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

• DOI: 10.1084/jem.20031023
• Publication Date: 2003-09-30T01:04:55Z
• Authors: Katherine A. Fitz...; Daniel C. Rowe; Betsy J. Barnes; Daniel R. Caffrey; Alberto Visintin; Eicke Latz; Brian Monks; Paula M. Pitha; Douglas T. Golenbock
• Keywords: Lipopolysaccharides; 0301 basic medicine; 570; Interferon Regulatory Factor-7; Molecular Sequence Data; 610; Receptors, Cell Surface; Article; Cell Line; Mice; 03 medical and health sciences; Animals; Humans; Amino Acid Sequence; RNA, Small Interfering; Chemokine CCL5; RNA, Double-Stranded; Membrane Glycoproteins; NF-kappa B; Toll-Like Receptor 3; DNA-Binding Proteins; Mice, Inbred C57BL; Adaptor Proteins, Vesicular Transport; Interferon Regulatory Factor-3; Signal Transduction

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.