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TRAIL-R as a negative regulator of innate immune cell responses

Gretchen E Diehl1, Herman H Yue, Kristina Hsieh

  • 1Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California, Berkeley, CA 94720, USA.

Immunity
|December 14, 2004
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor signaling negatively regulates innate immunity. TRAIL-receptor knockout mice show enhanced responses to pathogens due to altered cytokine production and NF-kappa B activity.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor signaling is known for its role in tumor cell apoptosis.
  • The physiological functions of TRAIL receptor signaling, particularly in innate immunity, remain largely uncharacterized.

Purpose of the Study:

  • To investigate the physiological role of TRAIL receptor signaling in the innate immune system.
  • To characterize the immune responses in mice lacking TRAIL receptor (TRAIL-R(-/-)).

Main Methods:

  • Generation and characterization of TRAIL-R(-/-) mice.
  • Assessment of innate immune responses, including pathogen clearance and cytokine production (IL-12, IFN-alpha, IFN-gamma).
  • Stimulation of macrophages and dendritic cells with Toll-like receptor (TLR) ligands and analysis of TRAIL upregulation, cytokine production, and NF-kappa B signaling.

Main Results:

  • TRAIL-R(-/-) mice exhibited normal lymphocyte populations but enhanced innate immune responses.
  • Increased clearance of murine cytomegalovirus was observed in TRAIL-R(-/-) mice, correlating with elevated IL-12, IFN-alpha, and IFN-gamma levels.
  • Macrophages from TRAIL-R(-/-) mice showed increased TRAIL upregulation and cytokine production upon stimulation with Mycobacterium and TLR-2, -3, and -4 ligands.
  • While early TLR signaling was normal, later I kappa B-alpha homeostatic regulation and NF-kappa B activity were perturbed in TRAIL-R(-/-) cells.

Conclusions:

  • TRAIL receptor signaling acts as a negative regulator of innate immune responses.
  • Dysregulation of TRAIL-R signaling impacts cytokine production and NF-kappa B pathway activation in innate immune cells.
  • These findings reveal a novel role for TRAIL-R in modulating host defense mechanisms.

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