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Divisions of
*
Pediatric Critical Care and
Pediatric Infectious Diseases, Steven Spielberg Pediatric Research Center Cedars-Sinai Medical Center, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90048; and
Department of Microbiology, Montana State University, Bozeman, MT 59717
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B activation contribute fundamentally
to atherogenesis and plaque disruption. Accumulating evidence has
implicated specific infectious agents including
Chlamydia pneumoniae in the progression
of atherogenesis. Chlamydial heat shock protein 60 (cHSP60) has been
implicated in the induction of deleterious immune responses in human
chlamydial infections and has been found to colocalize with
infiltrating macrophages in atheroma lesions. cHSP60 might stimulate,
enhance, and maintain innate immune and inflammatory responses and
contribute to atherogenesis. In this study, we investigated the
signaling mechanism of cHSP60. Recombinant cHSP60 rapidly activated
NF-B in human microvascular endothelial cells (EC) and in mouse
macrophages, and induced human IL-8 promoter activity in EC. The
inflammatory effect of cHSP60 was heat labile, thus excluding a role of
contaminating LPS, and was blocked by specific anti-chlamydial
HSP60 mAb. In human vascular EC which express Toll-like receptor 4
(TLR4) mRNA and protein, nonsignaling TLR4 constructs that act as
dominant negative blocked cHSP60-mediated NF-B activation.
Furthermore, an anti-TLR4 Ab abolished cHSP60-induced cellular
activation, whereas a control Ab had no effect. In 293 cells,
cHSP60-mediated NF-B activation required both TLR4 and MD2. A
dominant-negative MyD88 construct also inhibited cHSP60-induced NF-B
activation. Collectively, our results indicate that cHSP60 is a potent
inducer of vascular EC and macrophage inflammatory responses, which are
very relevant to atherogenesis. The inflammatory effects are mediated
through the innate immune receptor complex TLR4-MD2 and proceeds via
the MyD88-dependent signaling pathway. These findings may help
elucidate the mechanisms by which chronic asymptomatic chlamydial
infection contribute to atherogenesis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Heat shock protein 60 (HSP60),3 bacterial LPSs, and molecular mimicry have all been suggested as potential mediators linking infection to atherosclerosis (19, 20). Oxidation of low-density lipoprotein (LDL) into an atherogenic lipoprotein and production of foam cells from macrophages and smooth muscle cells are two key events in the initiation and development of atherosclerotic lesions. Recent studies have demonstrated that specific chlamydial molecules, such as chlamydial LPS and chlamydial HSP60 (cHSP60) can induce these activities. The component of C. pneumoniae that induces macrophage foam cell formation is chlamydial LPS and the component that induces oxidative modification of LDL is cHSP60 (21, 22). cHSP60 has been implicated in the induction of deleterious immune responses in human chlamydial infections and has been found to colocalize with infiltrating macrophages in the atheroma lesions (23). Collectively, these data support a potential role of C. pneumoniae as a cofactor in the development and progression of atherosclerosis. However, available data also underscore the current lack of a complete understanding of the molecular mechanisms that link C. pneumoniae infection to the activation of the innate immune system, which triggers the signals for enhanced inflammation and atherogenesis.
HSPs, a ubiquitous family of highly conserved proteins, function to stabilize cellular proteins during a variety of conditions such as heat shock, infection, and inflammation (24, 25). Atheromatous vessels contain both endogenous (human) HSP60 and cHSP60 (23). cHSP60 is abundantly produced during chronic chlamydial infection of the blood vessel, and might stimulate and enhance innate immune and inflammatory responses and contribute to atherogenesis (23). cHSP60 induces cytokine production by macrophages (23), and a recent study demonstrated that cHSP60 is the chlamydial Ag responsible for inducing the inflammatory responses by this microorganism (26). How cHSP60 interacts with host cells to transduce activating signals has only recently been investigated and is not completely delineated. Kol et al. (27) demonstrated that human HSP60 activates human PBMCs and monocyte-derived macrophages through CD14 signaling and p38 mitogen-activated protein kinase, sharing this pathway with LPS (27). Human HSP60 has been identified as an endogenous ligand for Toll-like receptor (TLR) 4 (27, 28). However Vabulas et al. (29) suggested that endogenous and cHSP60 are recognized by both TLR2 and TLR4. To better understand how cHSP60 activates cells of the immune system, including vascular endothelial cells and macrophages, we investigated the interaction of recombinant cHSP60 with human dermal microvessel endothelial cells (HMEC) and mouse macrophages. The results suggest that TLR4 but not TLR2 is the signaling receptor for recombinant chlamydial HSP60.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immortalized HMEC (generous gift from Dr. F. J. Candal of the 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. Tissue culture reagents were purchased from Life Technologies (Rockville, MD). Mouse macrophage cell line, RAW 264.7 cells, and HEK 293 cell line cells were obtained from American Type Culture Collection (Manassas, VA) and were cultured in DMEM medium supplemented with 10% heat-inactivated FBS, 2 mM glutamine, and 100 µg/ml penicillin and streptomycin in 24-well plates as previously described (30, 31, 32, 33).
Chlamydial HSP60 and other reagents
Recombinant chlamydial HSP60 protein was isolated and purified as described earlier (34). Chlamydia trachomatis serovar A HSP60, fused with eight additional amino acids (arginine, serine, and six histidine residues) at the carboxyl terminus, was expressed in Escherichia coli, and recombinant protein was purified by affinity chromatography with Ni-NTA resin, as previously described (34). The endotoxin concentration of this preparation was <0.04 EU/µg, as determined by Limulus amebocyte lysate assay (Associates of Cape Cod, Falmouth, MA). Anti-chlamydial HSP60 mAbs (mAb A57-B9) (IgG1) were obtained from mice immunized with purified recombinant C. trachomatis serovar A HSP60, as described and characterized previously (35). Neutralizing anti-human TLR2 mAb was provided by T. Espevik (Trondheim, Norway) and neutralizing anti-human TLR4 mAb was provided by Kensuke Miyake (Saga Medical School, Nabeshima, Saga, Japan) as described earlier (31, 32, 33). Highly purified, phenol-water extracted, and protein-free (<0.0008% protein) E. coli K235 LPS was obtained from S. Vogel (Uniformed Services University, Bethesda, MD). The purity of this LPS preparation has been previously demonstrated (36, 37), and this preparation of LPS is active on TLR4-transfected HEK 293 cells and not on TLR2 transfectants (S. N. Vogel, unpublished observation). Purified Rhodobacter sphaeroides lipid A (RsDPLA) was obtained from N. Qureshi (University of Missouri, Kansas City, MO).
cDNA constructs and transient transfection
ELAM-NF-B luciferase, human IL-8 promoter luciferase,
pCMV-
-galactosidase, and dominant negative MyD88 vectors were used
as described previously (30, 31, 32, 33). Dominant-negative TLR2
constructs were obtained from C. J. Kirschning (Technical
University of Munich, Munich, Germany), the C3H/HeJ TLR4 cDNA was
obtained from B. Beutler (The Scripps Institute, La Jolla, CA), and
were described earlier (30, 31, 32, 33). C3H/HeJ mice express
dominant-negative TLR4 encoding a single missense mutation,
which converts a cytoplasmic proline residue to histidine (P712H) (38).
A FLAG-tagged mutant of the human TLR4 construct with a deletion
in the intracellular domain (TLR4 Dicd) with COOH-terminal truncation
was obtained from Tularik (San Francisco, CA) as described earlier
(30, 31). A FLAG-tagged human MD2 cDNA construct was
obtained from K. Miyake (Saga Medical Schhol, Saga, Japan). All
constructs were verified by sequencing. Transient transfection of
cultured cells was conducted by FuGene 6 Transfection reagent (Roche
Molecular Laboratories, Burlington, NC ) as described earlier
(31). All reagents were verified to be LPS free by the
Limulus amebocyte lysate assay (Pyrotell, < 0.03 endotoxin
units/ml; Associates of Cape Cod).
NF-B and IL-8 promoter luciferase activation in HMEC and RAW
264.7
HMEC and/or RAW 264.7 were plated in 24-well plates and
cotransfected the following day with FuGene 6 Transfection reagent
(Roche Molecular Laboratories) following the manufacturer’s
instructions. Reporter genes pCMV-gal (0.1 µg) and
ELAM-NF-B (0.5 µg), and pCMV empty vector (0.5 µg) or C3H/HeJ
TLR4 (0.5 µg), an intracellular deletion mutant of TLR4 TLR4 Dicd
(0.5 µg), dominant-negative TLR2 (0.5 µg), or dominant-negative
MyD88 
MyD88 (0.1 µg) were cotransfected as described earlier
(30, 31, 32, 33). Total amount of DNA transfected to each cell was
kept constant with pCMV empty vector. After overnight transfection,
cells were stimulated for 5 h with LPS (20 ng/ml) or cHSP60 (10
µg/ml). Following a 5-h incubation, cells were washed once in PBS and
lysed, and luciferase activity was measured with a Promega kit
(Promega, Madison, WI) and a luminometer as described earlier
(30). -Galactosidase activity was determined using the
colorimetric method to normalize transfection efficiency as described
previously (30). Data shown are the mean and the SD of
three independent experiments and are expressed as percent luciferase
activity induced by LPS or cHSP60 (indicated as 100%).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B and IL-8 promoter luciferase
activities in HMEC and macrophages in a dose-dependent manner
Activation of NF-B is essential for the regulation of a variety
of genes involved in the inflammatory and proliferative responses of
cells critical to atherogenesis (39, 40). Both NF-B and
genes regulated by NF-B are expressed in atherosclerotic lesions
(40). Accumulating evidence indicates that chronic
infection with C. pneumoniae may be an additional risk
factor for atherosclerosis. Therefore, we investigated whether cHSP60
stimulated NF-B activation in endothelial cells and macrophages and
whether TLR4 was involved in this process. HMEC and RAW 264.7 cells
were transiently transfected with a NF-B-dependent ELAM promoter
reporter or human IL-8 promoter luciferase construct. Transfected cells
were stimulated with increasing concentrations of cHSP60 or LPS for
5 h. Cells were then lysed and assayed for luciferase and
-galactosidase activities as described in Materials and
Methods. Recombinant cHSP60 induced a dose-dependent
transactivation of NF-B in HMEC (Fig. 1
A) and RAW 264.7 (Fig. 1B). Chlamydial HSP60 also induced the activation of human
IL-8 promoter luciferase activity in HMEC in a dose-dependent manner
(Fig. 2). These experiments indicated
that recombinant cHSP60 was able to induce NF-B and IL-8 promoter
transactivation in vascular endothelium and in macrophages, which is
indicative of a robust inflammatory response.
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B by cHSP60 in HMEC is TLR4 and MyD88 dependent
Recent studies have documented the role of the innate immune
system and transmembrane TLRs in cellular activation by microbial
pathogens (41, 42, 43, 44, 45). We (30, 31) and others
(46, 47) have shown that LPS signals via TLR4 in HMEC and
macrophages and that activation of NF-B is MyD88 dependent. However,
a MyD88-independent pathway of TLR4 activation has been described as
well (48, 49). Although endogenous (human) HSP60 has been
reported to signal through TLR4 (27, 28, 29) as well as TLR2
(29), the signaling pathway stimulated by cHSP60 has not
been fully delineated. A recent study suggested that cHSP60 signals via
both TLR4 and TLR2, while another study showed that cHSP60 induces
human vascular smooth muscle cell proliferation via TLR4
(50). To investigate the potential involvement of TLR4 and
MyD88 signaling in cHSP60-induced inflammatory responses, we
transiently transfected HMEC with nonsignaling, dominant-negative TLR4
constructs, such as C3H/HeJ TLR4 or intracellular deletion mutant of
human TLR4 (TLR4 Dicd), and tested their response to cHSP60 and
to LPS by monitoring expression of the luciferase activity driven by
the NF-B-responsive enhancer of the ELAM gene as described earlier
(30). As shown in Fig. 3A, coexpression of C3H/HeJ
TLR4 construct blocked cHSP60- as well as LPS-induced NF-B
activation in HMEC. Similarly, overexpression of an intracellular
deletion mutant of TLR4 (TLR4 Dicd) with COOH-terminal truncation led
to a significant inhibition of cHSP60-mediated NF-B activation in
HMEC (Fig. 3A). Coexpression of C3H/HeN TLR4 or a
dominant-negative mutant of TLR2 had no effect on LPS- and
cHSP60-mediated NF-B activation (data not shown). A
dominant-negative mutant of MyD88 (MyD88), which abrogates IL-1- and
LPS-induced NF-B activation, significantly inhibited cHSP60-induced
NF-B activation as well (Fig. 3A). To further confirm the
role of TLR4 in cHSP60-induced NF-B activation in endothelial cells,
we preincubated HMEC with function blocking mAbs against TLR2 or TLR4
and measured cHSP60-mediated cellular activation. The anti-TLR4 mAb
significantly blocked LPS- and cHSP60-induced NF-B activation (Fig. 3B), whereas an isotype-matched control Ab (data not shown)
and the anti-TLR2 Ab were ineffective (Fig. 3B). Taken
together, these results support the hypothesis that TLR4 is essential
for cHSP60 signaling and that the cHSP60-TLR4 signaling to NF-B
proceeds through MyD88.
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B activation at
the TLR4 level, but is unable to block TLR2 signaling by TLR2 ligands
(31). Therefore, we next investigated whether RsDPLA is
able to block cHSP60-induced signaling in HMEC. Pretreatment of HMEC
with RsDPLA (1 µg/ml) for 60 min significantly inhibited
cHSP60-induced NF-B activation (Fig. 3
B). These
observations further support the observation that TLR4 is the signaling
receptor for cHSP60 as well as LPS.
Activation of NF-B by cHSP60/TLR4 is MD2 dependent
To respond efficiently to LPS, TLR4 requires an accessory protein,
MD2 (51). MD2 is a 20- to 30-kDa glycoprotein, which binds
to the extracellular domain of TLR4 (51). Photoaffinity
labeling studies have recently shown that LPS binds directly to the
TLR4-MD2 complex and that both molecules are in close proximity to the
bound LPS (52). Although both LPS and Taxol have been
shown to require MD2 to signal through TLR4, is it unknown whether
cHSP60-TLR4 interaction requires the presence of MD2 as well for
signaling. To investigate the requirement of MD2 in cHSP60-TLR4
signaling, NF-B reporter gene- and TLR4-transfected 293 cells were
stimulated either with increasing concentrations of cHSP60 or with LPS
in the presence and absence of MD2 cotransfection. Fig. 4 shows that neither LPS nor cHSP60 is
able to signal in the absence of MD2 and that both molecules require
the presence of TLR4 as well as MD2 to activate NF-B. cHSP60 induced
a dose-dependent increase in NF-B activation in 293 cells
transfected with TLR4 and MD2 (Fig. 4). We conclude that MD2 is not
specific for LPS-TLR4 signaling and is also required for another TLR4
ligand, i.e., cHSP60 signaling as well.
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B activation is not due to endotoxin
contamination
In this study, we used recombinant cHSP60. The concentration of
LPS measured in the undiluted recombinant protein was <0.06 ng/ml,
which corresponds to <0.0012 ng/ml LPS in 10 µg of protein used in
each well, a concentration well below what is needed for cellular
activation. To further exclude the possibility of endotoxin
contamination in the cHSP60-mediated responses that we observed, cHSP60
and E. coli LPS preparations were heat treated (100°C, 20
min) before incubation with cells. Heat treatment abolished the ability
of cHSP60 to induce NF-B activation, but did not affect the
activation of NF-B by LPS (Fig. 5),
further suggesting that the observed activity of the recombinant cHSP60
was not due to endotoxin contamination. Furthermore, preincubation of
cells with a specific mAb raised against cHSP60 (A57-B9, 50 µg/ml)
significantly blocked cHSP60-induced NF-B activation, whereas mouse
IgG1 control (Fig. 4) and an isotype-matched (mouse IgG1) irrelevant
control Ab did not block LPS signaling (data not shown). Also,
anti-cHSP60 mAb did not inhibit LPS-induced cellular activation
(data not shown). Together, these observations suggest that
cHSP60-mediated NF-B activation through TLR4 was not due to
endotoxin contamination of this recombinant protein and that the
responses observed were specific to cHSP60.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HSPs or chaperonins are generally considered to act intracellularly to
preserve cellular protein stability in response to conditions such as
heat shock, nutrient deprivation, infections, and inflammatory
reactions (24, 25). The ability of cHSP60 or human HSP60
to activate human vascular cells and to trigger NF-B activation
suggests a novel amplification loop in vascular inflammation. Chronic,
persistent C. pneumoniae infection could provoke the
expression of cHSP60 in the vessel wall. This protein could then
amplify the ongoing inflammatory process through its actions on human
vascular cells.
How cHSP60 interacts with host cells, including vascular endothelial
cells, to transduce activating signals is not completely understood.
Recent evidence supports the hypothesis that cHSP60 activates the
innate immune system via TLRs, the sensors of innate immunity. TLRs are
transmembrane proteins with an extracellular domain consisting of
leucine-rich repeats involved in recognition of microbial components.
To date, at least 10 TLRs have been identified in humans, but only a
few of their ligands have been identified (41, 42, 43, 44, 45).
Because of its potential role in the pathogenesis of atherosclerosis,
several laboratories have begun to investigate the interaction of
cHSP60 with cell surface receptors. Ohashai et al. (28)
reported that human HSP60 stimulates TNF-
and NO production in mouse
macrophages, whereas macrophages derived from C3H/HeJ mice that express
a nonfunctional form of TLR4 were unresponsive to HSP60, supporting a
role of TLR4 in human HSP60-induced cell activation (28).
Also, CD14-dependent signaling by human HSP60 has been reported in U373
cells, an astrocytoma cell line that expresses TLR4 but not TLR2
(27). However, Vabulas et al. (29) reported
that endogenous and cHSP60 are recognized by both TLR2 and TLR4. More
recently, Sasu et al. (50) reported that C.
pneumoniae elementary bodies and cHSP60 stimulate vascular smooth
muscle cell proliferation in vitro. Proliferation in that system is
attenuated by a TLR4 antagonist, suggesting TLR4-dependent signaling
(50). In another recent study, C.
pneumoniae was shown to be taken up by bone marrow-derived
murine dendritic cells and the recognition of the organism by these
cells depends largely on TLR2 and only to a minor extent on TLR4
(55).
To better understand how cHSP60 activates cells of the immune system,
including endothelial cells (EC) and macrophages, we used EC and
macrophage cell lines and various nonsignaling TLR constructs to
identify potential receptors and signaling pathways stimulated by
cHSP60. We demonstrated that TLR4 but not the TLR2 is the signaling
receptor for recombinant cHSP60. cHSP60 induced NF-B and human IL-8
promoter activity in both HMEC and macrophages in a dose-dependent
manner. We have previously shown that HMEC respond to LPS through TLR4,
but do not express TLR2 and are unresponsive to known TLR2 ligands
(31, 33). cHSP60 induced a strong response in HMEC, thus
excluding the role of TLR2 in this response. Overexpression of
nonsignaling TLR4 constructs and anti-TLR4 mAb blocked cHSP60- as
well as LPS-induced NF-B activation, whereas the dominant-negative
TLR2 construct and anti-TLR2 mAb had no effect. These findings
suggest that cHSP60 activates HMEC and macrophages through TLR4 and not
TLR2. The biological effect of the recombinant cHSP60 was not due to
endotoxin contamination, as the concentration of LPS in the recombinant
cHSP60 preparation used was below the level needed for cellular
activation, and heat treatment abolished the ability of cHSP60 but not
of LPS to induce NF-B activation. Furthermore, a mAb against cHSP60
significantly blocked cHSP60-mediated NF-B activation, while an
isotype-matched control Ab had no effect. Taken together, these
observations suggest that the biological effects that we observed were
specific to cHSP60.
Our results are consistent with the recent studies, which suggest that recombinant human HSP60 signals through TLR4 (27, 28), and with a more recent study by Sasu et al. (50) showing that cHSP60-mediated signaling proceeds via TLR4 as well. Our data differ from those reported by Vabulas et al. (29), who described that TLR2-transfected 293T cells are responsive to cHSP60. The purity of the cHSP60 protein used by these investigators was not noted, and therefore the response of TLR2-transfected 293T cells to cHSP60 in their study may have been due to contamination of HSP60 with lipoproteins which utilize the TLR2 pathway. Indeed, earlier studies with the TLR2 overexpression system in 293 cells found that TLR2 could transduce enteric LPS signaling (56). However, follow-up studies determined that the TLR2 signaling was triggered by contaminating lipoproteins in the commercial LPS preparations, while protein-free enteric LPS signals through TLR4 (57). We have used recombinant cHSP60 as opposed to purified protein from Chlamydia and observed that this protein signals via TLR4 and not through TLR2.
Recent studies have established MyD88-dependent and MyD88-independent
pathways for TLR4 signaling (48, 49). Although both
pathways induce NF-B activation, only the MyD88-dependent activation
pathway of NF-B leads to cytokine production. The MyD88-independent
activation pathway is linked to dendritic cell maturation (48, 58). Our data indicate that overexpression of a
dominant-negative mutant of MyD88 (MyD88), which inhibits both LPS-
and IL-1-induced NF-B activation, inhibits cHSP60-induced NF-B
activation. Our data further extend our current understanding of
cHSP60-mediated signaling by demonstrating that this pathway is MyD88
dependent.
We recently demonstrated that TLR4 is preferentially expressed by infiltrating macrophages in murine and human lipid-rich atherosclerotic lesions where it may play a role to enhance and sustain the innate immune and inflammatory responses (59). Given that TLR4 plays a critical role in inflammatory signaling, and that chlamydial Ags such as cHSP60 signals through TLR4, TLR4 may represent a biochemical link between chronic infection and atherosclerosis. In this context, ultimately, understanding how cHSP60 interacts with host cells to transduce signals and promote atherogenic events such as LDL oxidation may elucidate how C. pneumoniae contributes to the pathogenesis of atherosclerosis.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Moshe Arditi, Department of Pediatrics, Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 4220, Los Angeles, CA 90048. E-mail address: moshe.arditi{at}cshs.org
3 Abbreviations used in this paper: HSP, heat shock protein; LDL, low-density lipoprotein; TLR, Toll-like receptor; cLPS, chlamydial HSP; cHSP60, chalmydial HSP60; HMEC, human dermal microvessel endothelial cell; RsDPLA, Rhodobacter sphaeroides lipid A; EC, endothelial cells.
Received for publication October 3, 2001. Accepted for publication December 5, 2001.
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S.-J. Jiang, C.-C. Kuo, M. W. Berry, A. W. Lee, and L. A. Campbell Identification and Characterization of Chlamydia pneumoniae-Specific Proteins That Activate Tumor Necrosis Factor Alpha Production in RAW 264.7 Murine Macrophages Infect. Immun., April 1, 2008; 76(4): 1558 - 1564. [Abstract] [Full Text] [PDF]
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 J. R. Caso, J. M. Pradillo, O. Hurtado, J. C. Leza, M. A. Moro, and I. Lizasoain Toll-Like Receptor 4 Is Involved in Subacute Stress-Induced Neuroinflammation and in the Worsening of Experimental Stroke Stroke, April 1, 2008; 39(4): 1314 - 1320. [Abstract] [Full Text] [PDF]
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S. Bas, L. Neff, M. Vuillet, U. Spenato, T. Seya, M. Matsumoto, and C. Gabay The Proinflammatory Cytokine Response to Chlamydia trachomatis Elementary Bodies in Human Macrophages Is Partly Mediated by a Lipoprotein, the Macrophage Infectivity Potentiator, through TLR2/TLR1/TLR6 and CD14 J. Immunol., January 15, 2008; 180(2): 1158 - 1168. [Abstract] [Full Text] [PDF]
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R. W. LaRue, B. D. Dill, D. K. Giles, J. D. Whittimore, and J. E. Raulston Chlamydial Hsp60-2 Is Iron Responsive in Chlamydia trachomatis Serovar E-Infected Human Endometrial Epithelial Cells In Vitro Infect. Immun., May 1, 2007; 75(5): 2374 - 2380. [Abstract] [Full Text] [PDF]
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 A. Shamaei-Tousi, J. P. Halcox, and B. Henderson Stressing the obvious? Cell stress and cell stress proteins in cardiovascular disease Cardiovasc Res, April 1, 2007; 74(1): 19 - 28. [Abstract] [Full Text] [PDF]
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 J. R. Caso, J. M. Pradillo, O. Hurtado, P. Lorenzo, M. A. Moro, and I. Lizasoain Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke Circulation, March 27, 2007; 115(12): 1599 - 1608. [Abstract] [Full Text] [PDF]
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J. Y. H. Chan, H.-L. Cheng, J. L. J. Chou, F. C. H. Li, K.-Y. Dai, S. H. H. Chan, and A. Y. W. Chang Heat Shock Protein 60 or 70 Activates Nitric-oxide Synthase (NOS) I- and Inhibits NOS II-associated Signaling and Depresses the Mitochondrial Apoptotic Cascade during Brain Stem Death J. Biol. Chem., February 16, 2007; 282(7): 4585 - 4600. [Abstract] [Full Text] [PDF]
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 M.-F. Tsan and Baochong Gao Review: Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors Innate Immunity, February 1, 2007; 13(1): 6 - 14. [Abstract] [PDF]
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 Y. Zhao, K. Yokota, K. Ayada, Y. Yamamoto, T. Okada, L. Shen, and K. Oguma Helicobacter pylori heat-shock protein 60 induces interleukin-8 via a Toll-like receptor (TLR)2 and mitogen-activated protein (MAP) kinase pathway in human monocytes J. Med. Microbiol., February 1, 2007; 56(2): 154 - 164. [Abstract] [Full Text] [PDF]
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 G. Nussbaum, A. Zanin-Zhorov, F. Quintana, O. Lider, and I. R. Cohen Peptide p277 of HSP60 signals T cells: inhibition of inflammatory chemotaxis Int. Immunol., October 1, 2006; 18(10): 1413 - 1419. [Abstract] [Full Text] [PDF]
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K. Miyake Invited review: Roles for accessory molecules in microbial recognition by Toll-like receptors Innate Immunity, August 1, 2006; 12(4): 195 - 204. [Abstract] [PDF]
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O. Equils, D. Lu, M. Gatter, S. S. Witkin, C. Bertolotto, M. Arditi, J. A. McGregor, C. F. Simmons, and C. J. Hobel Chlamydia Heat Shock Protein 60 Induces Trophoblast Apoptosis through TLR4 J. Immunol., July 15, 2006; 177(2): 1257 - 1263. [Abstract] [Full Text] [PDF]
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P. Rallabhandi, J. Bell, M. S. Boukhvalova, A. Medvedev, E. Lorenz, M. Arditi, V. G. Hemming, J. C. G. Blanco, D. M. Segal, and S. N. Vogel Analysis of TLR4 Polymorphic Variants: New Insights into TLR4/MD-2/CD14 Stoichiometry, Structure, and Signaling J. Immunol., July 1, 2006; 177(1): 322 - 332. [Abstract] [Full Text] [PDF]
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 M. Krull, P. Bockstaller, F. N. Wuppermann, A. C. Klucken, J. Muhling, B. Schmeck, J. Seybold, C. Walter, M. Maass, S. Rosseau, et al. Mechanisms of Chlamydophila pneumoniae-Mediated GM-CSF Release in Human Bronchial Epithelial Cells Am. J. Respir. Cell Mol. Biol., March 1, 2006; 34(3): 375 - 382. [Abstract] [Full Text] [PDF]
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S. N. Vogel, A. A. Awomoyi, P. Rallabhandi, and A. E. Medvedev Mutations in TLR4 signaling that lead to increased susceptibility to infection in humans: an overview Innate Immunity, December 1, 2005; 11(6): 333 - 339. [Abstract] [PDF]
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 X. Yang, D. Coriolan, K. Schultz, D. T. Golenbock, and D. Beasley Toll-Like Receptor 2 Mediates Persistent Chemokine Release by Chlamydia pneumoniae-Infected Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2308 - 2314. [Abstract] [Full Text] [PDF]
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F. J. Quintana and I. R. Cohen Heat Shock Proteins as Endogenous Adjuvants in Sterile and Septic Inflammation J. Immunol., September 1, 2005; 175(5): 2777 - 2782. [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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G. Foteinos, A. R. Afzal, K. Mandal, M. Jahangiri, and Q. Xu Anti-Heat Shock Protein 60 Autoantibodies Induce Atherosclerosis in Apolipoprotein E-Deficient Mice via Endothelial Damage Circulation, August 23, 2005; 112(8): 1206 - 1213. [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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A. A. R. Tobian, C. V. Harding, and D. H. Canaday Mycobacterium tuberculosis Heat Shock Fusion Protein Enhances Class I MHC Cross-Processing and -Presentation by B Lymphocytes J. Immunol., May 1, 2005; 174(9): 5209 - 5214. [Abstract] [Full Text] [PDF]
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A. R. Weatherill, J. Y. Lee, L. Zhao, D. G. Lemay, H. S. Youn, and D. H. Hwang Saturated and Polyunsaturated Fatty Acids Reciprocally Modulate Dendritic Cell Functions Mediated through TLR4 J. Immunol., May 1, 2005; 174(9): 5390 - 5397. [Abstract] [Full Text] [PDF]
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 G. Pfister, C. M. Stroh, H. Perschinka, M. Kind, M. Knoflach, P. Hinterdorfer, and G. Wick Detection of HSP60 on the membrane surface of stressed human endothelial cells by atomic force and confocal microscopy J. Cell Sci., April 15, 2005; 118(8): 1587 - 1594. [Abstract] [Full Text] [PDF]
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A. Lentschat, H. Karahashi, K. S. Michelsen, L. S. Thomas, W. Zhang, S. N. Vogel, and M. Arditi Mastoparan, a G Protein Agonist Peptide, Differentially Modulates TLR4- and TLR2-Mediated Signaling in Human Endothelial Cells and Murine Macrophages J. Immunol., April 1, 2005; 174(7): 4252 - 4261. [Abstract] [Full Text] [PDF]
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S.-N. Lin, K. Ayada, Y. Zhao, K. Yokota, R. Takenaka, H. Okada, R. Kan, S. Hayashi, M. Mizuno, Y. Hirai, et al. Helicobacter pylori heat-shock protein 60 induces production of the pro-inflammatory cytokine IL8 in monocytic cells J. Med. Microbiol., March 1, 2005; 54(3): 225 - 233. [Abstract] [Full Text] [PDF]
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B. Opitz, S. Forster, A. C. Hocke, M. Maass, B. Schmeck, S. Hippenstiel, N. Suttorp, and M. Krull Nod1-Mediated Endothelial Cell Activation by Chlamydophila pneumoniae Circ. Res., February 18, 2005; 96(3): 319 - 326. [Abstract] [Full Text] [PDF]
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B. J. Johnson, T. T. T. Le, C. A. Dobbin, T. Banovic, C. B. Howard, F. d. M. L. Flores, D. Vanags, D. J. Naylor, G. R. Hill, and A. Suhrbier Heat Shock Protein 10 Inhibits Lipopolysaccharide-induced Inflammatory Mediator Production J. Biol. Chem., February 11, 2005; 280(6): 4037 - 4047. [Abstract] [Full Text] [PDF]
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 T. Hirata, Y. Osuga, Y. Hirota, K. Koga, O. Yoshino, M. Harada, C. Morimoto, T. Yano, O. Nishii, O. Tsutsumi, et al. Evidence for the Presence of Toll-Like Receptor 4 System in the Human Endometrium J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 548 - 556. [Abstract] [Full Text] [PDF]
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I. H Haralambieva, I. D Iankov, P. V Ivanova, V. Mitev, and I. G Mitov Chlamydophila pneumoniae induces p44/p42 mitogen-activated protein kinase activation in human fibroblasts through Toll-like receptor 4 J. Med. Microbiol., December 1, 2004; 53(12): 1187 - 1193. [Abstract] [Full Text] [PDF]
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L. L. Stoll, G. M. Denning, and N. L. Weintraub Potential Role of Endotoxin as a Proinflammatory Mediator of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2227 - 2236. [Abstract] [Full Text] [PDF]
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K. S. Michelsen, T. M. Doherty, P. K. Shah, and M. Arditi TLR Signaling: An Emerging Bridge from Innate Immunity to Atherogenesis J. Immunol., November 15, 2004; 173(10): 5901 - 5907. [Abstract] [Full Text] [PDF]
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A. A. R. Tobian, D. H. Canaday, and C. V. Harding Bacterial Heat Shock Proteins Enhance Class II MHC Antigen Processing and Presentation of Chaperoned Peptides to CD4+ T Cells J. Immunol., October 15, 2004; 173(8): 5130 - 5137. [Abstract] [Full Text] [PDF]
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 R Arroyo-Espliguero, P Avanzas, S Jeffery, and J C Kaski CD14 and toll-like receptor 4: a link between infection and acute coronary events? Heart, September 1, 2004; 90(9): 983 - 988. [Abstract] [Full Text] [PDF]
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M.-F. Tsan and B. Gao Endogenous ligands of Toll-like receptors J. Leukoc. Biol., September 1, 2004; 76(3): 514 - 519. [Abstract] [Full Text] [PDF]
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J. A. Whitsett, C. J. Bachurski, K. C. Barnes, P. A. Bunn Jr., L. M. Case, D. N. Cook, D. Crooks, M. W. Duncan, L. Dwyer-Nield, R. C. Elston, et al. Functional Genomics of Lung Disease Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2/S1): S1 - S81. [Full Text] [PDF]
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 R. Mahanonda, N. Sa-Ard-Iam, O. Charatkulangkun, A. Promsudthi, R.E. Schifferle, K. Yongvanichit, and S. Pichyangkul Monocyte Activation by Porphyromonas gingivalis LPS in Aggressive Periodontitis with the Use of Whole-blood Cultures Journal of Dental Research, July 1, 2004; 83(7): 540 - 545. [Abstract] [Full Text] [PDF]
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A. G. Rothfuchs, C. Trumstedt, H. Wigzell, and M. E. Rottenberg Intracellular Bacterial Infection-Induced IFN-{gamma} Is Critically but Not Solely Dependent on Toll-Like Receptor 4-Myeloid Differentiation Factor 88-IFN-{alpha}{beta}-STAT1 Signaling J. Immunol., May 15, 2004; 172(10): 6345 - 6353. [Abstract] [Full Text] [PDF]
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W.-F. Lo, C. D. Dunn, H. Ong, E. S. Metcalf, and M. J. Soloski Bacterial and Host Factors Involved in the Major Histocompatibility Complex Class Ib-Restricted Presentation of Salmonella Hsp 60: Novel Pathway Infect. Immun., May 1, 2004; 72(5): 2843 - 2849. [Abstract] [Full Text] [PDF]
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A. A. R. Tobian, D. H. Canaday, W. H. Boom, and C. V. Harding Bacterial Heat Shock Proteins Promote CD91-Dependent Class I MHC Cross-Presentation of Chaperoned Peptide to CD8+ T Cells by Cytosolic Mechanisms in Dendritic Cells versus Vacuolar Mechanisms in Macrophages J. Immunol., May 1, 2004; 172(9): 5277 - 5286. [Abstract] [Full Text] [PDF]
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 M.-F. Tsan and B. Gao Cytokine function of heat shock proteins Am J Physiol Cell Physiol, April 1, 2004; 286(4): C739 - C744. [Abstract] [Full Text] [PDF]
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C. Monaco and E. Paleolog Nuclear factor {kappa}B: a potential therapeutic target in atherosclerosis and thrombosis Cardiovasc Res, March 1, 2004; 61(4): 671 - 682. [Abstract] [Full Text] [PDF]
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A. B. Lichtenwalner, D. L. Patton, W. C. Van Voorhis, Y. T. C. Sweeney, and C.-C. Kuo Heat Shock Protein 60 Is the Major Antigen Which Stimulates Delayed-Type Hypersensitivity Reaction in the Macaque Model of Chlamydia trachomatis Salpingitis Infect. Immun., February 1, 2004; 72(2): 1159 - 1161. [Abstract] [Full Text] [PDF]
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K. Chen, J. Lu, L. Wang, and Y.-H. Gan Mycobacterial heat shock protein 65 enhances antigen cross-presentation in dendritic cells independent of Toll-like receptor 4 signaling J. Leukoc. Biol., February 1, 2004; 75(2): 260 - 266. [Abstract] [Full Text] [PDF]
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A. P. Gobert, J.-C. Bambou, C. Werts, V. Balloy, M. Chignard, A. P. Moran, and R. L. Ferrero Helicobacter pylori Heat Shock Protein 60 Mediates Interleukin-6 Production by Macrophages via a Toll-like Receptor (TLR)-2-, TLR-4-, and Myeloid Differentiation Factor 88-independent Mechanism J. Biol. Chem., January 2, 2004; 279(1): 245 - 250. [Abstract] [Full Text] [PDF]
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S. R. Coats, R. A. Reife, B. W. Bainbridge, T.-T. T. Pham, and R. P. Darveau Porphyromonas gingivalis Lipopolysaccharide Antagonizes Escherichia coli Lipopolysaccharide at Toll-Like Receptor 4 in Human Endothelial Cells Infect. Immun., December 1, 2003; 71(12): 6799 - 6807. [Abstract] [Full Text] [PDF]
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T. Darville, J. M. O'Neill, C. W. Andrews Jr., U. M. Nagarajan, L. Stahl, and D. M. Ojcius Toll-Like Receptor-2, but Not Toll-Like Receptor-4, Is Essential for Development of Oviduct Pathology in Chlamydial Genital Tract Infection J. Immunol., December 1, 2003; 171(11): 6187 - 6197. [Abstract] [Full Text] [PDF]
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F. Re and J. L. Strominger Separate Functional Domains of Human MD-2 Mediate Toll-Like Receptor 4-Binding and Lipopolysaccharide Responsiveness J. Immunol., November 15, 2003; 171(10): 5272 - 5276. [Abstract] [Full Text] [PDF]
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 E. S. Van Amersfoort, T. J. C. Van Berkel, and J. Kuiper Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock Clin. Microbiol. Rev., July 1, 2003; 16(3): 379 - 414. [Abstract] [Full Text] [PDF]
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B. Gao and M.-F. Tsan Recombinant Human Heat Shock Protein 60 Does Not Induce the Release of Tumor Necrosis Factor {alpha} from Murine Macrophages J. Biol. Chem., June 13, 2003; 278(25): 22523 - 22529. [Abstract] [Full Text] [PDF]
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O. Equils, M. L. Schito, H. Karahashi, Z. Madak, A. Yarali, K. S. Michelsen, A. Sher, and M. Arditi Toll-Like Receptor 2 (TLR2) and TLR9 Signaling Results in HIV-Long Terminal Repeat Trans-Activation and HIV Replication in HIV-1 Transgenic Mouse Spleen Cells: Implications of Simultaneous Activation of TLRs on HIV Replication J. Immunol., May 15, 2003; 170(10): 5159 - 5164. [Abstract] [Full Text] [PDF]
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F. Bea, M. H. Puolakkainen, T. McMillen, F. N. Hudson, N. Mackman, C. C. Kuo, L. A. Campbell, and M. E. Rosenfeld Chlamydia pneumoniae Induces Tissue Factor Expression in Mouse Macrophages via Activation of Egr-1 and the MEK-ERK1/2 Pathway Circ. Res., March 7, 2003; 92(4): 394 - 401. [Abstract] [Full Text] [PDF]
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B. Gao and M.-F. Tsan Endotoxin Contamination in Recombinant Human Heat Shock Protein 70 (Hsp70) Preparation Is Responsible for the Induction of Tumor Necrosis Factor alpha Release by Murine Macrophages J. Biol. Chem., January 3, 2003; 278(1): 174 - 179. [Abstract] [Full Text] [PDF]
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 W van Eden, R van der Zee, P van Kooten, S E Berlo, P M Cobelens, A Kavelaars, C J Heijnen, B Prakken, S Roord, and S Albani Balancing the immune system: Th1 and Th2 Ann Rheum Dis, November 1, 2002; 61(90002): ii25 - 28. [Full Text] [PDF]
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Q. Xu Role of Heat Shock Proteins in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1547 - 1559. [Abstract] [Full Text] [PDF]
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