Regulation of lipopolysaccharide-induced translation of tumor necrosis factor-alpha by the toll-like receptor 4 adaptor protein TRAM.

Citation data:

Journal of innate immunity, ISSN: 1662-8128, Vol: 3, Issue: 5, Page: 437-46

Publication Year:
2011
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Citations 13
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Repository URL:
https://escholarship.umassmed.edu/infdis_pp/130; https://works.bepress.com/katherine_fitzgerald/64
PMID:
21494017
DOI:
10.1159/000324833
PMCID:
PMC3186711; 3186711
Author(s):
Wang, Lijian; Trebicka, Estela; Fu, Ying; Waggoner, Lisa; Akira, Shizuo; Fitzgerald, Katherine A.; Kagan, Jonathan C.; Cherayil, Bobby J.
Publisher(s):
S. Karger AG
Tags:
Medicine; Toll-Like Receptor 4; Lipopolysaccharides; Tumor Necrosis Factor-alpha; Adaptor Proteins, Vesicular Transport; Macrophages; Immunology and Infectious Disease
article description
Lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-α requires the recruitment of two pairs of adaptors to the Toll-like receptor 4 cytoplasmic domain. The contribution of one pair - Toll-interleukin-1 receptor domain-containing adaptor inducing interferon-β (TRIF) and TRIF-related adaptor molecule (TRAM) - to TNF-α expression is not well understood. To clarify this issue, we studied TRAM knockout bone marrow-derived macrophages (BMDM). LPS-stimulated TRAM-deficient BMDM had decreased TNF-α protein expression even at times when TNF-α mRNA levels were normal, suggesting impaired translation. Consistent with this idea, knockdown of TRAM in RAW264.7 macrophages decreased translation of a reporter controlled by the TNF-α 3' untranslated region, while transfection of TRAM in HEK293T cells increased translation of this reporter. Also consistent with a role for TRAM in TNF-α translation, LPS-induced activation of MK2, a kinase involved in this process, was impaired in TRAM-deficient BMDM. TRIF did not increase translation of the TNF-α 3' untranslated region reporter when expressed in HEK293T cells. However, BMDM that lacked functional TRIF produced reduced levels of TNF-α protein in response to LPS despite normal amounts of the mRNA. Unlike BMDM, LPS-stimulated TRAM-deficient peritoneal macrophages displayed equivalent reductions in TNF-α protein and mRNA. Our results indicate that TRAM- and TRIF-dependent signals have a previously unappreciated, cell type-specific role in regulating TNF-α translation.