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B Activation and Cytokine Production in Primary Human Cells: TRAM Is an Adaptor for LPS and LTA Signaling1
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom
TLR signal via Toll-IL-1R (TIR) homology domain-containing adaptor proteins. One of these adaptors, Toll-IL-1R domain-containing adaptor inducing IFN-
-related adaptor molecule (TRAM), has been shown to be essential for TLR4 signaling in TRAM–/– mice and cell lines. Previously, we showed that MyD88 or Mal dominant-negative constructs did not inhibit LPS induction of cytokines in primary human M-CSF-derived macrophages. A possible explanation was redundancy of the adaptors during LPS signaling. TRAM is a suitable candidate to compensate for these adaptors. To investigate a potential role for TRAM in LPS signaling in human M-CSF-derived macrophages, we engineered an adenoviral construct expressing dominant-negative TRAM-C117H (AdTRAMdn). Synovial fibroblasts (SF) and human umbilical endothelial cells (HUVECs) were used as a nonmyeloid comparison. AdTRAMdn inhibited LPS-induced signaling in SFs and HUVECs, reducing NF-
B activation and cytokine production, but did not inhibit LPS signaling in M-CSF-derived human macrophages. Further investigation of other TLR ligands showed that AdTRAMdn was also able to inhibit signaling initiated by lipoteichoic acid, a TLR2 ligand, in SFs and HUVECs and lipoteichoic acid and macrophage-activating lipopeptide 2 signaling was also inhibited in TRAM–/– murine embryonic fibroblasts. We conclude that TRAM is an adaptor protein for both TLR4 and TLR2/6 signaling in SFs, HUVECs, and murine embryonic fibroblasts, but cannot demonstrate a role in human macrophages.
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 Arthritis Research Council.
2 Address correspondence and reprint requests to Prof. Brian M. Foxwell, Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, Hammersmith, London W6 8LH, U.K. E-mail address: b.foxwell{at}imperial.ac.uk
3 Abbreviations used in this paper: LTA, lipoteichoic acid; IRF, IFN regulatory factor; TIR, Toll-IL-1R; Mal, MyD88 adaptor like; TIRAP, TIR domain-containing adaptor protein; TRIF, TIR domain-containing adaptor-inducing IFN-; TICAM, TIR-containing adaptor molecule; TRAM, TRIF-related adaptor molecule; SARM, sterile 
and HEAT-Armadillo motif; HUVEC, human umbilical endothelial cell; SF, synovial fibroblast; dn, dominant negative; MEF, murine embryonic fibroblast; MOI, multiplicity of infection; Malp, macrophage-activating lipopeptide; IP-10, IFN-inducible protein 10; WT, wild type.
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