) are known to induce necroptosis and inflammation via MAPK signaling.
  • The precise regulation of RIPK1/3 kinase activity in cytokine production remains unclear.

Purpose of the Study:

  • To investigate the role of RIPK1/3 kinase activity in regulating cytokine translation.
  • To elucidate the mechanisms by which type I interferon (IFN) signaling modulates RIPK1/3-driven inflammation.

Main Methods:

  • Utilized mouse and human macrophages to study cytokine production.
  • Investigated the impact of type I IFN signaling on RIPK1/3-mediated inflammatory pathways.
  • Analyzed the activation of cap-dependent translation initiation components (AKT, mTORC1, 4E-BP, eIF4E).

Main Results:

  • RIPK1/3 kinase activity was found to regulate cytokine translation in macrophages.
  • Type I IFN signaling downregulated RIPK1/3-driven inflammation independently of cell death.
  • Constitutive IFN signaling inhibited AKT/mTORC1/4E-BP/eIF4E pathway activation, reducing cytokine translation.
  • IFN signaling promoted RIPK1-dependent cell death.

Conclusions:

  • Constitutive type I IFN signaling acts as a negative regulator of RIPK1-dependent inflammation.
  • Cap-dependent translation initiation is a critical regulatory checkpoint for cytokine production.
  • These findings provide new insights into the interplay between RIPK1, IFN signaling, and inflammatory responses.
Keywords:
constitutive IFNinflammationmacrophagenecroptosisreceptor-interacting protein kinasestranslation

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