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A correction to this article has been published: J. Exp. Med. 198 (9) 1451
Published online 29 September 2003 doi:10.1084/jem.20031023
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© Rockefeller University Press, 0022-1007/2003/10/1043 $5.00
The Journal of Experimental Medicine, Volume 198, Number 7, 1043-1055

LPS-TLR4 Signaling to IRF-3/7 and NF-{kappa}B Involves the Toll Adapters TRAM and TRIF

Katherine A. Fitzgerald1, Daniel C. Rowe1, Betsy J. Barnes2, Daniel R. Caffrey3, Alberto Visintin1, Eicke Latz1, Brian Monks1, Paula M. Pitha2 and Douglas T. Golenbock1

1 Division of Infectious Disease and Immunology, Department of Medicine, The University of Massachusetts Medical School, Worcester, MA 01605
2 The Sidney Kimmel Comprehensive Cancer Center, Oncology Department, Johns Hopkins School of Medicine, Baltimore, MD 21231
3 Pfizer Discovery Technology Center, Cambridge, MA 02139

Address correspondence to Douglas Golenbock, Div. of Infectious Disease and Immunology, Dept. of Medicine, The University of Massachusetts Medical School, Worcester, MA 01605. Phone: (508) 856-5980; Fax: (508) 856-5463; email: Douglas.Golenbock{at}umassmed.edu

Toll–IL-1–resistance (TIR) domain–containing adaptor-inducing IFN-ß (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-{kappa}B-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-{alpha}/ß, regulated on activation, normal T cell expressed and secreted (RANTES), and {gamma} 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.

Key Words: innate immunity • endotoxin • interferon • signal transduction • host defense


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