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

Gretchen E. Diehl, Herman H. Yue, Kristina Hsieh, Anna A. Kuang, Mary Ho, Lisa A. Morici, Laurel L. Lenz, Dragana Cado, Lee W. Riley, Astar Winoto

    Research output: Contribution to journalArticlepeer-review

    199 Scopus citations

    Abstract

    TRAIL receptor (TRAIL-R) signaling has been implicated in inducing apoptosis in tumor cells, but little is understood about its physiological function. Here, we report the generation and characterization of TRAIL-R -/- mice, which develop normal lymphocyte populations but possess enhanced innate immune responses. TRAIL-R-/- mice exhibited increased clearance of murine cytomegalovirus that correlated with increased levels of IL-12, IFN-α, and IFN-γ. Stimulation of macrophages with Mycobacterium and Toll-like receptor (TLR)-2, -3, and -4, but not TLR9, ligands resulted in high levels of TRAIL upregulation and enhanced cytokine production in TRAIL-R-/- cells. The immediate-early TLR signaling events in TRAIL-R-/- macrophages and dendritic cells are normal, but IκB-α homeostatic regulation and NF-κB activity at later time points is perturbed. These data suggest that TRAIL-R negatively regulates innate immune responses.

    Original languageEnglish (US)
    Pages (from-to)877-889
    Number of pages13
    JournalImmunity
    Volume21
    Issue number6
    DOIs
    StatePublished - Dec 2004

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology
    • Infectious Diseases

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