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J Biol Chem, Vol. 274, Issue 47, 33419-33425, November 19, 1999
From the Toll-like receptors (TLRs) 2 and 4 are signal
transducers for lipopolysaccharide, the major proinflammatory
constituent in the outer membrane of Gram-negative bacteria. We
observed that membrane lipoproteins/lipopeptides from Borrelia
burgdorferi, Treponema pallidum, and Mycoplasma
fermentans activated cells heterologously expressing TLR2 but not
those expressing TLR1 or TLR4. These TLR2-expressing cells were also
stimulated by living motile B. burgdorferi, suggesting that
TLR2 recognition of lipoproteins is relevant to natural
Borrelia infection. Importantly, a TLR2 antibody inhibited
bacterial lipoprotein/lipopeptide-induced tumor necrosis factor release
from human peripheral blood mononuclear cells, and TLR2-null Chinese
hamster macrophages were insensitive to lipoprotein/lipopeptide
challenge. The data suggest a role for the native protein in cellular
activation by these ligands. In addition, TLR2-dependent
responses were seen using whole Mycobacterium avium and
Staphylococcus aureus, demonstrating that this receptor can
function as a signal transducer for a wide spectrum of bacterial products. We conclude that diverse pathogens activate cells through TLR2 and propose that this molecule is a central pattern recognition receptor in host immune responses to microbial invasion.
Microbial invasion of the host is followed by a series of events
designed to control and eventually resolve the infection. The immediate
response to the invading organism is coordinated by the innate immune
system. The cells of this system are responsible for first-line
bacterial clearance and modulation of the adaptive immune response
through soluble factors or co-stimulatory signals provided by
antigen-presenting cells (1). Janeway and co-workers (2, 3) have
hypothesized that the innate immune system can sense invading pathogens
by virtue of nonclonal pattern recognition receptors that interact with
microbial structures and deliver a danger signal to the host cell.
Toll is a type I transmembrane receptor, first described in
Drosophila, that shares homology to components of the
interleukin-1 (IL-1)1
signaling pathway (4). Toll, and the related molecule 18-Wheeler, appear to control important antimicrobial responses against both fungi
and bacteria in the fruit fly (5, 6). In evolutionary terms, these
proteins are primordial pattern recognition receptors for animals that
totally lack acquired immunity. Recently, mammalian homologues of Toll
have been cloned and designated Toll-like receptors (TLRs) (7-9). At
least 10 such receptors have been identified, but only 2 TLRs have any
known function. TLR2 and TLR4 have been implicated in cellular
responses to lipopolysaccharide (LPS), the major constituent of the
Gram-negative bacterial outer membrane (10-12). However, the mechanism
behind TLR-mediated recognition of LPS, the interactions with other
receptor molecules, such as CD14 (13, 14), and the details of the
subsequent cellular activation pathway still require elucidation.
Lyme disease and syphilis are acute and chronic inflammatory disorders
caused by the spirochetal pathogens Borrelia burgdorferi and
Treponema pallidum subsp. pallidum, respectively
(15, 16). Both spirochetes lack LPS (17, 18); however, they do possess abundant membrane lipoproteins (19). There now exists a large body of
evidence that spirochetal lipoproteins and synthetic lipohexapeptide analogs are potent activators of monocytes/macrophages, neutrophils, lymphocytes, endothelial cells, and fibroblasts and that acyl modification of the peptides is essential for these proinflammatory activities (20-29). More recent observations suggest that the
mechanisms underlying monocytic cell activation by motile B. burgdorferi and T. pallidum are identical to those
employed by their purified membrane constituents (30). These results
support the notion that lipoproteins are the principle component of
intact spirochetes driving the host immune response during Lyme disease
and syphilis. Similarly, lipoproteins and lipopeptides derived from the
human pathogen Mycoplasma fermentans are also potent
activators of monocytes/macrophages and may play an important role in
the inflammatory response during infection (31-33).
The cellular activation induced by the lipoproteins or
lipoprotein-derived lipopeptides from B. burgdorferi and
T. pallidum resembles that of the LPS signaling pathway, as
CD14 appears to facilitate cellular activation by both types of
pathogenic membrane structures (21, 25). However, several differences
have been observed between LPS and lipoprotein cellular activation,
indicating the utilization of different signaling elements. For
example, spirochetal and mycoplasma lipoproteins and lipopeptides
activate macrophages from LPS hyporesponsive C3H/HeJ mice (23, 24, 27,
31). In addition, whereas Chinese hamster ovary (CHO)-K1 cells become
remarkably sensitive to LPS after transfection with CD14 (34-36), they
remain insensitive to the lipoproteins, lipopeptides, and motile
B. burgdorferi (21, 30, 32). These observations led us to
hypothesize that differences in main signaling components exist between
lipoproteins and LPS.
We have recently found that CHO-K1 cells do not express an mRNA
transcript for full-length and functional TLR2 (37). This observation
raised the possibility that the lack of functional TLR2 might account
for the failure of CHO/CD14 cells to respond to bacterial structures
other than LPS. To test this hypothesis, we engineered stable CHO/CD14
fibroblast cell lines that express TLR2. The transfected cells were
highly susceptible to activation by lipoproteins and lipopeptides from
B. burgdorferi, T. pallidum, and M. fermentans, as well as to activation by live motile B. burgdorferi. In contrast, cells expressing TLR1 or TLR4 did not acquire responsiveness to bacterial lipoproteins/lipopeptides. Moreover, we observed a TLR2-mediated cell activation by
Mycobacterium avium, an important pathogen in AIDS. Similar
studies have documented inducible responses to other bacteria as well,
including staphylococci, listeria, tuberculosis, and the pneumococcus,
suggestive of wide-spread recognition of bacteria by TLR2 (10, 11, 38,
39).2,3
We propose that TLR2 mediates cellular responses to structures from
numerous microbial cell wall constituents and may thus be central in
host recognition of diverse bacterial pathogens. Therapies directed at
the TLRs may be useful anti-inflammatory agents for a large variety of
chronic and acute bacterial infections.
Reagents--
PBS, Ham's F-12 medium, RPMI 1640 medium, and
trypsin-versene mixture (trypsin-EDTA) were from BioWhittaker
(Walkersville, MD). Low endotoxin FBS was from Summit Biotechnologies
(Greeley, CO), and ciprofloxacin was a gift from Miles Pharmaceuticals
(West Haven, CT). Hygromycin B was purchased from Calbiochem (San
Diego, CA), puromycin was from Sigma, and G418 was from Life
Technologies, Inc. Protein-free LPS from Salmonella
minnesota Re595 was a gift from N. Qureshi (Middleton Veterans
Affairs Hospital, Madison, WI). Antibodies for flow cytometry were
purchased from Becton Dickinson, and human IL-1 Lipoproteins and Lipopeptides--
Native OspA (nOspA) was
immunoaffinity purified from B. burgdorferi strain TI1-EV
(40). Hexapeptides similar to the N termini of B. burgdorferi OspA (CKQNVS)), OspC (CNNSGK), and T. pallidum 47-kDa major lipoprotein (CGSSHH) were synthesized on an
Applied Biosystems (Foster City, CA) peptide synthesizer. Lipopeptides (OspAL, OspCL, and 47L) corresponding to the acylated N termini of
natural OspA, OspC and 47-kDa lipoprotein were synthesized using
tripalmitoyl-S-glyceryl-cysteine in a solid-phase procedure (41). A synthetic (s) lipopeptide based upon the full-length MALP-2
membrane lipopeptide from M. fermentans (sMALP-2;
CGNNDESNISFKEK) was prepared using dipalmitoyl-S-glyceryl
cysteine as described (32) An unlipidated version of sMALP-2 was also
synthesized (32). Lipoproteins and lipopeptides were frozen at
Bacterial Strains--
B. burgdorferi strain B31 (42)
(provided by R. Lathigra, MedImmune, Inc., Gaithersburg, MD) was grown
in vitro at 34 °C in Barbour-Stoenner-Kelly H medium
(Sigma). Microorganisms were quantified by dark-field microscopy.
Spirochetes were passaged five times or less prior to experimentation,
and infectivity was assessed by intradermal infection of C3H/HeJ mice
(The Jackson Laboratory, Bar Harbor, ME), followed by culture of an ear
biopsy. For flow cytometry experiments, B. burgdorferi were
labeled with PKH2 green fluorescent dye (Sigma) according to the
manufacturer's instructions. M. avium strain 969 A45,
originally a clinical isolate, was grown in Middlebrook 7H9 medium with
OADC supplementation (Baltimore Biological Laboratories, Baltimore,
MD). The bacterial cells were harvested by centrifugation, washed twice
and resuspended in PBS, passed through a 5 µm filter to remove cell
clumps, and enumerated by plating. Heat-killed Staphylococcus
aureus (ATCC 25923) was prepared as described (38). Bioparticles
consisting of killed Escherichia coli K-12 strain were
purchased from Molecular Probes (Eugene, OR) and resuspended in PBS.
Cell Lines--
The CHO/CD14.ELAM.Tac reporter cell line (clone
3E10) expresses inducible membrane CD25 under control of a region from
the human E-selectin promoter containing nuclear factor- Flow Cytometry Analysis--
Cells were plated at a density of
1 × 105 cells/well in 24-well dishes. The following
day, the cells were stimulated as indicated in Ham's F-12 medium
containing 10% FBS (total volume of 0.25 ml/well). Subsequently, the
cells were harvested with trypsin-EDTA and labeled with fluorescein
isothiocyanate anti-CD25 in PBS, 1% FBS for 30 min on ice. After
labeling, the cells were washed once and resuspended in PBS, 1% FBS
containing propidium iodide to exclude dead cells. The cells were
analyzed by flow cytometry using a FACScan microfluorometer (Becton Dickinson).
Peritoneal Macrophages--
Ten-week-old Chinese hamsters
(Cytogen Research and Development, West Roxbury, MA) and C3H/OuJ mice
(The Jackson Laboratory) were injected intraperitoneally with 2 ml of
3% thioglycollate (Sigma). After 3 days, peritoneal exudate cells were
harvested by lavage with 7 ml of RPMI 1640 medium containing 10% FBS
and 10 µg/ml ciprofloxacin. The cells were washed with medium,
counted, and plated at a density at 1.2 × 106
cells/well in six-well dishes, followed by overnight incubation. The
nonadherent cells were then removed by washing with medium. Two days
after harvesting, the cells were washed twice with medium and
stimulated for 1 h. Nuclear extracts were isolated and analyzed for binding to a 32P-labeled NF- Isolation of Peripheral Blood Mononuclear Cells (PBMC) and
Measurement of TNF--
Human PBMC were isolated by gradient
centrifugation of heparinized blood on Histopaque® 1077 (Sigma)
according to the manufacturer's protocol. The cells were resuspended
in RPMI 1640 medium containing 10% human serum and plated at a density
of 7 × 105 cells/well in a 96-well dish. Immediately
before stimulation with the indicated compounds, 1:5 (v/v) dilutions of
a hybridoma supernatant containing the TLR2-specific antibody
TL2.12 or a control antibody (mouse IgG, Sigma, diluted in
hybridoma medium), to a final antibody concentration of 5 µg/ml, was
added. The cells were stimulated for 12 h, and cell-free
supernatants were harvested and analyzed for TNF TLR2, but Not TLR4 or TLR1, Imparts Cellular Activation by B. burgdorferi, T. pallidum, and M. fermentans Lipoproteins and
Lipopeptides--
In order to test the potential role of TLRs in
B. burgdorferi and T. pallidum infections, we
constructed several TLR-expressing reporter cell lines in a CHO
fibroblast background that contained an inducible
NF-
The N terminus of mature B. burgdorferi and T. pallidum lipoproteins consists of a diacylglyceryl moiety in
thioether linkage to a cysteine residue and a third fatty acid
amide-linked to the The Lack of TLR4 Activity after Lipoprotein/Lipopeptide Exposure Is
Due to the Lack of Ligand-specific Recognition--
Although the
inability of the CHO/CD14/TLR4 cell line to respond to lipoproteins and
lipopeptides may reflect the fact that TLR4 is not involved in
lipoprotein recognition, it is possible that these cell lines expressed
a nonfunctional TLR4. Control conditions were difficult to establish,
because LPS already activates CHO/CD14 cells through the endogenous
hamster TLR4. Therefore, an alternative approach was employed to
confirm the functionality of the transfected TLR4 protein before
concluding that bacterial lipoproteins and lipopeptides were not TLR4 ligands.
Our laboratory has recently described CHO/CD14 cells with a genetic
defect in LPS, but not in IL-1- or TNF-induced signal transduction
(43). These cells respond to LPS after transfection with TLR2 or TLR4,
as these Toll proteins bypass their genetic lesion.4 As
shown in Fig. 2, transfection with TLR2
enabled the cells to respond to lipopeptides, lipoproteins, and LPS. In
stark contrast, TLR4-transfected cells responded to LPS only,
demonstrating that the transfected TLR4 is functional in CHO/CD14 cells
but will not transduce a signal in response to
lipoproteins/lipopeptides. These data suggest that TLR2 is able to
serve as a receptor for a broad repertoire of bacterially derived
ligands, whereas TLR4 appears to be a more specific receptor for
LPS.
TLR2 Mediates Cellular Responses upon Exposure to Live B. burgdorferi--
Similar to spirochetal lipoproteins/lipopeptides,
live B. burgdorferi and T. pallidum activated
monocytic cells but failed to stimulate CHO/CD14 cells (30). These
findings are one of several pieces of evidence supporting the
hypothesis that live spirochetes and their constituent lipoproteins
activate cells by similar, if not identical, mechanisms. In light of
these results and the above observations it was of interest to test
whether motile spirochetes signal through TLR2. We found that only
TLR2-transfected cells were activated upon exposure to B. burgdorferi (Fig. 3A), whereas CHO/CD14/TLR4 cells remained insensitive to spirochetal challenge (data not shown). Experiments with fluorescein
isothiocyanate-labeled B. burgdorferi showed a similar high
degree of binding of the spirochete to all cell lines (data not shown),
indicating that membrane attachment was not sufficient to initiate
cellular responses. Again, motile B. burgdorferi stimulated
the TLR2-transfected LPS nonresponder mutant CHO/CD14 cells, whereas
TLR4-transfected cells were enabled to respond to LPS, but not to the
spirochetes (Fig. 3B). Thus, the recognition of lipopeptides
and lipoproteins by TLR2 appears to be relevant to the responses
observed during natural infection in man. These results demonstrate
that TLR2 but not TLR4 mediates responses to whole B. burgdorferi and that TLR4 is unlikely to be involved in responses
to spirochetes.
TLR2 Is a Pattern Recognition Receptor--
Many microbial
infections induce similar clinical symptoms, which may reflect
similarities in host responses to invasion. Recent observations suggest
that bacterial cell wall structures, such as peptidoglycan from
Gram-positive organisms (38, 39), are able to signal through TLR2.
M. avium is an opportunistic pathogen, which leads to
serious complications in HIV-1 disease; patients with M. avium experience profound fevers, diffuse pains, and generalized
wasting (44). Recent observations suggest that structures from M. avium activate the LPS signaling pathway by utilizing CD14 (45).
We exposed the transfected fibroblasts to live M. avium and
killed S. aureus and E. coli in order to determine whether there were similarities in utilization of TLR2 by
bacteria containing different membrane constituents. The patterns of
response demonstrated the following (Fig.
4): CHO cells required expression of CD14
in order to respond to Gram-negative cell wall products. However, cells
that co-expressed CD14 with TLR2 were capable of responding to
stimulation by all the bacteria tested, including the atypical
mycobacterium M. avium and the Gram-positive bacterium
S. aureus. Hence, although they are phylogenetically diverse
and contain a variety of proinflammatory constituents, M. avium,
S. aureus, B. burgdorferi, T. pallidum, and M. fermentans all appear to activate cells through the same receptor
system.
TLR2-null Chinese Hamster Macrophages Fail to Respond to
Lipoproteins/Lipopeptides--
Chinese hamster macrophages respond to
LPS, although they do not express mRNA for a full-length TLR2 (37).
Sequence analysis of TLR2 from the Chinese hamster, compared with human
and mouse TLR2, revealed a single base pair deletion that resulted in a frameshift mutation; this mutation encodes a protein fragment devoid of
transmembrane and intracellular domains. In contrast, CHO/CD14 cells
and macrophages from Chinese hamsters appear to have a full-length and
functional TLR4.5 We isolated
peritoneal macrophages from Chinese hamsters in order to test the
action of lipoproteins/lipopeptides toward TLR2-null primary
phagocytes. We found that the hamster macrophages responded to LPS, but
not to nOspA or 47L, as measured by nuclear translocation of NF- The anti-TLR2 mAb TL2.1 Inhibits Lipoprotein/Lipopeptide and M. avium-induced Release of TNF from Human Peripheral Blood Mononuclear
Cells--
In order to determine whether our findings in transfected
cell lines reflect the signal transduction systems used by native phagocytes, we stimulated freshly isolated human PBMC with nOspA, 47L,
and M. avium in the presence of the TLR2 antibody TL2.1. As
shown in Fig. 5B, TL2.1 inhibited TNF production from PBMC after exposure to nOspA, 47L, and live M. avium by 40-70%.
These data support the hypothesis that TLR2 may play an important role in in vivo responses to various bacterial structures. In the
presence of TL2.1, LPS-induced responses in primary cells were only
minimally reduced (results not shown). Although the relative importance of TLR2 in LPS signaling remains unclear, expression of TLR2 (unlike TLR4) does not appear to be required for cell responses to low concentrations of LPS (37).
The severity of clinical symptoms associated with bacterial
diseases varies according to the type of infectious agent, bacterial burden, affected tissue, and co-existing illness. Nevertheless, in many
aspects, similar host responses are observed. For example, several
clinical and immunological similarities can be seen between therapy-induced Jarisch-Herxheimer reaction during infection with Treponema and Borrelia spp. (46, 47) and
Gram-negative and Gram-positive sepsis (48). Hence, one is tempted to
speculate that the pathophysiological similarities observed with these
diverse infections are due to the activation of analogous signaling
pathways in response to bacterial exposure. The present study
implicates TLR2 in host interactions with B. burgdorferi, T. pallidum, M. fermentans, and M. avium, as well as
components of Gram-negative and Gram-positive bacteria. Thus, this
receptor can mediate host inflammatory reactions to a variety of
microbial pathogens, indicating a remarkable spectrum of bacterial recognition.
Previous reports have identified mechanisms of cellular activation by
many microbial structures that are similar, yet never identical, to the
LPS signaling pathway. In most cases, the reported observations
concerned the ability of the microbes to utilize CD14. In addition to
being a high affinity receptor for LPS, CD14 has been implicated in the
responses to several bacteria and their microbial products, including
Borrelia and Treponema sp. (21, 25),
peptidoglycan, and other cell wall components of S. aureus (14, 49), group B streptococci (50), structures from mycobacteria (14,
45, 51, 52), and mannuronic acid polymers from Pseudomonas aeruginosa (53). Because it can facilitate responses to all of
these bacterial structures listed, CD14 has been termed a pattern recognition receptor by Pugin et al. (14). Yet CD14 lacks
specificity in bacterial product recognition, and some controversy
exists about whether CD14 is a true pattern recognition receptor (54). The identification of TLR2 in the recognition of most of these pathogens adds another layer of complexity to our understanding of the
mammalian response to microbes. In contrast to CD14, TLR2 contains all
of the characteristics that one would expect from a true pattern
recognition receptor, including the presence of a true
signal-transducing intracellular domain. Although only recently
described, the list of putative ligands for TLR2 is already impressively large (Table I). Of
particular interest is the observation that despite the apparent
interactions of TLR2 with many Gram-positive bacteria, group B
streptococci do not seem to stimulate cells through this
receptor.2 This highlights the fact that we cannot exclude
the involvement of additional receptors, functioning either alone or as
part of a receptor complex, in host responses to the microbial
structures described.
Although TLR2 has the features of a pattern recognition receptor, it is
difficult to define a common microbial pattern among all of these
putative ligands. The list of TLR2 ligands is still not complete, and
there is no evidence yet that TLR2 directly binds these microbial
products. Thus, attempting to define the biophysical properties
responsible for TLR2/ligand interactions may be premature.
Nevertheless, we hypothesize that elements of amphipathicity may prove
to be the most important for the stimulation of cells through TLR2. All
of the lipoproteins/lipopeptides tested in this study activated
TLR2-expressing cells, and acylation of the spirochetal proteins was
the critical modification that enabled their activation of TLR2 (Fig.
1B). Other putative TLR2 ligands, including peptidoglycan,
may also have amphipathic characteristics that are not yet appreciated.
Both TLR2 (10, 11, 37) and TLR4 (12, 55) have been reported to function
as LPS signal transducers. Our data support these conclusions, although
they suggest that the two related proteins clearly have different roles
in pathogen recognition: TLR4 is required for sensitive responses to
LPS, whereas TLR2 is not. For example, cells from Chinese hamsters,
which express a truncated and nonfunctional TLR2 (37) but a full-length
TLR4,5 respond to LPS but not to lipoproteins/lipopeptides.
This contrasts with the finding that TLR4 is responsible for the LPS
nonresponder phenotype of the C3H/HeJ mouse (12). Although these mice
fail to respond to low concentrations of LPS, the ability of
Borrelia spirochetes and lipoproteins to activate the
C3H/HeJ mice (23, 24, 27, 56) demonstrates that these ligands do not
require TLR4 expression to elicit productive responses and strongly
suggests a functional TLR2 in these animals. In a broad sense, the
accumulated data indicate that the preferential utilization of TLRs
underlies both the observed similarities, as well as the differences,
in specific pathogen recognition.
What remains unclear is why, if TLR2 is expressed in phagocytic cells
under resting conditions, TLR4 mutant mice (C3H/HeJ and C57BL10/ScCr
(12)) are not still sensitive to LPS via the signal transduction
capabilities of TLR2. It may be that the levels of TLR2 expression in
native phagocytes, in contrast to transfected cells, are insufficient
to enable LPS responses in the mice. We note that chronically
stimulated C3H/HeJ mice have been reported to exhibit immune activation
in response to LPS challenge (57), an effect that may be due to the
up-regulation of TLR2. Furthermore, the present data do not rule out
the possibility that TLR2 may have a more important function in LPS
recognition by nonphagocytic cells.
The downstream signaling molecules involved in TLR-mediated cellular
activation have not been definitively defined. However, both TLR2 and
TLR4 have a cytoplasmic domain that is homologous to the IL-1 receptor.
Thus, it is likely that both TLRs activate the NF- *
This work was supported by National Institutes of Health
Grants GM54060, AI38515, and AI01476 (to R. R. I. and D. T. G.), AI09973 (to T. J. S.), AI31628-08 (to R. W. F.), and AI29735 and AI38894 (to J. D. R.); the Research Council of Norway; the Norwegian Cancer Society (to E. L., T. H. F., and T. E.); and a grant from the Arthritis Foundation (to T. J. S.).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.
§§
To whom correspondence should be addressed: The Maxwell Finland
Laboratory for Infectious Diseases, Boston University School of
Medicine, Boston Medical Center, 774 Albany St., Boston, MA 02118.
Tel.: 617-414-7965; Fax: 617-414-5843; E-mail: Douglas.Golenbock@ bmc.org.
2
T. H. Flo, Ø. Halaas, E. Lien, L. Ryan, G. Teti, D. T. Golenbock, A. Sundan, and T. Espevik, submitted for publication.
3
Means, T. K., Wang, S., Lien E., Yoshimura, A.,
Golenbock, D. T. and Fenton, M. J. (1999) J. Immunol. 163, 3920-3927 and Brightbill, H. D., Libraty, D. H., Krutzik, S. R.,
Yang, R. B., Belisle, J. T., Bleharski, J. R., Maitland, M., Norgard,
M. V., Plevy, S. E., Smale, S. T., Brennan, P. J., Bloom, B. R., Godowski, P. J. and Modlin, R. L. (1999) Science 285, 732-736
4
A. Yoshimura, H. Heine, and D. T. Golenbock,
manuscript in preparation.
5
H. Heine, E. Lien, B. Monks, and D. T. Golenbock, unpublished observations.
The abbreviations used are:
IL, interleukin;
TLR, Toll-like receptor;
LPS, lipopolysaccharide;
Osp, outer surface
protein;
nOspA, native OspA;
CHO, Chinese hamster ovary;
sMALP-2, synthetic macrophage-activating lipopeptide-2;
TNF, tumor necrosis
factor;
NF-
Toll-like Receptor 2 Functions as a Pattern Recognition Receptor
for Diverse Bacterial Products*
§,,
,,,§§
Maxwell Finland Laboratory for Infectious
Diseases, Boston University Medical Center,
Boston, Massachusetts 02118, the § Institute of Cancer
Research and Molecular Biology, Norwegian University of Science and
Technology, 7489 Trondheim, Norway, the ¶ Center for Microbial
Pathogenesis, University of Connecticut Health Center,
Farmington, Connecticut 06030, the Département de
Bacteriologie, Institut Pasteur, 75724 Paris Cedex 15, France, the
Department of Medicine, Boston University
School of Medicine, Boston Veterans Affairs Medical Center,
Boston, Massachusetts 02130, and the ** Laboratory of Infectious
Diseases, Dana-Farber Cancer Institute,
Boston, Massachusetts 02115
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
and tumor necrosis
factor 
(TNF) were from Genzyme (Cambridge, MA).
20 °C as 1 mg/ml or 200 µM (sMALP-2) stock solutions
in PBS (OspAL, OspCL, and 47L) or in PBS, 25 mM octyl
glucoside (nOspA and sMALP-2). Endotoxin levels were undetectable in
all lipoprotein/lipopeptide stock solutions as measured by
Limulus assay.
B (NF-B) binding sites; this promoter element is absolutely dependent upon NF-B (43). Control reporter cells (CHO/ELAM.Tac (clone EL1)) were
similarly constructed to express surface CD25 upon IL-1 or TNF
stimulation by transfecting cells with the reporter construct and the
hygromycin vector pCEP4 alone (i.e. without CD14). CHO/CD14 cells expressing TLRs were engineered by stable transfection of the
CHO/CD14 reporter cell line with the cDNA for human TLR1, TLR2, or
TLR4 in the pFLAG-CMV-1 vector (a gift from C. Kirschning and M. Rothe,
Tularik Inc., South San Francisco, CA (11)) as described (38). All CHO
reporter cell lines were grown in Ham's F-12 medium containing 10%
FBS, 10 µg/ml ciprofloxacin, and 400 units/ml hygromycin B. The TLR
expressing cell lines contained additional selection antibiotics (for
CD14/TLR2, 0.5 mg/ml G418; for CD14/TLR1 and CD14/TLR4, 50 µg/ml
puromycin). A CHO/CD14 reporter cell line with defects in the LPS
signaling pathway (clone 7.7 (43)) was stably transfected with TLR2 or
TLR4 using calcium phosphate as described
elsewhere4 and grown in the
presence of hygromycin and G418.
B specific
oligonucleotide by electrophoretic mobility shift assay, as described
(35).
release by
enzyme-linked immunosorbent assay (matching antibody pair from Roche
Molecular Biochemicals).
RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
B-dependent promoter driving the surface expression of membrane CD25 (43). Thus, the induction of proinflammatory activity
could be quantified by flow cytometry. We exposed CHO/CD14, CHO/CD14/TLR1, CHO/CD14/TLR2, and CHO/CD14/TLR4 reporter cell lines to
the purified native B. burgdorferi outer surface protein A
(nOspA), a synthetic lipohexapeptide based upon the N terminus of the
47-kDa major T. pallidum lipoprotein (47L), and a
synthesized version of the sMALP-2 full-length M. fermentans
lipopeptide. All of the cell lines were engineered to express CD14,
thereby conferring responsiveness to LPS, as indicated by increased
membrane expression of the CD25 reporter transgene. Cells expressing
TLR2 were activated by lipoprotein or lipopeptide structures (Fig. 1A). In contrast, CHO/CD14,
CHO/CD14/TLR1, and CHO/CD14/TLR4 cells were not activated by any of the
spirochetal molecules. These results also illustrate an important point
concerning the purity of our preparations. Lack of stimulation of the
highly LPS-sensitive CHO/CD14 line is strong evidence against the
possibility that environmental endotoxin contaminated our
preparations.
View larger version (30K):
[in a new window]
Fig. 1.
Expression of TLR2 in CHO cells confers
responsiveness to B. burgdorferi natural lipoprotein
nOspA, T. pallidum synthetic lipopeptide 47L, and
M. fermentans synthetic lipopeptide sMALP-2.
A, CHO/CD14, CHO/CD14/TLR1, CHO/CD14/TLR2 and CHO/CD14/TLR4
reporter cells were incubated with medium alone (dotted
lines), B. burgdorferi nOspA (broken lines)
(300 ng/ml), T. pallidum 47L (thin lines) (10 µg/ml), M. fermentans sMALP-2 (thick lines) (25 nM) and LPS (insets, thin lines) (100 ng/ml) for
20 h. Activation of NF- B was measured by the appearance of
reporter transgene (surface CD25) by flow cytometry. Relative cell
number is given on the y axis and fluorescence on the
x axis. B, the CHO/CD14/TLR2 reporter cell line
was exposed to 3.4 µM synthetic lipopeptides OspAL and
47L, 6.8 µM OspCL, and 100 nM sMALP-2 or
similar amounts of the corresponding unlipidated hexapeptides as
described in A. Cells stimulated with lipopeptides are
indicated by the thick lines; the corresponding unlipi- dated peptides are represented by thin lines,
and unstimulated cells are represented by dotted lines. Shown is one
representative experiment out of four performed.
-amino group of the cysteine (19). In contrast,
M. fermentans MALP-2 possesses an
N-acyl-S-diacylglceryl cysteine with a free N
terminus (31). Several reports demonstrate dependence on lipid modification for both in vivo and in vitro
cellular activation by B. burgdorferi, T. pallidum, and M. fermentans lipoproteins and synthetic
lipopeptides (22, 23, 29, 32). As shown in Fig. 1B, only
lipidated peptides (B. burgdorferi OspCL, OspAL, T. pallidum 47L, and M. fermentans sMALP-2) activated the
CHO/CD14/TLR2 reporter cell line, whereas the nonlipidated peptides
completely lacked stimulatory activity. These data demonstrate that
TLR2 mediates cellular activation by lipoproteins/lipopeptides and that
the N-acyl-S-diacylglceryl moiety appears to be
more important than the amide/linked fatty acid for their biological activity.
View larger version (37K):
[in a new window]
Fig. 2.
Transfection of a mutant LPS nonresponder
CHO/CD14 cell line with TLR2, but not TLR4, renders the cells
responsive to bacterial lipoproteins and lipopeptides. LPS
nonresponder mutant CHO/CD14 cells (CHO/CD14 mut.) (43) were
transfected with TLR2 or TLR4. Clonal derivatives were analyzed in
comparison to LPS responsive CHO/CD14 cells, and the untransfected
mutant cell line for responses to IL-1 (gray bars), LPS
(hatched bars), or lipoprotein/lipopeptides (black
bars). 0 signifies no treatment (open bars);
concentrations for 47L and nOspA are given in µg of ligand per ml;
sMALP-2 in nM, LPS was used at 100 ng/ml, and IL-1 was at 1 ng/ml. Cells were stimulated for 20 h. The cells were then stained
for reporter transgene expression and analyzed by flow cytometry.
Activation is expressed as the fold induction of median channel
fluorescence in comparison to unstimulated cells. Shown is one
representative experiment out of two performed.
View larger version (44K):
[in a new window]
Fig. 3.
TLR2 mediates cellular activation upon
exposure to live B. burgdorferi. A,
CHO/CD14 or CHO/CD14/TLR2 cells were left untreated (dotted
lines) or exposed to motile B. burgdorferi (thick
lines) (1000 spirochetes/cell = 2.5 × 107
spirochetes/ml) for 8 h. The cells were harvested, stained for
reporter gene expression, and analyzed by flow cytometry, as in Fig. 1.
Indicated in insets is the fold increase of median
fluorescence relative to unstimulated cells. From left to
right: untreated cells (0, open bars), cells
exposed to different doses of live B. burgdorferi
(black bars) (1, 10, 100, and 1000 spirochetes/cell,
respectively) and LPS (hatched bars) (100 ng/ml).
B, LPS nonresponder mutant CHO/CD14 cells transfected with
TLR2 or TLR4 were exposed to medium (dotted lines), 1000 spirochetes/ml (thick lines), or LPS (thin lines)
(100 ng/ml). Shown is one representative experiment out of three
performed.
View larger version (35K):
[in a new window]
Fig. 4.
Microbial pattern recognition via CD14 and
TLR2. CHO control, CHO/CD14, or CHO/CD14/TLR2 reporter cell lines
were exposed to the following stimuli (from left to
right): medium (0, open bars), live M. avium (black bars), heat-killed S. aureus
(dark gray bars), E. coli bioparticles
(light gray bars), or LPS (hatched bars) (100 ng/ml). Numbers indicate the density of the bacteria per ml.
After 20 h, the cells were harvested, stained for reporter gene
expression, and analyzed by flow cytometry, as in Fig. 1. The
y axis indicates fold increase of median fluorescence
compared with unstimulated cells. Shown is one representative
experiment out of three performed.
B
(Fig. 5A). In contrast,
macrophages from C3H/OuJ mice responded to LPS, nOspA, and 47L. These
results suggested that the lack of TLR2 in primary Chinese hamster
macrophages made them unable to recognize bacterial lipoproteins and
lipopeptides.
View larger version (37K):
[in a new window]
Fig. 5.
TLR2 mediates responses to
lipoproteins/lipopeptides in primary cells. A,
TLR2-null peritoneal macrophages from Chinese hamsters and C3H/OuJ mice
were stimulated with nOspA, 47L, and LPS for 1 h in RPMI 1640 medium containing 10% FBS. Nuclear extracts were isolated and analyzed
for binding to a NF- B specific probe by electrophoretic mobility
shift assay. Shown is the NF-B band, in one representative
experiment out of two performed. B, human PBMC were isolated
by gradient centrifugation, resuspended in RPMI 1640 medium containing
10% human serum, and plated at a density of 7 × 105
cells/well in a 96-well dish. The mouse anti-human TLR2 antibody TL2.1
or control antibodies (mouse IgG) were added to a final concentration
of 5 µg/ml, and the cells were exposed to M. avium (5 × 106 bacteria/ml), 47L (1 µg/ml), or nOspA (300 ng/ml)
in a total volume of 0.2 ml for 12 h. The supernatants were
harvested and assayed for TNF by immunoassay. The antibody did not
block activation induced by phorbol ester (not shown). Data are from
one representative experiment out of three performed. Shown is the mean
of duplicate wells ± S.D.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
Bacterial strains and compounds reported to activate cells via TLR2
B pathway, and
perhaps other proinflammatory pathways as well, via their interactions
with IL-1 receptor signaling genes, including MyD88, TRAF6, and IRAK
(11, 58, 59). The similarities in the signal transduction process that
appear to constitute the inflammatory response to invasion by a variety
of bacteria suggest the exciting possibility that novel therapies
directed against the harmful proinflammatory response to nearly all
forms of infectious illnesses can one day be developed.
FOOTNOTES
ABBREVIATIONS
B, nuclear factor-B;
FBS, fetal bovine serum;
PBMC, peripheral blood mononuclear cells.
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S. C. Nance, A.-K. Yi, F. C. Re, and E. A. Fitzpatrick MyD88 is necessary for neutrophil recruitment in hypersensitivity pneumonitis J. Leukoc. Biol., May 1, 2008; 83(5): 1207 - 1217. [Abstract] [Full Text] [PDF]
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V. M. Abrahams, P. B. Aldo, S. P. Murphy, I. Visintin, K. Koga, G. Wilson, R. Romero, S. Sharma, and G. Mor TLR6 Modulates First Trimester Trophoblast Responses to Peptidoglycan J. Immunol., May 1, 2008; 180(9): 6035 - 6043. [Abstract] [Full Text] [PDF]
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M. Leendertse, R. J. L. Willems, I. A. J. Giebelen, P. S. van den Pangaart, W. J. Wiersinga, A. F. de Vos, S. Florquin, M. J. M. Bonten, and T. van der Poll TLR2-Dependent MyD88 Signaling Contributes to Early Host Defense in Murine Enterococcus faecium Peritonitis J. Immunol., April 1, 2008; 180(7): 4865 - 4874. [Abstract] [Full Text] [PDF]
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K. Farhat, S. Riekenberg, H. Heine, J. Debarry, R. Lang, J. Mages, U. Buwitt-Beckmann, K. Roschmann, G. Jung, K.-H. Wiesmuller, et al. Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling J. Leukoc. Biol., March 1, 2008; 83(3): 692 - 701. [Abstract] [Full Text] [PDF]
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M. Davey, X. Liu, T. Ukai, V. Jain, C. Gudino, F. C. Gibson III, D. Golenbock, A. Visintin, and C. A. Genco Bacterial Fimbriae Stimulate Proinflammatory Activation in the Endothelium through Distinct TLRs J. Immunol., February 15, 2008; 180(4): 2187 - 2195. [Abstract] [Full Text] [PDF]
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W. Piao, C. Song, H. Chen, L. M. Wahl, K. A. Fitzgerald, L. A. O'Neill, and A. E. Medvedev Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance J. Biol. Chem., February 8, 2008; 283(6): 3109 - 3119. [Abstract] [Full Text] [PDF]
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T. Shimizu, Y. Kida, and K. Kuwano Mycoplasma pneumoniae-Derived Lipopeptides Induce Acute Inflammatory Responses in the Lungs of Mice Infect. Immun., January 1, 2008; 76(1): 270 - 277. [Abstract] [Full Text] [PDF]
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H. Chen, M. J. Cowan, J. D. Hasday, S. N. Vogel, and A. E. Medvedev Tobacco Smoking Inhibits Expression of Proinflammatory Cytokines and Activation of IL-1R-Associated Kinase, p38, and NF-{kappa}B in Alveolar Macrophages Stimulated with TLR2 and TLR4 Agonists J. Immunol., November 1, 2007; 179(9): 6097 - 6106. [Abstract] [Full Text] [PDF]
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F. Debierre-Grockiego, M. A. Campos, N. Azzouz, J. Schmidt, U. Bieker, M. G. Resende, D. S. Mansur, R. Weingart, R. R. Schmidt, D. T. Golenbock, et al. Activation of TLR2 and TLR4 by Glycosylphosphatidylinositols Derived from Toxoplasma gondii J. Immunol., July 15, 2007; 179(2): 1129 - 1137. [Abstract] [Full Text] [PDF]
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J. Rogers, A. Hakki, I. Perkins, C. Newton, R. Widen, N. Burdash, T. Klein, and H. Friedman Legionella pneumophila Infection Up-Regulates Dendritic Cell Toll-Like Receptor 2 (TLR2)/TLR4 Expression and Key Maturation Markers Infect. Immun., June 1, 2007; 75(6): 3205 - 3208. [Abstract] [Full Text] [PDF]
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A. E. Medvedev, W. Piao, J. Shoenfelt, S. H. Rhee, H. Chen, S. Basu, L. M. Wahl, M. J. Fenton, and S. N. Vogel Role of TLR4 Tyrosine Phosphorylation in Signal Transduction and Endotoxin Tolerance J. Biol. Chem., June 1, 2007; 282(22): 16042 - 16053. [Abstract] [Full Text] [PDF]
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A. Hasebe, H.-H. Mu, L. R. Washburn, F. V. Chan, N. D. Pennock, M. L. Taylor, and B. C. Cole Inflammatory Lipoproteins Purified from a Toxigenic and Arthritogenic Strain of Mycoplasma arthritidis Are Dependent on Toll-Like Receptor 2 and CD14 Infect. Immun., April 1, 2007; 75(4): 1820 - 1826. [Abstract] [Full Text] [PDF]
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K. R. Alugupalli, S. Akira, E. Lien, and J. M. Leong MyD88- and Bruton's Tyrosine Kinase-Mediated Signals Are Essential for T Cell-Independent Pathogen-Specific IgM Responses J. Immunol., March 15, 2007; 178(6): 3740 - 3749. [Abstract] [Full Text] [PDF]
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A. K. Mayer, M. Muehmer, J. Mages, K. Gueinzius, C. Hess, K. Heeg, R. Bals, R. Lang, and A. H. Dalpke Differential Recognition of TLR-Dependent Microbial Ligands in Human Bronchial Epithelial Cells J. Immunol., March 1, 2007; 178(5): 3134 - 3142. [Abstract] [Full Text] [PDF]
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R. Kapetanovic, M.-A. Nahori, V. Balloy, C. Fitting, D. J. Philpott, J.-M. Cavaillon, and M. Adib-Conquy Contribution of Phagocytosis and Intracellular Sensing for Cytokine Production by Staphylococcus aureus-Activated Macrophages Infect. Immun., February 1, 2007; 75(2): 830 - 837. [Abstract] [Full Text] [PDF]
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D. D. Bolz, R. S. Sundsbak, Y. Ma, S. Akira, J. H. Weis, T. G. Schwan, and J. J. Weis Dual Role of MyD88 in Rapid Clearance of Relapsing Fever Borrelia spp. Infect. Immun., December 1, 2006; 74(12): 6750 - 6760. [Abstract] [Full Text] [PDF]
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J. J. Lazarus, M. J. Meadows, R. E. Lintner, and R. M. Wooten IL-10 Deficiency Promotes Increased Borrelia burgdorferi Clearance Predominantly through Enhanced Innate Immune Responses J. Immunol., November 15, 2006; 177(10): 7076 - 7085. [Abstract] [Full Text] [PDF]
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K. W. Boehme, M. Guerrero, and T. Compton Human Cytomegalovirus Envelope Glycoproteins B and H Are Necessary for TLR2 Activation in Permissive Cells J. Immunol., November 15, 2006; 177(10): 7094 - 7102. [Abstract] [Full Text] [PDF]
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R. S. Kornbluth and G. W. Stone Immunostimulatory combinations: designing the next generation of vaccine adjuvants J. Leukoc. Biol., November 1, 2006; 80(5): 1084 - 1102. [Abstract] [Full Text] [PDF]
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A. Hasebe, N. D. Pennock, H.-H. Mu, F. V. Chan, M. L. Taylor, and B. C. Cole A Microbial TLR2 Agonist Imparts Macrophage-Activating Ability to Apolipoprotein A-1 J. Immunol., October 1, 2006; 177(7): 4826 - 4832. [Abstract] [Full Text] [PDF]
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V. C. B. Bittencourt, R. T. Figueiredo, R. B. da Silva, D. S. Mourao-Sa, P. L. Fernandez, G. L. Sassaki, B. Mulloy, M. T. Bozza, and E. Barreto-Bergter An {alpha}-Glucan of Pseudallescheria boydii Is Involved in Fungal Phagocytosis and Toll-like Receptor Activation J. Biol. Chem., August 11, 2006; 281(32): 22614 - 22623. [Abstract] [Full Text] [PDF]
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L. Sweet and J. S. Schorey Glycopeptidolipids from Mycobacterium avium promote macrophage activation in a TLR2- and MyD88-dependent manner J. Leukoc. Biol., August 1, 2006; 80(2): 415 - 423. [Abstract] [Full Text] [PDF]
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S. Lehnardt, P. Henneke, E. Lien, D. L. Kasper, J. J. Volpe, I. Bechmann, R. Nitsch, J. R. Weber, D. T. Golenbock, and T. Vartanian A Mechanism for Neurodegeneration Induced by Group B Streptococci through Activation of the TLR2/MyD88 Pathway in Microglia J. Immunol., July 1, 2006; 177(1): 583 - 592. [Abstract] [Full Text] [PDF]
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M. Malik, C. S. Bakshi, B. Sahay, A. Shah, S. A. Lotz, and T. J. Sellati Toll-Like Receptor 2 Is Required for Control of Pulmonary Infection with Francisella tularensis. Infect. Immun., June 1, 2006; 74(6): 3657 - 3662. [Abstract] [Full Text] [PDF]
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A. E. Medvedev, I. Sabroe, J. D. Hasday, and S. N. Vogel Invited review: Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease Innate Immunity, June 1, 2006; 12(3): 133 - 150. [Abstract] [PDF]
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L. E. Cole, K. L. Elkins, S. M. Michalek, N. Qureshi, L. J. Eaton, P. Rallabhandi, N. Cuesta, and S. N. Vogel Immunologic Consequences of Francisella tularensis Live Vaccine Strain Infection: Role of the Innate Immune Response in Infection and Immunity. J. Immunol., June 1, 2006; 176(11): 6888 - 6899. [Abstract] [Full Text] [PDF]
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U. Buwitt-Beckmann, H. Heine, K.-H. Wiesmuller, G. Jung, R. Brock, S. Akira, and A. J. Ulmer TLR1- and TLR6-independent Recognition of Bacterial Lipopeptides J. Biol. Chem., April 7, 2006; 281(14): 9049 - 9057. [Abstract] [Full Text] [PDF]
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B. Schmeck, S. Huber, K. Moog, J. Zahlten, A. C. Hocke, B. Opitz, S. Hammerschmidt, T. J. Mitchell, M. Kracht, S. Rosseau, et al. Pneumococci induced TLR- and Rac1-dependent NF-{kappa}B-recruitment to the IL-8 promoter in lung epithelial cells Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L730 - L737. [Abstract] [Full Text] [PDF]
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J. Fan, Y. Li, Y. Vodovotz, T. R. Billiar, and M. A. Wilson Hemorrhagic shock-activated neutrophils augment TLR4 signaling-induced TLR2 upregulation in alveolar macrophages: role in hemorrhage-primed lung inflammation Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L738 - L746. [Abstract] [Full Text] [PDF]
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C. Zhang, S.-H. Wang, M. E. Lasbury, D. Tschang, C.-P. Liao, P. J. Durant, and C.-H. Lee Toll-Like Receptor 2 Mediates Alveolar Macrophage Response to Pneumocystis murina Infect. Immun., March 1, 2006; 74(3): 1857 - 1864. [Abstract] [Full Text] [PDF]
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N. Banaiee, E. Z. Kincaid, U. Buchwald, W. R. Jacobs Jr., and J. D. Ernst Potent Inhibition of Macrophage Responses to IFN-{gamma} by Live Virulent Mycobacterium tuberculosis Is Independent of Mature Mycobacterial Lipoproteins but Dependent on TLR2. J. Immunol., March 1, 2006; 176(5): 3019 - 3027. [Abstract] [Full Text] [PDF]
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H. D'Avila, R. C. N. Melo, G. G. Parreira, E. Werneck-Barroso, H. C. Castro-Faria-Neto, and P. T. Bozza Mycobacterium bovis Bacillus Calmette-Guerin Induces TLR2-Mediated Formation of Lipid Bodies: Intracellular Domains for Eicosanoid Synthesis In Vivo. J. Immunol., March 1, 2006; 176(5): 3087 - 3097. [Abstract] [Full Text] [PDF]
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K. E. Thomas, A. Sapone, A. Fasano, and S. N. Vogel Gliadin Stimulation of Murine Macrophage Inflammatory Gene Expression and Intestinal Permeability Are MyD88-Dependent: Role of the Innate Immune Response in Celiac Disease J. Immunol., February 15, 2006; 176(4): 2512 - 2521. [Abstract] [Full Text] [PDF]
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V. Regueiro, M. A. Campos, J. Pons, S. Alberti, and J. A. Bengoechea The uptake of a Klebsiella pneumoniae capsule polysaccharide mutant triggers an inflammatory response by human airway epithelial cells Microbiology, February 1, 2006; 152(2): 555 - 566. [Abstract] [Full Text] [PDF]
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C. M. O'Connell, I. A. Ionova, A. J. Quayle, A. Visintin, and R. R. Ingalls Localization of TLR2 and MyD88 to Chlamydia trachomatis Inclusions: EVIDENCE FOR SIGNALING BY INTRACELLULAR TLR2 DURING INFECTION WITH AN OBLIGATE INTRACELLULAR PATHOGEN J. Biol. Chem., January 20, 2006; 281(3): 1652 - 1659. [Abstract] [Full Text] [PDF]
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D. Londono, Y. Bai, W. R. Zuckert, H. Gelderblom, and D. Cadavid Cardiac Apoptosis in Severe Relapsing Fever Borreliosis Infect. Immun., November 1, 2005; 73(11): 7669 - 7676. [Abstract] [Full Text] [PDF]
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C. Collins, J. Wolfe, K. Roessner, C. Shi, L. H. Sigal, and R. C. Budd Lyme Arthritis Synovial {gamma}{delta} T Cells Instruct Dendritic Cells via Fas Ligand J. Immunol., November 1, 2005; 175(9): 5656 - 5665. [Abstract] [Full Text] [PDF]
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C. A. Petersen, K. A. Krumholz, and B. A. Burleigh Toll-Like Receptor 2 Regulates Interleukin-1{beta}-Dependent Cardiomyocyte Hypertrophy Triggered by Trypanosoma cruzi Infect. Immun., October 1, 2005; 73(10): 6974 - 6980. [Abstract] [Full Text] [PDF]
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T. Shimizu, Y. Kida, and K. Kuwano A Dipalmitoylated Lipoprotein from Mycoplasma pneumoniae Activates NF-{kappa}B through TLR1, TLR2, and TLR6 J. Immunol., October 1, 2005; 175(7): 4641 - 4646. [Abstract] [Full Text] [PDF]
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P. G. Arndt, S. K. Young, and G. S. Worthen Regulation of Lipopolysaccharide-Induced Lung Inflammation by Plasminogen Activator Inhibitor-1 through a JNK-Mediated Pathway J. Immunol., September 15, 2005; 175(6): 4049 - 4059. [Abstract] [Full Text] [PDF]
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S. Al-Robaiy, J. Knauer, and R. K. Straubinger Borrelia burgdorferi Organisms Lacking Plasmids 25 and 28-1 Are Internalized by Human Blood Phagocytes at a Rate Identical to That of the Wild-Type Strain Infect. Immun., September 1, 2005; 73(9): 5547 - 5553. [Abstract] [Full Text] [PDF]
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G. Mancuso, A. Midiri, C. Biondo, C. Beninati, M. Gambuzza, D. Macri, A. Bellantoni, A. Weintraub, T. Espevik, and G. Teti Bacteroides fragilis-Derived Lipopolysaccharide Produces Cell Activation and Lethal Toxicity via Toll-Like Receptor 4 Infect. Immun., September 1, 2005; 73(9): 5620 - 5627. [Abstract] [Full Text] [PDF]
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B. C. Cole, H.-H. Mu, N. D. Pennock, A. Hasebe, F. V. Chan, L. R. Washburn, and M. R. Peltier Isolation and Partial Purification of Macrophage- and Dendritic Cell-Activating Components from Mycoplasma arthritidis: Association with Organism Virulence and Involvement with Toll-Like Receptor 2 Infect. Immun., September 1, 2005; 73(9): 6039 - 6047. [Abstract] [Full Text] [PDF]
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H. Echchannaoui, K. Frei, M. Letiembre, R. M. Strieter, Y. Adachi, and R. Landmann CD14 deficiency leads to increased MIP-2 production, CXCR2 expression, neutrophil transmigration, and early death in pneumococcal infection J. Leukoc. Biol., September 1, 2005; 78(3): 705 - 715. [Abstract] [Full Text] [PDF]
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S. Shi, A. Blumenthal, C. M. Hickey, S. Gandotra, D. Levy, and S. Ehrt Expression of Many Immunologically Important Genes in Mycobacterium tuberculosis-Infected Macrophages Is Independent of Both TLR2 and TLR4 but Dependent on IFN-{alpha}{beta} Receptor and STAT1 J. Immunol., September 1, 2005; 175(5): 3318 - 3328. [Abstract] [Full Text] [PDF]
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H. S. Youn, J. Y. Lee, K. A. Fitzgerald, H. A. Young, S. Akira, and D. H. Hwang Specific Inhibition of MyD88-Independent Signaling Pathways of TLR3 and TLR4 by Resveratrol: Molecular Targets Are TBK1 and RIP1 in TRIF Complex J. Immunol., September 1, 2005; 175(5): 3339 - 3346. [Abstract] [Full Text] [PDF]
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N. W. J. Schroder, I. Diterich, A. Zinke, J. Eckert, C. Draing, V. v. Baehr, D. Hassler, S. Priem, K. Hahn, K. S. Michelsen, et al. Heterozygous Arg753Gln Polymorphism of Human TLR-2 Impairs Immune Activation by Borrelia burgdorferi and Protects from Late Stage Lyme Disease J. Immunol., August 15, 2005; 175(4): 2534 - 2540. [Abstract] [Full Text] [PDF]
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J. C. Salazar, C. D. Pope, M. W. Moore, J. Pope, T. G. Kiely, and J. D. Radolf Lipoprotein-Dependent and -Independent Immune Responses to Spirochetal Infection Clin. Vaccine Immunol., August 1, 2005; 12(8): 949 - 958. [Abstract] [Full Text] [PDF]
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C.-L. Hahn, H. A. Schenkein, and J. G. Tew Endocarditis-Associated Oral Streptococci Promote Rapid Differentiation of Monocytes into Mature Dendritic Cells Infect. Immun., August 1, 2005; 73(8): 5015 - 5021. [Abstract] [Full Text] [PDF]
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C. Roura-Mir, L. Wang, T.-Y. Cheng, I. Matsunaga, C. C. Dascher, S. L. Peng, M. J. Fenton, C. Kirschning, and D. B. Moody Mycobacterium tuberculosis Regulates CD1 Antigen Presentation Pathways through TLR-2 J. Immunol., August 1, 2005; 175(3): 1758 - 1766. [Abstract] [Full Text] [PDF]
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B. Fournier and D. J. Philpott Recognition of Staphylococcus aureus by the Innate Immune System Clin. Microbiol. Rev., July 1, 2005; 18(3): 521 - 540. [Abstract] [Full Text] [PDF]
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K. Craig-Mylius, G. F. Weber, J. Coburn, and L. Glickstein Borrelia burgdorferi, an extracellular pathogen, circumvents osteopontin in inducing an inflammatory cytokine response J. Leukoc. Biol., May 1, 2005; 77(5): 710 - 718. [Abstract] [Full Text] [PDF]
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Y. Wang, H. M. Curry, B. S. Zwilling, and W. P. Lafuse Mycobacteria Inhibition of IFN-{gamma} Induced HLA-DR Gene Expression by Up-Regulating Histone Deacetylation at the Promoter Region in Human THP-1 Monocytic Cells J. Immunol., May 1, 2005; 174(9): 5687 - 5694. [Abstract] [Full Text] [PDF]
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Q. Zhou, T. Desta, M. Fenton, D. T. Graves, and S. Amar Cytokine Profiling of Macrophages Exposed to Porphyromonas gingivalis, Its Lipopolysaccharide, or Its FimA Protein Infect. Immun., February 1, 2005; 73(2): 935 - 943. [Abstract] [Full Text] [PDF]
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M. R.-E.-I. Benhnia, D. Wroblewski, M. N. Akhtar, R. A. Patel, W. Lavezzi, S. C. Gangloff, S. M. Goyert, M. J. Caimano, J. D. Radolf, and T. J. Sellati Signaling through CD14 Attenuates the Inflammatory Response to Borrelia burgdorferi, the Agent of Lyme Disease J. Immunol., February 1, 2005; 174(3): 1539 - 1548. [Abstract] [Full Text] [PDF]
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Y. Nakao, K. Funami, S. Kikkawa, M. Taniguchi, M. Nishiguchi, Y. Fukumori, T. Seya, and M. Matsumoto Surface-Expressed TLR6 Participates in the Recognition of Diacylated Lipopeptide and Peptidoglycan in Human Cells J. Immunol., February 1, 2005; 174(3): 1566 - 1573. [Abstract] [Full Text] [PDF]
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T. M. Schaefer, J. V. Fahey, J. A. Wright, and C. R. Wira Innate Immunity in the Human Female Reproductive Tract: Antiviral Response of Uterine Epithelial Cells to the TLR3 Agonist Poly(I:C) J. Immunol., January 15, 2005; 174(2): 992 - 1002. [Abstract] [Full Text] [PDF]
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M. Akamine, F. Higa, N. Arakaki, K. Kawakami, K. Takeda, S. Akira, and A. Saito Differential Roles of Toll-Like Receptors 2 and 4 in In Vitro Responses of Macrophages to Legionella pneumophila Infect. Immun., January 1, 2005; 73(1): 352 - 361. [Abstract] [Full Text] [PDF]
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X. Wang, Y. Ma, J. H. Weis, J. F. Zachary, C. J. Kirschning, and J. J. Weis Relative Contributions of Innate and Acquired Host Responses to Bacterial Control and Arthritis Development in Lyme Disease Infect. Immun., January 1, 2005; 73(1): 657 - 660. [Abstract] [Full Text] [PDF]
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S. K. Pathak, A. Bhattacharyya, S. Pathak, C. Basak, D. Mandal, M. Kundu, and J. Basu Toll-like Receptor 2 and Mitogen- and Stress-activated Kinase 1 Are Effectors of Mycobacterium avium-induced Cyclooxygenase-2 Expression in Macrophages J. Biol. Chem., December 31, 2004; 279(53): 55127 - 55136. [Abstract] [Full Text] [PDF]
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D. S. Zamboni, M. A. Campos, A. C. T. Torrecilhas, K. Kiss, J. E. Samuel, D. T. Golenbock, F. N. Lauw, C. R. Roy, I. C. Almeida, and R. T. Gazzinelli Stimulation of Toll-like Receptor 2 by Coxiella burnetii Is Required for Macrophage Production of Pro-inflammatory Cytokines and Resistance to Infection J. Biol. Chem., December 24, 2004; 279(52): 54405 - 54415. [Abstract] [Full Text] [PDF]
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C. W. Wieland, S. Knapp, S. Florquin, A. F. de Vos, K. Takeda, S. Akira, D. T. Golenbock, A. Verbon, and T. van der Poll Non-Mannose-capped Lipoarabinomannan Induces Lung Inflammation via Toll-like Receptor 2 Am. J. Respir. Crit. Care Med., December 15, 2004; 170(12): 1367 - 1374. [Abstract] [Full Text] [PDF]
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D. Nicolle, C. Fremond, X. Pichon, A. Bouchot, I. Maillet, B. Ryffel, and V. J. F. Quesniaux Long-Term Control of Mycobacterium bovis BCG Infection in the Absence of Toll-Like Receptors (TLRs): Investigation of TLR2-, TLR6-, or TLR2-TLR4-Deficient Mice Infect. Immun., December 1, 2004; 72(12): 6994 - 7004. [Abstract] [Full Text] [PDF]
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 Y. Wu, S. Adam, L. Hamann, H. Heine, A. J. Ulmer, U. Buwitt-Beckmann, and C. Stamme Accumulation of Inhibitory {kappa}B-{alpha} as a Mechanism Contributing to the Anti-Inflammatory Effects of Surfactant Protein-A Am. J. Respir. Cell Mol. Biol., December 1, 2004; 31(6): 587 - 594. [Abstract] [Full Text] [PDF]
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N. Hyakushima, H. Mitsuzawa, C. Nishitani, H. Sano, K. Kuronuma, M. Konishi, T. Himi, K. Miyake, and Y. Kuroki Interaction of Soluble Form of Recombinant Extracellular TLR4 Domain with MD-2 Enables Lipopolysaccharide Binding and Attenuates TLR4-Mediated Signaling J. Immunol., December 1, 2004; 173(11): 6949 - 6954. [Abstract] [Full Text] [PDF]
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A. Grabiec, G. Meng, S. Fichte, W. Bessler, H. Wagner, and C. J. Kirschning Human but Not Murine Toll-like Receptor 2 Discriminates between Tri-palmitoylated and Tri-lauroylated Peptides J. Biol. Chem., November 12, 2004; 279(46): 48004 - 48012. [Abstract] [Full Text] [PDF]
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L. Mandell, A. P. Moran, A. Cocchiarella, J. Houghton, N. Taylor, J. G. Fox, T. C. Wang, and E. A. Kurt-Jones Intact Gram-Negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus Bacteria Activate Innate Immunity via Toll-Like Receptor 2 but Not Toll-Like Receptor 4 Infect. Immun., November 1, 2004; 72(11): 6446 - 6454. [Abstract] [Full Text] [PDF]
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A.-C. Oliveira, J. R. Peixoto, L. B. de Arruda, M. A. Campos, R. T. Gazzinelli, D. T. Golenbock, S. Akira, J. O. Previato, L. Mendonca-Previato, A. Nobrega, et al. Expression of Functional TLR4 Confers Proinflammatory Responsiveness to Trypanosoma cruzi Glycoinositolphospholipids and Higher Resistance to Infection with T. cruzi J. Immunol., November 1, 2004; 173(9): 5688 - 5696. [Abstract] [Full Text] [PDF]
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M. K. Dahle, G. Overland, A. E. Myhre, J. F. Stuestol, T. Hartung, C. D. Krohn, O. Mathiesen, J. E. Wang, and A. O. Aasen The Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Pathway Is Activated by Lipoteichoic Acid and Plays a Role in Kupffer Cell Production of Interleukin-6 (IL-6) and IL-10 Infect. Immun., October 1, 2004; 72(10): 5704 - 5711. [Abstract] [Full Text] [PDF]
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 A. Kumar, J. Zhang, and F.-S. X. Yu Innate Immune Response of Corneal Epithelial Cells to Staphylococcus aureus Infection: Role of Peptidoglycan in Stimulating Proinflammatory Cytokine Secretion Invest. Ophthalmol. Vis. Sci., October 1, 2004; 45(10): 3513 - 3522. [Abstract] [Full Text] [PDF]
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V. M. Abrahams, P. Bole-Aldo, Y. M. Kim, S. L. Straszewski-Chavez, T. Chaiworapongsa, R. Romero, and G. Mor Divergent Trophoblast Responses to Bacterial Products Mediated by TLRs J. Immunol., October 1, 2004; 173(7): 4286 - 4296. [Abstract] [Full Text] [PDF]
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N. Nilsen, U. Nonstad, N. Khan, C. F. Knetter, S. Akira, A. Sundan, T. Espevik, and E. Lien Lipopolysaccharide and Double-stranded RNA Up-regulate Toll-like Receptor 2 Independently of Myeloid Differentiation Factor 88 J. Biol. Chem., September 17, 2004; 279(38): 39727 - 39735. [Abstract] [Full Text] [PDF]
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A. J. Gehring, K. M. Dobos, J. T. Belisle, C. V. Harding, and W. H. Boom Mycobacterium tuberculosis LprG (Rv1411c): A Novel TLR-2 Ligand That Inhibits Human Macrophage Class II MHC Antigen Processing J. Immunol., August 15, 2004; 173(4): 2660 - 2668. [Abstract] [Full Text] [PDF]
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