DOI: 10.1084/jem.20031023. LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF

LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF

10.1084/jem.20031023

Crossref journal-article

Rockefeller University Press

The Journal of Experimental Medicine (291)

Abstract

Toll–IL-1–resistance (TIR) domain–containing adaptor-inducing IFN-β (TRIF)–related adaptor molecule (TRAM) is the fourth TIR domain–containing adaptor protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-κB-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-α/β, regulated on activation, normal T cell expressed and secreted (RANTES), and γ interferon–inducible protein 10 (IP-10) expression independently of the adaptor protein myeloid differentiation factor 88 (MyD88). Dominant negative and siRNA studies performed here demonstrate that TRIF functions downstream of both the TLR3 (dsRNA) and TLR4 (LPS) signaling pathways, whereas the function of TRAM is restricted to the TLR4 pathway. TRAM interacts with TRIF, MyD88 adaptor–like protein (Mal)/TIRAP, and TLR4 but not with TLR3. These studies suggest that TRIF and TRAM both function in LPS-TLR4 signaling to regulate the MyD88-independent pathway during the innate immune response to LPS.

Bibliography

Fitzgerald, K. A., Rowe, D. C., Barnes, B. J., Caffrey, D. R., Visintin, A., Latz, E., Monks, B., Pitha, P. M., & Golenbock, D. T. (2003). LPS-TLR4 Signaling to IRF-3/7 and NF-ÎºB Involves the Toll Adapters TRAM and TRIF. The Journal of Experimental Medicine, 198(7), 1043â1055.

Authors 9

Katherine A. Fitzgerald (first)
Daniel C. Rowe (additional)
Betsy J. Barnes (additional)
Daniel R. Caffrey (additional)
Alberto Visintin (additional)
Eicke Latz (additional)
Brian Monks (additional)
Paula M. Pitha (additional)
Douglas T. Golenbock (additional)

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Dates

Type	When
Created	21 years, 11 months ago (Sept. 29, 2003, 9:04 p.m.)
Deposited	2 years, 1 month ago (July 28, 2023, 6:09 p.m.)
Indexed	1 week, 2 days ago (Aug. 23, 2025, 12:59 a.m.)
Issued	21 years, 11 months ago (Sept. 29, 2003)
Published	21 years, 11 months ago (Sept. 29, 2003)
Published Online	21 years, 11 months ago (Sept. 29, 2003)
Published Print	21 years, 10 months ago (Oct. 6, 2003)

Funders 0

None

BibTeX

@article{Fitzgerald_2003, title={LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF}, volume={198}, ISSN={0022-1007}, url={http://dx.doi.org/10.1084/jem.20031023}, DOI={10.1084/jem.20031023}, number={7}, journal={The Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Fitzgerald, Katherine A. and Rowe, Daniel C. and Barnes, Betsy J. and Caffrey, Daniel R. and Visintin, Alberto and Latz, Eicke and Monks, Brian and Pitha, Paula M. and Golenbock, Douglas T.}, year={2003}, month=sep, pages={1043–1055} }

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  "abstract": "<jats:p>Toll\u2013IL-1\u2013resistance (TIR) domain\u2013containing adaptor-inducing IFN-\u03b2 (TRIF)\u2013related adaptor molecule (TRAM) is the fourth TIR domain\u2013containing adaptor protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-\u03baB-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-\u03b1/\u03b2, regulated on activation, normal T cell expressed and secreted (RANTES), and \u03b3 interferon\u2013inducible protein 10 (IP-10) expression independently of the adaptor protein myeloid differentiation factor 88 (MyD88). Dominant negative and siRNA studies performed here demonstrate that TRIF functions downstream of both the TLR3 (dsRNA) and TLR4 (LPS) signaling pathways, whereas the function of TRAM is restricted to the TLR4 pathway. TRAM interacts with TRIF, MyD88 adaptor\u2013like protein (Mal)/TIRAP, and TLR4 but not with TLR3. These studies suggest that TRIF and TRAM both function in LPS-TLR4 signaling to regulate the MyD88-independent pathway during the innate immune response to LPS.</jats:p>",
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