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(Circulation Research. 2006;98:1134.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Absence of TRAM Restricts Toll-Like Receptor 4 Signaling in Vascular Endothelial Cells to the MyD88 Pathway

Olivier A. Harari, Pilar Alcaide, Daniela Ahl, F. William Luscinskas, James K. Liao

From the Vascular Medicine Research (O.A.H., D.A., J.K.L.) and Department of Pathology (P.A., F.W.L.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass. O.A.H.’s current address: Rheumatology Hammersmith Hospital, Faculty of Medicine Imperial College London, W12 0HS, UK.

Correspondence to James K. Liao, MD, Vascular Medicine Research, Brigham and Women’s Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu

Mammalian cells respond to bacterial lipopolysaccharide (LPS) through a cognate receptor: Toll-like receptor 4 (TLR4). The signaling pathways, which link TLR4 to the proinflammatory transcription factor nuclear factor B (NF-B), occur through the intracellular docking proteins MyD88 and Trif. We hypothesize that unlike antigen-presenting cells, vascular endothelial cells (ECs) lack the Trif protein TRAM and are therefore incapable of eliciting Trif-dependent immune responses to LPS. Stimulation of wild-type mice with LPS leads to the activation of NF-B in ECs and macrophages in vitro and in vivo. In contrast to macrophages, LPS did not activate endothelial NF-B or NF-B–dependent genes in MyD88^–/– mice, suggesting the absence of a functional Trif pathway in vascular ECs. Indeed, the Trif-dependent gene cxcl10 was not expressed in ECs after LPS stimulation. This correlated with diminished expression of the Trif accessory TIR protein TRAM in ECs. Overexpression of TRAM cDNA in ECs reconstituted LPS-induced Trif-dependent NF-B activation and cxcl10 promoter activity. The functional absence of TRAM in vascular ECs restricts TLR4 signaling to MyD88-dependent pathway. This is in contrast to macrophages, which respond to LPS via both Trif- and MyD88-dependent pathways. These findings indicate that vascular ECs do not express the Trif-dependent gene subset. This implies that these genes may be dispensable for the endothelial response to bacterial infection and play no role in the endothelial contribution to the development of atherosclerosis.

Key Words: endothelial • toll-like • Trif • TRAM • MyD88

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