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Regulation of Lipopolysaccharide-Induced Translation of Tumor Necrosis Factor-Alpha by the Toll-Like Receptor 4 Adaptor Protein TRAM

Wang L.a · Trebicka E.a · Fu Y.a · Waggoner L.d · Akira S.e · Fitzgerald K.A.d · Kagan J.C.b, c · Cherayil B.J.a, b

Author affiliations

aMucosal Immunology Laboratory, Division of Pediatric Gastroenterology, Massachusetts General Hospital, Charlestown, Mass., bDepartment of Pediatrics, Harvard Medical School, and cDivision of Gastroenterology, Children’s Hospital, Boston, Mass., dDivision of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Mass., USA; eLaboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan

Corresponding Author

Dr. Bobby J. Cherayil

Pediatric Gastroenterology Unit, Massachusetts General Hospital

Building 114, 16th Street

Charlestown, MA 02129 (USA)

Tel. +1 617 726 4170, E-Mail cherayil@helix.mgh.harvard.edu

Related Articles for ""

J Innate Immun 2011;3:437–446

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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.

© 2011 S. Karger AG, Basel

Article / Publication Details

First-Page Preview
Abstract of Review

Received: November 19, 2010
Accepted: February 03, 2011
Published online: April 14, 2011
Issue release date: August 2011

Number of Print Pages: 10
Number of Figures: 8
Number of Tables: 1

ISSN: 1662-811X (Print)
eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN

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