Published online before print March 30, 2006, doi: 10.1161/01.RES.0000220105.85182.28
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 5, 2005
Revised on March 10, 2006
Accepted on March 22, 2006
Absence of TRAM Restricts Toll-Like Receptor 4 Signaling in Vascular Endothelial Cells to the MyD88 Pathway
Olivier A. Harari ;
From the Vascular Medicine Research (O.A.H., D.A., J.K.L.) and Department of Pathology (O.A.H., 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.
* To whom correspondence should be addressed. 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 Toll/interleukin-1 receptor 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
This article has been cited by other articles:
 |
|
 |
|
  A. Csiszar, M. Wang, E. G. Lakatta, and Z. Ungvari Inflammation and endothelial dysfunction during aging: role of NF-{kappa}B J Appl Physiol, October 1, 2008; 105(4): 1333 - 1341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Lloyd-Jones, M. M. Kelly, and P. Kubes Varying Importance of Soluble and Membrane CD14 in Endothelial Detection of Lipopolysaccharide J. Immunol., July 15, 2008; 181(2): 1446 - 1453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Tamassia, V. Le Moigne, F. Calzetti, M. Donini, S. Gasperini, T. Ear, A. Cloutier, F. O. Martinez, M. Fabbri, M. Locati, et al. The MYD88-Independent Pathway Is Not Mobilized in Human Neutrophils Stimulated via TLR4 J. Immunol., June 1, 2007; 178(11): 7344 - 7356. [Abstract] [Full Text] [PDF]
|
|