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TRIL, a Functional Component of the TLR4 Signaling Complex, Highly Expressed in Brain¹

Susan Carpenter^*,, Thaddeus Carlson, Jerome Dellacasagrande, Amaya Garcia^,¶, Sharon Gibbons, Paul Hertzog^||, Anthony Lyons, Lih-Ling Lin, Marina Lynch, Tom Monie^#, Caroline Murphy^*,, Katherine J. Seidl, Christine Wells^**, Aisling Dunne^2,* and Luke A. J. O'Neill^2,3,*

^* School of Biochemistry and Immunology and Trinity Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland; Opsona Therapeutics, Institute for Molecular Medicine, St. James’s Hospital, Dublin, Ireland; Inflammation Discovery Research, Wyeth Research, Cambridge, MA; ^¶ Dublin Institute of Technology, Dublin, Ireland; ^|| Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Victoria, Australia; ^# Department of Biochemistry, University of Cambridge, United Kingdom; and ^** Eskitis Institute for Cell and Molecular Therapies, Griffith University, Queensland, Australia

TLR4 is the primary sensor of LPS. In this study, we describe for the first time TLR4 interactor with leucine-rich repeats (TRIL), which is a novel component of the TLR4 complex. TRIL is expressed in a number of tissues, most prominently in the brain but also in the spinal cord, lung, kidney, and ovary. TRIL is composed of a signal sequence, 13 leucine-rich repeats, a fibronectin domain, and a single transmembrane spanning region. TRIL is induced by LPS in the human astrocytoma cell line U373, in murine brain following i.p. injection, and in human PBMC. Endogenous TRIL interacts with TLR4 and this interaction is greatly enhanced following LPS stimulation. TRIL also interacts with the TLR4 ligand LPS. Furthermore, U373 cells stably overexpressing TRIL display enhanced cytokine production in response to LPS. Finally, knockdown of TRIL using small interfering RNA attenuates LPS signaling and cytokine production in cell lines, human PBMC, and primary murine mixed glial cells. These results demonstrate that TRIL is a novel component of the TLR4 complex which may have particular relevance for the functional role of TLR4 in the brain.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Science Foundation of Ireland.

² A.D. and L.A.J.O. contributed equally to this study.

³ Address correspondence and reprint requests to Prof. Luke A. J. O'Neill, School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland. E-mail address: laoneill{at}tcd.ie

⁴ Abbreviations used in this paper: LRR, leucine-rich repeat; TRIL, TLR4 interactor with leucine rich repeats; CHO, Chinese hamster ovary; siRNA, small interfering RNA; BMDM, bone marrow-derived macrophage.

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The JI 2009 183: 3557-3558. [Full Text]