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J Biol Chem, Vol. 275, Issue 15, 11058-11063, April 14, 2000
From the A missense mutation in the cytoplasmic domain of
the Toll-like receptor-4 (TLR-4) has been identified as the defect
responsible for lipopolysaccharide (LPS) hyporesponsiveness in C3H/HeJ
mice. TLR-4 and TLR-2 have recently been implicated in LPS signaling in
studies where these receptors were overexpressed in LPS non-responsive 293 human embryonic kidney cells. However, the signaling role of TLR-4
or TLR-2 in human cells with natural LPS response remains largely
undefined. Here we show that human dermal microvessel endothelial cells
(HMEC) and human umbilical vein endothelial cells express predominantly
TLR-4 but very weak TLR-2 and respond vigorously to LPS but not to
Mycobacterium tuberculosis 19-kDa lipoprotein. Transient
transfection of non-signaling mutant forms of TLR-4 and anti-TLR-4
monoclonal antibody inhibited LPS-induced NF-
Bacterial Lipopolysaccharide Activates NF-
B through Toll-like
Receptor 4 (TLR-4) in Cultured Human Dermal Endothelial Cells
DIFFERENTIAL EXPRESSION OF TLR-4 AND TLR-2 IN ENDOTHELIAL
CELLS*
,,,,
,, and**
Division of Pediatric Infectious Diseases,
Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research
Center, Cedars-Sinai Medical Center and UCLA School of Medicine, Los
Angeles, California 90048, the § Division of Dermatology,
Department of Medicine, UCLA School of Medicine, Los Angeles,
California 90095, the ¶ Institute for Medical Microbiology and
Immunology, Technical University of Munich, 81675 Munich, Germany,
and the Department of Immunology and Cell Biology, Mario Negri
Institute, I-20157 Milan, Italy
B activation in HMEC,
while a monoclonal antibody against TLR-2 was ineffective. In contrast
to LPS responsiveness, the ability of HMEC to respond to 19-kDa
lipoprotein correlated with the expression of TLR-2. Transfection of
TLR-2 into HMEC conferred responsiveness to 19-kDa lipoprotein. These
data indicate that TLR-4 is the LPS signaling receptor in HMEC and that
human endothelial cells (EC) express predominantly TLR-4 and weak
TLR-2, which may explain why they do not respond to 19-kDa lipoprotein.
The differential expression of TLRs on human EC may have important
implications in the participation of vascular EC in innate immune
defense mechanisms against various infectious pathogens, which may use
different TLRs to signal.
*
This work was supported by National Institutes of Health
Grant AI40275 (to M. A.) and by grants from MURST and AIRC (to
M. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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