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Induce Toll-Like Receptor 2 and Toll-Like Receptor 4 Expression in Human Endothelial Cells: Role of NF-
B Activation1
*
Division of Pediatric Infectious Diseases, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center and
Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048; and
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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, or IFN-
induce
TLR2 expression in both human dermal microvessel EC and HUVEC.
Furthermore, LPS and IFN- act synergistically to induce TLR2
expression in EC, and LPS-induced TLR2 expression is NF-
B dependent.
LPS and IFN- also up-regulate TLR4 mRNA expression in EC. These data
indicate that TLR2 and TLR4 expression in ECs is regulated by
inflammatory molecules such as LPS, TNF-, or IFN-. TLR2 and TLR4
molecules may render EC responsive to TLR2 ligands and may help to
explain the synergy between LPS and lipoproteins, and between LPS and
IFN-, in inducing shock associated with Gram-negative
sepsis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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200,000 deaths annually in
the United States (3). The endothelium, although initially envisioned as a passive, inert vascular lining, is now considered important in the regulation of vascular tone, coagulation and fibrinolysis, cellular growth, differentiation, and immune and inflammatory responses (5, 6, 7). Furthermore, the vascular EC, like macrophages, are critical targets for LPS and many cytokines (5, 7, 8, 9, 10). Activation of vascular endothelium by LPS results in EC production of various proinflammatory molecules, including leukocyte adhesion molecules, as well as soluble cytokines and chemokines (5, 6, 7).
Janeway and coworkers (11) have hypothesized that the
innate immune system senses invading pathogens by virtue of
germline-encoded pattern recognition receptors that interact with
microbial structures and deliver a danger signal to the host cell
(12). Vertebrates and invertebrates initiate a series of
defense mechanisms in response to infection by various microorganisms
by sensing the presence of conserved pathogen-associated molecular
patterns, such as bacterial LPS or lipoproteins (5, 13).
Host organisms have developed a set of receptors, referred to as
pattern recognition receptors, that specifically recognize
pathogen-associated molecular patterns (14, 15). The
family of human Toll-like receptors (TLRs) has recently been shown to
be involved in innate immune recognition and cellular activation in
response to microbial Ags (13, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27). TLR family members
are type I transmembrane proteins with leucine-rich repeat
extracellular domains and conserved cytoplasmic domains with homology
to the mammalian IL-1R (27, 28). Ligand engagement of TLRs
results in activation of NF-B and induction of the cytokines and
costimulatory molecules required for the activation of the adaptive
immune response (27, 28, 29, 30, 31, 32). At least eight human homologues
of Drosophila Toll have been cloned and designated TLRs 1–8
(Refs. 27, 29 , and 33 , and GenBank accession
number NM 016562 for TLR7 and NM 016610 for TLR8), but only two TLRs,
TLR2 and TLR4, have known functions. It is now well established that
TLR4 is the primary signaling receptor for enterobacterial LPS
(16, 23, 26, 31, 34), a conclusion further substantiated
by recent work by Hoshino et al. (35), who showed that
mice in which the tlr4 gene has been deleted fail to respond
to LPS. Recent reports have shown that mice lacking TLR2 respond
normally to enterobacterial LPS and that neither human nor murine TLR2
plays a role in LPS signaling in the absence of contaminating endotoxin
proteins (23), further supporting the concept that TLR4 is
the transducing subunit of the receptor for enteric LPS (23, 26). However, current data do not rule out a role for TLR2 in
signaling induced by LPS of nonenterobacterial origin. TLR2 has been
implicated mainly as the signaling receptor for Gram-positive cell wall
components; bacterial, mycobacterial, and spirochetal lipoproteins; and
fungi (19, 21, 22, 23, 24, 25, 36, 37, 38). Therefore, a concept of
"division of labor" between these two receptors in recognizing
diverse microbial pathogens and alerting the immune system has emerged
(39). Bacterial lipoprotein, a TLR2 ligand, is one of the
most abundant proteins in the outer membrane of Gram-negative and
Gram-positive bacteria (40) and acts synergistically with
LPS to induce proinflammatory cytokine production and lethal shock
(41).
We have reported recently that human dermal microvessel EC (HMEC) and
HUVEC express TLR4 predominantly (42). HMEC and HUVEC
express little TLR2 and respond vigorously to Escherichia
coli LPS via TLR4, but not to Mycobacterium
tuberculosis 19-kDa lipoprotein, a TLR2 ligand (42).
Transfection of TLR2 confers to HMEC responsiveness to 19-kDa
lipoprotein (42). Because several microbial Ags, e.g.,
Gram-positive cell wall fragments; bacterial, spirochetal, and
mycobacterial lipoproteins; and fungal Ags, require TLR2 to activate
cells, the regulation of TLR2 mRNA expression in vascular EC could
determine EC responses to these TLR2 ligands and influence the overall
immune responses. We now describe the regulation of TLR2 expression in
EC in response to inflammatory stimuli such as LPS, TNF-, and
IFN-. To investigate whether the transcriptional events that lead to
LPS-mediated TLR2 mRNA up-regulation in EC are mediated by NF-B, we
studied the effects of various NF-B inhibitors and NF-B p65
antisense oligonucleotide. Our results indicate 1) that LPS, TNF-,
and IFN- up-regulate TLR2 expression in vascular EC, 2) that
LPS-induced TLR2 expression and up-regulation in EC is NF-B
dependent, and 3) that LPS and IFN- synergize to induce expression
of TLR2 in EC. LPS and IFN- also induced TLR4 up-regulation in EC.
Induction and up-regulation of TLR2 in response to inflammatory stimuli
such as LPS, TNF-, or IFN- in vascular EC may have important
implications in host defense against bacterial, mycobacterial, and
spirochetal infections and may help explain the well-known synergy
between LPS and lipoproteins in the induction of septic shock. The
up-regulation of TLR4 by IFN- may represent a novel mechanism for
the well-described synergy between IFN- and LPS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The immortalized HMEC (43), a generous gift of Dr.
Candal (Center for Disease Control and Prevention, Atlanta, GA), were
cultured in MCDB-131 medium supplemented with 10% heat-inactivated
FBS, 2 mM glutamine, and 100 µg/ml penicillin and streptomycin in
24-well plates and used between passages 10 and 14. Tissue culture
reagents were obtained from Life Technologies (Gaithersburg, MD). HUVEC
were isolated and cultured as previously described (44)
and were cultured in Medium 199 with 20% heat-inactivated FBS, 2 mM
glutamine, and 100 µg/ml penicillin and streptomycin. PBMC from
healthy human volunteer donors were isolated by Ficoll-Paque (Amersham
Pharmacia Biotech, Piscataway, NJ) density gradient centrifugation .
PBMC (25 x 106) were resuspended in RPMI
1640 medium supplemented with 2 mM L-glutamine, 100 U/ml
penicillin, 100 µg/ml streptomycin, 10 mM HEPES, 0.3% sodium
bicarbonate, and 10% FBS. Highly purified, phenol-water-extracted
E. coli K235 LPS (<0.008% protein), which was prepared
according to the method of McIntire et al. (45), was
obtained from Stefanie N. Vogel (Uniformed Services University of the
Health Sciences, Bethesda, MD). The purity of this LPS preparation has
been previously demonstrated (46, 47), and this
preparation of E. coli LPS is active on TLR4-transfected HEK
293 cells and not on TLR2 transfectants (Stefanie N. Vogel, unpublished
observation). Human TNF- and IFN- were purchased from R&D Systems
(Minneapolis, MN), the
15-deoxy-
12,14-PGJ2
(15d-PGJ2) and proteasome inhibitor I from Cayman
Chemicals (Ann Arbor, MI), and cycloheximide from Sigma. The
anti-human TLR2 mAb (TL2.1), which recognizes a TLR2-associated
epitope and was generated by immunization of BALB/c mice with Chinese
hamster ovary-TLR2 cells (46), was kindly provided by
Terje Espevik (The Norwegian University of Science and Technology,
Trondheim, Norway). The specificity of this Ab for TLR2 has been
reported elsewhere (48). Phosphorothioate-modified
oligodeoxynucleotides for NF-B p65 sense
(5'-GCCATGGACGAACTGTTCCCC-3') and antisense
(5'-GGGAACAGTTCGTCCATGGC-3') were obtained from Isao Kitajima
(Kagoshima, Japan) (49).
RT-PCR analysis
Total RNA was isolated from resting and LPS-, TNF--, or
IFN--stimulated HMEC and HUVEC using an RNA Stat60 isolation reagent
(Tel-Test, Friendswood, TX) following the manufacturer’s instructions
and treated with RNase-free DNase I. For reverse transcription
reaction, the Moloney murine leukemia virus preamplification system
(Life Technologies, Gaithersburg, MD) was applied. PCR amplification
was performed with Taq polymerase (Perkin-Elmer, Foster
City, CA) for 32 cycles at 95°C for 45 s, 54°C for 45 s,
and 72°C for 1 min (for TLR2 and TLR4), as described earlier
(42). The TLR2 and TLR4 oligonucleotide primers used for
RT-PCR have been described elsewhere (42). GAPDH primers
were obtained from Clontech (Palo Alto, CA). The TLR2 and TLR4 RT-PCR
fragments were purified and sequenced to confirm the identity of the
fragments. Real-time quantitative PCR was done on the iCycler (Bio-Rad,
Hercules, CA) using PE Applied Biosystems (Foster City, CA) SYBR Green
PCR kit and the TLR primers described above. The semiquantitative
RT-PCR experiments were repeated with cells pretreated for 1 h
with 15d-PGJ2 (20 µM), proteasome inhibitor I
(100 µM), or cycloheximide (10 µg/ml). EC were pretreated with
NF-B p65 antisense and sense oligonucleotides (30 µM) for 24–48 h
three times before LPS stimulation (50 ng/ml) as described earlier
(49, 50). For densitometry analysis, the intensity of the
bands were measured by the Kodak Digital Science 1D Program with Kodak
(Rochester, NY) camera DS40-D2120 and normalized with GAPDH
intensity.
Western blot
Conditioned EC or PBMC were lysed for 30 min on ice in a lysis buffer containing 10 mM Tris-HCl (pH 7.8), 50 mM NaF, 1% Triton X-100, 2 mM EDTA, 100 mM NaCl, 1 mM sodium orthovanadate, 0.1 mM quercitin, and 1 µg/ml each of the protease inhibitors pepstatin, leupeptin, aprotinin, antipain, and chymostatin, 30 µg/ml TPCK, and 1 mM PMSF. Following lysis, cell debris was removed by centrifugation (14,000 x g, 4°C, 15 min), and supernatants were collected and stored at -80°C until use. Protein concentrations were determined using the Bio-Rad assay kit. One-hundred-thirty micrograms of total protein was added in Laemmli buffer, boiled for 5 min, resolved by SDS-10% PAGE in Tris/glycine/SDS buffer (25 mM Tris, 250 mM glycine, 0.1% SDS), and blotted onto Immunobilon P transfer membranes (Amersham Pharmacia Biotech) (100 V, 1.5 h, 4°C). After blocking for 2 h in TBST (20 mM Tris-HCl, 150 mM NaCl, 0.1% Tween 20) containing 5% nonfat milk, membranes were washed three times in TBST and probed for 18 h at 4°C with anti-TLR2 mAb TL2.1 (final concentration, 1 µg/ml) in TBST. After washing three times in TBST, membranes were incubated with secondary HRP-conjugated goat anti-mouse IgG (1:2500 dilution; Bio-Rad) and washed five times in TBST, and bands were detected using ECL reagents (Amersham Pharmacia Biotech) according to the manufacturer’s description.
Immunohistochemistry staining
HMEC were cultured on eight-chamber microscope slides. Cells were fixed in 4% paraformaldehyde and without drying were incubated with anti-TLR2 mAb TL2.1 (10 µg/ml) or with mouse IgG and an irrelevant IgG2a control Ab for 1 h. Primary Ab was detected with FITC-conjugated goat anti-mouse antiserum following the instructions from the manufacturer (ABC vector kit) (Vector Laboratories, Burlingame, CA). The cells were counterstained with hematoxylin. Samples were viewed and photographed using a Zeiss (Oberkochen, Germany) Axiophot microscope.
Transfection and NF-B-luciferase assay
HMEC were plated at a concentration of 50,000 cells/well
in 24-well plates and cotransfected the following day with reporter
genes pCMV-
-galactosidase (0.1 µg) and ELAM-NF-B-luciferase
(0.5 µg) using the FuGene 6 Transfection Reagent (Boehringer
Mannheim, Indianapolis, IN) as described earlier (31).
After overnight transfection, HMEC were stimulated for 5 h with 50
ng/ml LPS with and without pretreatment (for 60 min) with the
proteasome inhibitor I or 15d-PGJ2. Cells were
also pretreated with NF-B p65 antisense oligonucleotide (30 µM)
for 24 h three times before LPS stimulation. Cells were lysed in
60 µl of reporter lysis buffer (Promega, Madison, WI), and luciferase
activity was measured with a Promega kit and a luminometer (Promega),
and -galactosidase activity was determined by the calorimetric
method to normalize transfection efficiency as described earlier
(28).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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,
and IFN- on TLR2 mRNA and protein expression in HMEC and HUVEC by
RT-PCR, Western blot analysis, and immunohistochemical staining. HMEC
were stimulated with E. coli LPS (50 ng/ml), TNF- (20
ng/ml), or IFN- (20 ng/ml or 200 IU/ml) for 1, 2, 4, and 5 h,
and semiquantitative and real-time RT-PCR were performed by using human
TLR2 primers as described earlier (42). TLR2 mRNA
expression was significantly up-regulated by LPS, TNF-, and IFN-
in HMEC (Fig. 1
A). LPS-induced
TLR2 mRNA up-regulation was apparent by 30 min (data not shown) and
maximal at 2 h. Similar observations were made from primary HUVEC
stimulated with LPS (Fig. 1B) or IFN- (data not shown).
Real-time quantitative PCR confirmed the results obtained by
semiquantitative RT-PCR (data not shown). To determine whether
LPS-mediated TLR2 mRNA up-regulation in EC was dependent on new protein
synthesis, we preincubated EC with cycloheximide (10 µg/ml) for 60
min before LPS stimulation. Cycloheximide pretreatment inhibited
LPS-induced TLR2 up-regulation, suggesting the need for new protein
synthesis, i.e., that TLR2 is not an immediate early gene or primary
response gene for LPS activation (Fig. 1C). To test whether
LPS stimulation of TLR2 synthesis also requires de novo transcription,
HMEC were preincubated with the transcription inhibitor actinomycin D
before LPS stimulation. Actinomycin D also inhibited LPS-induced
up-regulation of TLR2 mRNA (data not shown), suggesting that LPS-TLR4
activation triggers both transcriptional and translational events in EC
that lead to TLR2 induction. Although our data suggest that the
regulation of TLR2 at the transcriptional level may be important, these
preliminary experiments about the mechanism of TLR2 mRNA up-regulation
do not rule out additional possible mechanisms, including mRNA
stabilization.
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A) and by
immunohistochemistry (Fig. 2B) using an anti-human TLR2
mAb (TL2.1). Unstimulated HMEC exhibited a low expression of TLR2
protein that was markedly up-regulated in response to LPS stimulation
for 4 h (Fig. 2A). Likewise, following 4 h of LPS
(50 ng/ml) stimulation, cellular expression of TLR2 protein was
significantly enhanced on fixed HMEC, whereas unstimulated HMEC showed
very weak TLR2 expression (Fig. 2B). An isotype-matched
control Ab (data not shown) and IgG control stainings were negative.
Vascular EC can be activated by LPS in one of two ways: a direct
pathway where LPS-sCD14 (soluble CD14) complexes directly activate ECs,
and an indirect pathway through various inflammatory mediators induced
by LPS-activated immune cells (i.e., IL-1, TNF-, IFN-)
(reviewed in Ref. 51). Induction and up-regulation of TLR2
in response to inflammatory stimuli such as LPS, TNF-, and IFN-
in vascular endothelium may have important implications in host
defenses against bacterial, mycobacterial, and spirochetal infections
by rendering these cells responsive and more sensitive to microbial
ligands that specifically use TLR2, and may help explain the well-known
synergy between LPS and lipoproteins in the induction of shock
(41). This study provides the basis for further
investigating the functional correlation of TLR2 up-regulation in EC by
various inflammatory mediators. Our observations also suggest that the
induction of TLR2 expression is not limited to TLR4 activation by LPS.
TNF- and IFN- stimulation also result in a similar level of TLR2
up-regulation, suggesting that multiple signaling pathways induced by
various inflammatory mediators converge to induce TLR2 expression.
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) and in primary HUVEC (data not shown).
To investigate whether IFN- also induces TLR4, we incubated HMEC
with IFN-. We show that, in addition to TLR2, IFN- also induces
the up-regulation of TLR4 mRNA in EC (Fig. 3). It is well known that
IFN- enhances both sensitivity and the magnitude of cellular
responses to LPS and causes synergistic activation of cells
(52, 53, 54). In the presence of IFN-, otherwise nontoxic
doses of LPS become highly lethal for mice (55). The
mechanisms of this synergistic toxicity are not well understood. In
addition, the combination of the direct and indirect pathways of
LPS-induced EC activation would provide a much more realistic
representation of the LPS-triggered inflammatory stimuli that the
endothelium is exposed to in the course of response to infection and
might reveal changes that are much more potent. To investigate whether
LPS and IFN- can act synergistically to induce TLR2 expression in
EC, we incubated HMEC with suboptimal concentrations of LPS (1 or 5
ng/ml), IFN- (1 or 5 ng/ml), or various combinations of LPS plus
IFN- and assessed TLR2 mRNA expression by RT-PCR. When used
together, LPS and IFN- acted synergistically to induce significant
up-regulation of TLR2 expression in HMEC at concentrations that were
ineffective when each was used alone (Fig. 4). We postulate that IFN--induced
up-regulation of TLR4 and TLR2 may transform a small amount of LPS or
lipoprotein into a lethal stimulus capable of causing shock. This
mechanism may also enable the host to respond quickly to relatively low
doses of LPS and lipoproteins, thereby enhancing the innate immune
response and antibacterial defenses.
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B and
regulation of several responsive genes (42). To
investigate whether LPS-induced TLR2 up-regulation in EC is dependent
on NF-B activation, we pretreated HMEC with various chemical
inhibitors of the transcription factor NF-B and with sense and
antisense p65 NF-B oligonucleotides and analyzed their effects on
LPS-mediated TLR2 mRNA up-regulation by RT-PCR. We observed that
pretreatment of HMEC with proteasome inhibitor I, an NF-B inhibitor
(56), or with antisense phosphorothioate
oligodeoxynucleotide against p65 NF-B inhibited LPS-induced TLR2
up-regulation (Fig. 5A) and
NF-B-luciferase activity (Fig. 5B), whereas NF-B p65
sense oligonuclotide had no significant effect on the mRNA TLR2. The
housekeeping enzyme, GAPDH, was unaffected in these cells (Fig. 5A). These inhibitors did not result in EC death as measured
by trypan blue uptake. Collectively, these results suggest that
LPS-induced TLR2 mRNA expression in EC is NF-B dependent. Our
findings are consistent with a recent report that mouse TLR2 promoter
contains NF-B binding sites (57). Another study,
investigating the putative 5'-proximal promoter of the human TLR4 gene,
did not find any NF-B binding site, at least in the proximal portion
of this promoter (58). Because LPS-mediated NF-B
activation in EC is sCD14 dependent (42), as expected, the
LPS-induced TLR2 up-regulation in EC was sCD14 dependent as well (data
not shown). Of interest, 15d-PGJ2, a
cyclopentenone PG (cyPG), also inhibited LPS-induced TLR2 up-regulation
(Fig. 5A) and NF-B-luciferase activity (Fig. 5B). It has been suggested that cyPGs exert
anti-inflammatory activity through the activation of peroxisome
proliferator-activated receptor- (PPAR-) (59, 60).
The bioactive cyPG, 15d-PGJ2, which is
physiologically formed by dehydration and isomerization of the
cyclooxygenase metabolite PGD2, can activate
PPAR-, a nuclear receptor that interferes with NF-B
transcriptional activity (59, 60). A recent study
demonstrated a novel mechanism of anti-inflammatory activity of
cyPGs that is PPAR- independent and based on the direct inhibition
and modification of the IB kinase (IKK) subunit of IKKs
(61). Elevated cyPG synthesis has been detected in late
phases of inflammation (59) and is associated with
resolution of inflammation (62). Concentrations of cyPG
that are sufficient to inhibit IKK may occur locally during the late
phase of inflammation, and down-regulation of TLR2 in response to LPS
or cytokines may be part of the resolution of inflammation. Our results
would also suggest that cyPG, and possibly more potent derivatives, may
have therapeutic value in the treatment of sepsis and inflammatory
diseases in which inhibition of NF-B activity may be desirable, and
where LPS-induced TLR2 up-regulation may synergistically augment the
inflammatory responses.
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and IFN-. Our
observations are consistent with and extend the findings of two recent
reports showing that LPS induces TLR2 in mouse adipose cells
(39) and TLR4 mRNA expression in rat coronary EC
(63). In the latter study, the investigators showed that
NF-B is involved in LPS induction of TLR4 mRNA, but found no
accompanying increase in TLR4 protein (63). Although LPS
was found to inhibit the expression of TLR4 mRNA in two earlier studies
using RAW 264 mouse macrophage cell lines (26, 64), a more
recent study reported that LPS and proinflammatory cytokines increase
TLR4 mRNA expression in human monocytes and polymorphonuclear cells
(65). This divergence most likely reflects differences in
cell types and differentiation stages. The observation that EC express
the receptor for LPS and induce the receptor for lipoproteins and
Gram-positive, spirochetal, and fungal cell wall components in response
to LPS suggests that the eventual responsiveness of EC to various TLR2
ligands may be modulated by external stimuli. Furthermore, a recent
study showed that TLR2 can also function as a "death receptor" that
mediates apoptosis in addition to NF-B activation in response to
bacterial lipoproteins (66). Therefore, TLR2 expression
and up-regulation in EC cells by LPS and/or various inflammatory
cytokines may also augment and contribute to endothelial cell apoptosis
in bacterial sepsis and septic shock leading to vascular collapse.
Indeed LPS has been shown to induce disseminated endothelial apoptosis
resulting in endotoxic shock (67). Our data also indicate that EC are involved at the earliest stages of the immune response and are capable of directly sensing the presence of bacterial cell wall components. These observations underline the importance and direct role of the vascular endothelium as an integral component of the innate immune response.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Moshe Arditi, Department of Pediatrics, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 4400, Los Angeles, CA 90048.
3 Abbreviations used in this paper: EC, endothelial cells; HMEC, human dermal microvessel EC; TLR, Toll-like receptor; sCD14, soluble CD14; cyPG, cyclopentenone PG; 15d-PGJ2, 15-deoxy-12, 14-PGJ2; PPAR-, peroxisome proliferator-activated receptor-; IKK, IB kinase.
Received for publication August 30, 2000. Accepted for publication November 3, 2000.
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S. Danese, E. Dejana, and C. Fiocchi Immune Regulation by Microvascular Endothelial Cells: Directing Innate and Adaptive Immunity, Coagulation, and Inflammation J. Immunol., May 15, 2007; 178(10): 6017 - 6022. [Abstract] [Full Text] [PDF]
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 T. Into, Y. Kanno, J.-i. Dohkan, M. Nakashima, M. Inomata, K.-i. Shibata, C. J. Lowenstein, and K. Matsushita Pathogen Recognition by Toll-like Receptor 2 Activates Weibel-Palade Body Exocytosis in Human Aortic Endothelial Cells J. Biol. Chem., March 16, 2007; 282(11): 8134 - 8141. [Abstract] [Full Text] [PDF]
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 N. Satta, S. Dunoyer-Geindre, G. Reber, R. J. Fish, F. Boehlen, E. K. O. Kruithof, and P. de Moerloose The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies Blood, February 15, 2007; 109(4): 1507 - 1514. [Abstract] [Full Text] [PDF]
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S. C. Mullaly and P. Kubes The Role of TLR2 In Vivo following Challenge with Staphylococcus aureus and Prototypic Ligands J. Immunol., December 1, 2006; 177(11): 8154 - 8163. [Abstract] [Full Text] [PDF]
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F.-Y. Lin, Y.-H. Chen, J.-S. Tasi, J.-W. Chen, T.-L. Yang, H.-J. Wang, C.-Y. Li, Y.-L. Chen, and S.-J. Lin Endotoxin Induces Toll-Like Receptor 4 Expression in Vascular Smooth Muscle Cells via NADPH Oxidase Activation and Mitogen-Activated Protein Kinase Signaling Pathways Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2630 - 2637. [Abstract] [Full Text] [PDF]
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J. Heidemann, W. Domschke, T. Kucharzik, and C. Maaser Intestinal microvascular endothelium and innate immunity in inflammatory bowel disease: a second line of defense? Infect. Immun., October 1, 2006; 74(10): 5425 - 5432. [Full Text] [PDF]
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 J. M. Buckley, J. H. Wang, and H. P. Redmond Cellular reprogramming by gram-positive bacterial components: a review J. Leukoc. Biol., October 1, 2006; 80(4): 731 - 741. [Abstract] [Full Text] [PDF]
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M. Strengell, A. Lehtonen, S. Matikainen, and I. Julkunen IL-21 enhances SOCS gene expression and inhibits LPS-induced cytokine production in human monocyte-derived dendritic cells J. Leukoc. Biol., June 1, 2006; 79(6): 1279 - 1285. [Abstract] [Full Text] [PDF]
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 R. Vlahos, S. Bozinovski, J. E. Jones, J. Powell, J. Gras, A. Lilja, M. J. Hansen, R. C. Gualano, L. Irving, and G. P. Anderson Differential protease, innate immunity, and NF-{kappa}B induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L931 - L945. [Abstract] [Full Text] [PDF]
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 R. E. Rumbaut, R. V. Bellera, J. K. Randhawa, C. N. Shrimpton, S. K. Dasgupta, J.-F. Dong, and A. R. Burns Endotoxin enhances microvascular thrombosis in mouse cremaster venules via a TLR4-dependent, neutrophil-independent mechanism Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1671 - H1679. [Abstract] [Full Text] [PDF]
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 K Harada, K Isse, and Y Nakanuma Interferon {gamma} accelerates NF-{kappa}B activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction J. Clin. Pathol., February 1, 2006; 59(2): 184 - 190. [Abstract] [Full Text] [PDF]
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H. Yumoto, H.-H. Chou, Y. Takahashi, M. Davey, F. C. Gibson III, and C. A. Genco Sensitization of Human Aortic Endothelial Cells to Lipopolysaccharide via Regulation of Toll-Like Receptor 4 by Bacterial Fimbria-Dependent Invasion Infect. Immun., December 1, 2005; 73(12): 8050 - 8059. [Abstract] [Full Text] [PDF]
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 M. G. Netea, T. Azam, G. Ferwerda, S. E. Girardin, M. Walsh, J.-S. Park, E. Abraham, J.-M. Kim, D.-Y. Yoon, C. A. Dinarello, et al. IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1{beta} and IL-6 production through a caspase 1-dependent mechanism PNAS, November 8, 2005; 102(45): 16309 - 16314. [Abstract] [Full Text] [PDF]
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V. C. Mehra, V. S. Ramgolam, and J. R. Bender Cytokines and cardiovascular disease J. Leukoc. Biol., October 1, 2005; 78(4): 805 - 818. [Abstract] [Full Text] [PDF]
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G. Vinderola, C. Matar, and G. Perdigon Role of Intestinal Epithelial Cells in Immune Effects Mediated by Gram-Positive Probiotic Bacteria: Involvement of Toll-Like Receptors Clin. Vaccine Immunol., September 1, 2005; 12(9): 1075 - 1084. [Abstract] [Full Text] [PDF]
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X. Yang, D. Coriolan, V. Murthy, K. Schultz, D. T. Golenbock, and D. Beasley Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signaling Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1069 - H1076. [Abstract] [Full Text] [PDF]
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H. Methe, J.-O. Kim, S. Kofler, M. Nabauer, and M. Weis Statins Decrease Toll-Like Receptor 4 Expression and Downstream Signaling in Human CD14+ Monocytes Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1439 - 1445. [Abstract] [Full Text] [PDF]
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Y. Bulut, K. S. Michelsen, L. Hayrapetian, Y. Naiki, R. Spallek, M. Singh, and M. Arditi Mycobacterium Tuberculosis Heat Shock Proteins Use Diverse Toll-like Receptor Pathways to Activate Pro-inflammatory Signals J. Biol. Chem., June 3, 2005; 280(22): 20961 - 20967. [Abstract] [Full Text] [PDF]
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G. K. Hansson and K. Edfeldt Toll To Be Paid at the Gateway to the Vessel Wall Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1085 - 1087. [Full Text] [PDF]
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D. Y. Jung, H. Lee, B.-Y. Jung, J. Ock, M.-S. Lee, W.-H. Lee, and K. Suk TLR4, but Not TLR2, Signals Autoregulatory Apoptosis of Cultured Microglia: A Critical Role of IFN-{beta} as a Decision Maker J. Immunol., May 15, 2005; 174(10): 6467 - 6476. [Abstract] [Full Text] [PDF]
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 S. Chakravarty and M. Herkenham Toll-Like Receptor 4 on Nonhematopoietic Cells Sustains CNS Inflammation during Endotoxemia, Independent of Systemic Cytokines J. Neurosci., February 16, 2005; 25(7): 1788 - 1796. [Abstract] [Full Text] [PDF]
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 M. Carrithers, S. Tandon, S. Canosa, M. Michaud, D. Graesser, and J. A. Madri Enhanced Susceptibility to Endotoxic Shock and Impaired STAT3 Signaling in CD31-Deficient Mice Am. J. Pathol., January 1, 2005; 166(1): 185 - 196. [Abstract] [Full Text] [PDF]
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 T. Homma, A. Kato, N. Hashimoto, J. Batchelor, M. Yoshikawa, S. Imai, H. Wakiguchi, H. Saito, and K. Matsumoto Corticosteroid and Cytokines Synergistically Enhance Toll-Like Receptor 2 Expression in Respiratory Epithelial Cells Am. J. Respir. Cell Mol. Biol., October 1, 2004; 31(4): 463 - 469. [Abstract] [Full Text] [PDF]
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 S. C. Mullaly and P. Kubes Toll Gates and Traffic Arteries: From Endothelial TLR2 to Atherosclerosis Circ. Res., October 1, 2004; 95(7): 657 - 659. [Full Text] [PDF]
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 I. A. Clark, L. M. Alleva, A. C. Mills, and W. B. Cowden Pathogenesis of Malaria and Clinically Similar Conditions Clin. Microbiol. Rev., July 1, 2004; 17(3): 509 - 539. [Abstract] [Full Text] [PDF]
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 H. F. Galley and N. R. Webster Physiology of the endothelium Br. J. Anaesth., July 1, 2004; 93(1): 105 - 113. [Abstract] [Full Text] [PDF]
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 M. A. Hermoso, T. Matsuguchi, K. Smoak, and J. A. Cidlowski Glucocorticoids and Tumor Necrosis Factor Alpha Cooperatively Regulate Toll-Like Receptor 2 Gene Expression Mol. Cell. Biol., June 1, 2004; 24(11): 4743 - 4756. [Abstract] [Full Text] [PDF]
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S.-H. Kim, S. M. Lessner, Y. Sakurai, and Z. S. Galis Cyclophilin A as a Novel Biphasic Mediator of Endothelial Activation and Dysfunction Am. J. Pathol., May 1, 2004; 164(5): 1567 - 1574. [Abstract] [Full Text] [PDF]
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Hongkuan Fan and J. A. Cook Review: Molecular mechanisms of endotoxin tolerance Innate Immunity, April 1, 2004; 10(2): 71 - 84. [Abstract] [PDF]
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M. A. Elovitz, Z. Wang, E. K. Chien, D. F. Rychlik, and M. Phillippe A New Model for Inflammation-Induced Preterm Birth: The Role of Platelet-Activating Factor and Toll-Like Receptor-4 Am. J. Pathol., November 1, 2003; 163(5): 2103 - 2111. [Abstract] [Full Text] [PDF]
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J. Watanabe, Y. Miyazaki, G. A. Zimmerman, K. H. Albertine, and T. M. McIntyre Endotoxin Contamination of Ovalbumin Suppresses Murine Immunologic Responses and Development of Airway Hyper-reactivity J. Biol. Chem., October 24, 2003; 278(43): 42361 - 42368. [Abstract] [Full Text] [PDF]
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S. Hirono, E. Dibrov, C. Hurtado, A. Kostenuk, R. Ducas, and G. N. Pierce Chlamydia pneumoniae Stimulates Proliferation of Vascular Smooth Muscle Cells Through Induction of Endogenous Heat Shock Protein 60 Circ. Res., October 17, 2003; 93(8): 710 - 716. [Abstract] [Full Text] [PDF]
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 K. Peters, R. E. Unger, J. Brunner, and C.J. Kirkpatrick Molecular basis of endothelial dysfunction in sepsis Cardiovasc Res, October 15, 2003; 60(1): 49 - 57. [Abstract] [Full Text] [PDF]
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D. de Kleijn and G. Pasterkamp Toll-like receptors in cardiovascular diseases Cardiovasc Res, October 15, 2003; 60(1): 58 - 67. [Abstract] [Full Text] [PDF]
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M. T. Abreu, L. S. Thomas, E. T. Arnold, K. Lukasek, K. S. Michelsen, and M. Arditi TLR signaling at the intestinal epithelial interface Innate Immunity, October 1, 2003; 9(5): 322 - 330. [Abstract] [PDF]
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W. C. Aird The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome Blood, May 15, 2003; 101(10): 3765 - 3777. [Abstract] [Full Text] [PDF]
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 O. Andres, K. Obojes, K. S. Kim, V. t. Meulen, and J. Schneider-Schaulies CD46- and CD150-independent endothelial cell infection with wild-type measles viruses J. Gen. Virol., May 1, 2003; 84(5): 1189 - 1197. [Abstract] [Full Text] [PDF]
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J. Macdonald, H. F. Galley, and N. R. Webster Oxidative stress and gene expression in sepsis Br. J. Anaesth., February 1, 2003; 90(2): 221 - 232. [Abstract] [Full Text] [PDF]
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G. Melmed, L. S. Thomas, N. Lee, S. Y. Tesfay, K. Lukasek, K. S. Michelsen, Y. Zhou, B. Hu, M. Arditi, and M. T. Abreu Human Intestinal Epithelial Cells Are Broadly Unresponsive to Toll-Like Receptor 2-Dependent Bacterial Ligands: Implications for Host-Microbial Interactions in the Gut J. Immunol., February 1, 2003; 170(3): 1406 - 1415. [Abstract] [Full Text] [PDF]
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A. E. Medvedev, A. Lentschat, L. M. Wahl, D. T. Golenbock, and S. N. Vogel Dysregulation of LPS-Induced Toll-Like Receptor 4-MyD88 Complex Formation and IL-1 Receptor-Associated Kinase 1 Activation in Endotoxin-Tolerant Cells J. Immunol., November 1, 2002; 169(9): 5209 - 5216. [Abstract] [Full Text] [PDF]
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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I. Ishida, H. Kubo, S. Suzuki, T. Suzuki, S. Akashi, K. Inoue, S. Maeda, H. Kikuchi, H. Sasaki, and T. Kondo Hypoxia Diminishes Toll-Like Receptor 4 Expression Through Reactive Oxygen Species Generated by Mitochondria in Endothelial Cells J. Immunol., August 15, 2002; 169(4): 2069 - 2075. [Abstract] [Full Text] [PDF]
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G. Andonegui, S. M. Goyert, and P. Kubes Lipopolysaccharide-Induced Leukocyte-Endothelial Cell Interactions: A Role for CD14 Versus Toll-Like Receptor 4 Within Microvessels J. Immunol., August 15, 2002; 169(4): 2111 - 2119. [Abstract] [Full Text] [PDF]
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 A. UEHARA, S. SUGAWARA, and H. TAKADA Priming of human oral epithelial cells by interferon-{gamma} to secrete cytokines in response to lipopolysaccharides, lipoteichoic acids and peptidoglycans J. Med. Microbiol., August 1, 2002; 51(8): 626 - 634. [Abstract] [Full Text] [PDF]
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M. Adib-Conquy and J.-M. Cavaillon Gamma Interferon and Granulocyte/Monocyte Colony-stimulating Factor Prevent Endotoxin Tolerance in Human Monocytes by Promoting Interleukin-1 Receptor-associated Kinase Expression and Its Association to MyD88 and Not by Modulating TLR4 Expression J. Biol. Chem., July 26, 2002; 277(31): 27927 - 27934. [Abstract] [Full Text] [PDF]
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 S. Kiechl, E. Lorenz, M. Reindl, C. J. Wiedermann, F. Oberhollenzer, E. Bonora, J. Willeit, and D. A. Schwartz Toll-like Receptor 4 Polymorphisms and Atherogenesis N. Engl. J. Med., July 18, 2002; 347(3): 185 - 192. [Abstract] [Full Text] [PDF]
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M. T. Abreu, E. T. Arnold, L. S. Thomas, R. Gonsky, Y. Zhou, B. Hu, and M. Arditi TLR4 and MD-2 Expression Is Regulated by Immune-mediated Signals in Human Intestinal Epithelial Cells J. Biol. Chem., May 31, 2002; 277(23): 20431 - 20437. [Abstract] [Full Text] [PDF]
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T. Shuto, A. Imasato, H. Jono, A. Sakai, H. Xu, T. Watanabe, D. D. Rixter, H. Kai, A. Andalibi, F. Linthicum, et al. Glucocorticoids Synergistically Enhance Nontypeable Haemophilus influenzae-induced Toll-like Receptor 2 Expression via a Negative Cross-talk with p38 MAP Kinase J. Biol. Chem., May 3, 2002; 277(19): 17263 - 17270. [Abstract] [Full Text] [PDF]
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 K. Edfeldt, J. Swedenborg, G. K. Hansson, and Z.-q. Yan Expression of Toll-Like Receptors in Human Atherosclerotic Lesions: A Possible Pathway for Plaque Activation Circulation, March 12, 2002; 105(10): 1158 - 1161. [Abstract] [Full Text] [PDF]
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G. Hajishengallis, M. Martin, H. T. Sojar, A. Sharma, R. E. Schifferle, E. DeNardin, M. W. Russell, and R. J. Genco Dependence of Bacterial Protein Adhesins on Toll-Like Receptors for Proinflammatory Cytokine Induction Clin. Vaccine Immunol., March 1, 2002; 9(2): 403 - 411. [Abstract] [Full Text] [PDF]
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P. Massari, P. Henneke, Y. Ho, E. Latz, D. T. Golenbock, and L. M. Wetzler Cutting Edge: Immune Stimulation by Neisserial Porins Is Toll-Like Receptor 2 and MyD88 Dependent J. Immunol., February 15, 2002; 168(4): 1533 - 1537. [Abstract] [Full Text] [PDF]
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Y. Bulut, E. Faure, L. Thomas, H. Karahashi, K. S. Michelsen, O. Equils, S. G. Morrison, R. P. Morrison, and M. Arditi Chlamydial Heat Shock Protein 60 Activates Macrophages and Endothelial Cells Through Toll-Like Receptor 4 and MD2 in a MyD88-Dependent Pathway J. Immunol., February 1, 2002; 168(3): 1435 - 1440. [Abstract] [Full Text] [PDF]
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K. A. Zarember and P. J. Godowski Tissue Expression of Human Toll-Like Receptors and Differential Regulation of Toll-Like Receptor mRNAs in Leukocytes in Response to Microbes, Their Products, and Cytokines J. Immunol., January 15, 2002; 168(2): 554 - 561. [Abstract] [Full Text] [PDF]
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 C. Li, Y. Wang, L. Gao, J. Zhang, J. Shao, S. Wang, W. Feng, X. Wang, M. Li, and Z. Chang Expression of Toll-like Receptors 2 and 4 and CD14 during Differentiation of HL-60 Cells Induced by Phorbol 12-Myristate 13-Acetate and 1{alpha}, 25-Dihydroxy-Vitamin D3 Cell Growth Differ., January 1, 2002; 13(1): 27 - 38. [Abstract] [Full Text] [PDF]
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X. H. Xu, P. K. Shah, E. Faure, O. Equils, L. Thomas, M. C. Fishbein, D. Luthringer, X.-P. Xu, T. B. Rajavashisth, J. Yano, et al. Toll-Like Receptor-4 Is Expressed by Macrophages in Murine and Human Lipid-Rich Atherosclerotic Plaques and Upregulated by Oxidized LDL Circulation, December 18, 2001; 104(25): 3103 - 3108. [Abstract] [Full Text] [PDF]
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S. Sugawara, A. Uehara, T. Nochi, T. Yamaguchi, H. Ueda, A. Sugiyama, K. Hanzawa, K. Kumagai, H. Okamura, and H. Takada Neutrophil Proteinase 3-Mediated Induction of Bioactive IL-18 Secretion by Human Oral Epithelial Cells J. Immunol., December 1, 2001; 167(11): 6568 - 6575. [Abstract] [Full Text] [PDF]
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S. T. Smiley, J. A. King, and W. W. Hancock Fibrinogen Stimulates Macrophage Chemokine Secretion Through Toll-Like Receptor 4 J. Immunol., September 1, 2001; 167(5): 2887 - 2894. [Abstract] [Full Text] [PDF]
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Y. Bulut, E. Faure, L. Thomas, O. Equils, and M. Arditi Cooperation of Toll-Like Receptor 2 and 6 for Cellular Activation by Soluble Tuberculosis Factor and Borrelia burgdorferi Outer Surface Protein A Lipoprotein: Role of Toll-Interacting Protein and IL-1 Receptor Signaling Molecules in Toll-Like Receptor 2 Signaling J. Immunol., July 15, 2001; 167(2): 987 - 994. [Abstract] [Full Text] [PDF]
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