TRIL, a functional component of the TLR4 signaling complex, highly expressed in brain.
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.
Carpenter
Susan
S
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
Carlson
Thaddeus
T
Dellacasagrande
Jerome
J
Garcia
Amaya
A
Gibbons
Sharon
S
Hertzog
Paul
P
Lyons
Anthony
A
Lin
Lih-Ling
LL
Lynch
Marina
M
Monie
Tom
T
Murphy
Caroline
C
Seidl
Katherine J
KJ
Wells
Christine
C
Dunne
Aisling
A
O'Neill
Luke A J
LA
D000818:Animals; D001254:Astrocytoma / Q000473:pathology; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000032:analysis* / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000032:analysis* / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D002352:Carrier Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C543715:Tril protein, mouse