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*
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;
Immunobiology Research Group, Gesellschaft für Biotechnologische Forschung, Braunschweig, Germany; and
Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, showing the synergy between TLR2- and TLR4-mediated
signaling pathways. Macrophages pretreated with LPS show
hyporesponsiveness to the second LPS stimulation, termed LPS tolerance.
The LPS tolerance has recently been shown to be primarily due to the
down-regulation of surface expression of the TLR4-MD2 complex. When
macrophages were treated with MALP-2, the cells showed
hyporesponsiveness to the second MALP-2 stimulation, like LPS
tolerance. Furthermore, macrophages pretreated with MALP-2 showed
reduced production of TNF- in response to LPS. LPS-induced
activation of both NF-
B and c-Jun NH2-terminal kinase
was severely impaired in MALP-2-pretreated cells. However,
MALP-2-pretreated macrophages did not show any reduction in surface
expression of the TLR4-MD2 complex. These findings indicate that
LPS-induced LPS tolerance mainly occurs through the down-regulation of
surface expression of the TLR4-MD2 complex; in contrast, MALP-2-induced
LPS tolerance is due to modulation of the downstream cytoplasmic
signaling pathways. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-6. Among the
bacterial cell wall components, LPS from the cell wall of Gram-negative
bacteria is best known as a component that activates monocytes and
macrophages. Excessive activation of monocytes and macrophages by LPS
leads to endotoxin shock, a systemic serious disorder with a high
mortality rate in human and experimental animals. Pre-exposure to LPS
reduces sensitivity to a second challenge with LPS, called LPS
tolerance (also called LPS hyporesponsiveness, or refractoriness)
(1). Animals pretreated with low doses of LPS showed
reduced febrile response and mortality rate after a second challenge
with LPS. LPS tolerance was also observed at the level of macrophages.
Macrophages pretreated with LPS showed no or reduced production of
inflammatory cytokines in response to the second stimulation with LPS.
Although molecular mechanisms of LPS tolerance have long been
investigated, they remain unclear. Several bacterial cell wall components as well as LPS have been shown to possess a potential to activate monocyte and macrophages and induce a symptom like endotoxin shock in experimental animals. These include bacterial lipopeptides, peptidoglycan, muramyl dipeptide from Gram-positive bacteria, and bacterial DNA containing unmethylated CpG motif. These bacterial components have also been shown to induce tolerance to the subsequent stimulation (2, 3, 4).
Recent studies have demonstrated that bacterial cell wall components are recognized by pattern recognition receptors on innate immune cells (5, 6). Especially, families of Toll-like receptors (TLR)3 have been shown involved in the recognition of bacterial components. In Drosophila, Toll family proteins specify the innate immune responses to microbial infections; Toll is responsible for the response to fungal infection, whereas 18-wheeler responds to bacterial infection (7, 8). Mutations in the Tlr4 gene have been found in LPS-hyporesponsive C3H/HeJ and C57BL/10ScCr mice (9, 10). Furthermore, analyses of gene-targeted mice have recently demonstrated that the TLR family recognizes the specific pattern of bacterial cell wall components (11, 12, 13). Recent studies reported that modulation of the signaling pathway via TLR4 is involved in development of LPS tolerance (14, 15). We have also analyzed the molecular mechanisms of LPS tolerance (16). When mouse peritoneal macrophages were treated with LPS, surface expression of the TLR4-MD2 complex was severely reduced, which led to hyporesponsiveness to LPS.
In the present study, we investigated the synergy and cross-tolerance between LPS and mycoplasmal lipopeptides (macrophage-activating lipopeptides, 2 kDa (MALP-2)), each of which is differentially recognized by TLR4 and TLR2, respectively.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Peritoneal macrophages were isolated from C57BL/6J mice, ICR mice (SLC, Shizuoka, Japan), or IL-10-deficient mice (The Jackson Laboratory, Bar Harbor, ME). Briefly, mice were i.p. injected with 2 ml of 4% thioglycolate. After 3 days of injection, peritoneal exudate cells were isolated by washing the peritoneal cavity with ice-cold HBSS. These cells were incubated for 2 h, and adherent cells were used as peritoneal macrophages. RPMI 1640 (Life Technologies, Gaithersburg, MD) supplemented with 10% FBS (Life Technologies), 2-ME (100 µM), penicillin (5 U/ml), and streptomycin (50 ng/ml) was used as culture medium.
Reagents and Abs
LPS from Salmonella minnesota Re595 prepared by a phenol-chloroform-petroleum ether extraction procedure was purchased from Sigma (St. Louis, MO). LPS from Escherichia coli serotype O55:B5 was obtained from List Biological Laboratories (Campbell, CA). MALP-2 was synthesized and purified as described previously (13).
The MTS510 mAb that specifically recognizes the mouse TLR4-MD2 complex was provided by K. Miyake (17). Anti-IL-1-receptor-associated kinase (IRAK) 1 Ab was provided by Hayashibara Biochemical Laboratories (Okayama, Japan). Rabbit anti-c-Jun NH2-terminal kinase 1 (anti-JNK), anti-extracellular-regulated kinase 1 and 2 (anti-ERK-1,2), anti-p50, and anti-p65 Abs were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Rabbit anti-phospho-ERK-1,2 Ab was obtained from New England Biolabs (Beverly, MA)
Measurement of cytokine concentration
Peritoneal macrophages (1 x 105)
were stimulated with the indicated concentrations of LPS and/or MALP-2
for 24 h. For tolerance experiment, cells were preincubated with
100 ng/ml LPS or 3 ng/ml MALP-2 for 24 h and washed twice with
culture medium. Then cells were stimulated with 100 ng/ml LPS or 3
ng/ml MALP-2 for 24 h. Concentrations of TNF- in the culture
supernatants were measured by ELISA according to the manufacturer’s
instructions (Genzyme Techne, Minneapolis, MN).
Northern blot analysis
Peritoneal macrophages (5 x 106)
were preincubated with 100 ng/ml of S. minnesota Re595 LPS
or 3 ng/ml MALP-2 for 24 h and washed twice with culture medium.
Cells were stimulated with 100 ng/ml S. minnesota Re595 LPS
or 3 ng/ml MALP-2 for 4 h. Then total RNA was extracted with an
RNeasy kit (Qiagen, Hilden, Germany). RNA (10 µg) was
electrophoresed, transferred to nylon membrane (Hybond
N+; Amersham Pharmacia Biotech, Uppsala, Sweden)
and hybridized with a specific cDNA probe for mouse TNF-. The same
membrane was stripped and rehybridized with a GAPDH cDNA probe for an
internal control.
RT-PCR analysis
Total RNA was extracted with an RNeasy kit (Qiagen) and reverse transcribed using Superscript II (Life Technologies). The cDNA products were PCR amplified with the gene-specific primers. The primer sequences are available upon request.
Western blot analysis
Peritoneal macrophages were lysed in the lysis buffer containing 1.0% Nonidet P-40, 150 mM NaCl, 10 mM Tris-Cl (pH 7.5), and 1 mM EDTA. The cell lysates were dissolved by SDS-PAGE and transferred onto a nitrocellulose membrane. The membrane was incubated with the indicated Abs and visualized with an enhanced chemiluminescence system.
Flow cytometric analysis
Peritoneal macrophages (2 x 106) were cultured with 1 µg/ml S. minnesota Re595 LPS or 3 ng/ml MALP-2 for 24 h or were not treated. Then cells were harvested and stained with PE-conjugated anti-mouse CD14 Ab or biotin-conjugated MTS510 Ab followed by streptavidin-PE. Stained cells were analyzed on FACScalibur using CellQuest software (Becton Dickinson, Lincoln Park, NJ).
EMSA and in vitro kinase assay
Peritoneal macrophages (2 x 106) were incubated with 100 ng/ml S. minnesota Re595 LPS or 3 ng/ml MALP-2 for 24 h and washed twice with HBSS. Cells were cultured with culture medium alone for 1 h and then stimulated with 100 ng/ml S. minnesota Re595 LPS or 3 ng/ml MALP-2 for 10 or 20 min. EMSA and in vitro kinase assay were performed as described previously (18).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production
We first examined whether LPS and MALP-2 act synergistically on
mouse peritoneal macrophages for induction of cytokine production.
Peritoneal macrophages were stimulated with S. minnesota
Re595 LPS and/or MALP-2 for 24 h, and then the TNF-
concentration in the culture supernatants of these cells was measured
by ELISA (Fig. 1
, left).
Stimulation with LPS or MALP-2 induced TNF- production from the
macrophages, and this production reached a plateau (2.5 or 1 ng/ml) at
concentrations of 10 or 0.3 ng/ml, respectively. When cells were
stimulated with combinations of 10 ng/ml LPS and 0.3 ng/ml MALP-2, the
TNF- concentration was increased to 5 ng/ml. In addition, when we
stimulated with higher concentrations of both LPS and MALP-2, TNF-
production was increased in a dose-dependent manner. The similar
synergistic action of MALP-2 and LPS was also observed when we used
E. coli O55:B5 LPS (Fig. 1, right). Thus, when
peritoneal macrophages were exposed to LPS and MALP-2 at the same time,
they showed synergistic action on cells to produce TNF-.
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Monocytes/macrophages pre-exposed to LPS show a hyporesponsive
state to LPS, which is known as LPS tolerance. Treatment with both
S. minnesota Re595 LPS and E. coli O55:B5 LPS
induced tolerance to the second stimulation with LPS (Fig. 2). Several reports indicated that the
similar tolerance could be induced by other bacterial cell components,
such as peptidoglycan and lipoproteins. We next examined whether MALP-2
has a potential to induce tolerance. When peritoneal macrophages were
pre-exposed to MALP-2 for 24 h, a second stimulation with MALP-2
did not induce TNF- production (Fig. 2). Thus, like LPS tolerance,
MALP-2 stimulation induced MALP-2 tolerance in mouse peritoneal
macrophages. We next analyzed whether MALP-2 treatment induced
tolerance to LPS and vice versa. MALP-2 pretreatment resulted in a
significant decrease in TNF- production in response to LPS,
indicating that MALP-2 treatment induced tolerance to LPS. In contrast,
when macrophages were pretreated with LPS, these cells produced a
significant level of TNF- in response to MALP-2, although the
TNF- level was somewhat decreased compared with that of nontreated
cells. These indicate that LPS-induced tolerance to MALP-2 was weaker
than LPS tolerance induced by MALP-2.
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mRNA expression in response to MALP-2 and
LPS by Northern blot analysis (Fig. 3A). Induction of TNF- mRNA
in response to MALP-2 or LPS was significantly reduced in MALP-2- and
LPS-pretreated macrophages, respectively. Thus, MALP-2 and LPS
tolerance was observed at the level of mRNA expression. We next
analyzed cross-tolerance to MALP-2 and LPS. In accordance with the
TNF- production determined by ELISA, LPS-induced TNF- mRNA
expression was significantly reduced in MALP-2-pretreated macrophages.
In contrast, MALP-2-induced expression was observed in LPS-pretreated
macrophages, although it was reduced compared with that in nontreated
cells (Fig. 3A). These results further indicate that
MALP-2-induced tolerance to LPS was more potent than LPS-induced
tolerance to MALP-2.
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B). Results of RT-PCR
analysis for TNF- and IL-6 mRNA expression showed the same pattern
as those of Northern blot and ELISA; that is, LPS did not, but MALP-2
did, induce TNF- and IL-6 mRNA expression in LPS-pretreated cells.
In MALP-2 pretreated cells, neither MALP-2 nor LPS induced these mRNA
expressions. Thus, RT-PCR analysis indicated that the similar
cross-tolerance occurred in IL-6 induction.
Several reports indicated that the induction of NO and IL-10 was not
affected in LPS tolerance (1, 19, 20). We analyzed mRNA
expression of inducible NO synthase (iNOS) and IL-10 by RT-PCR (Fig. 3B). Basal expression of both iNOS and IL-10 mRNA was
up-regulated in LPS-pretreated cells. However, MALP-2 stimulation led
to a further increase in the expression of both iNOS and IL-10 mRNA,
but LPS did not. In MALP-2-pretreated cells, expression of both mRNA
was slightly up-regulated. The second stimulation with MALP-2 did not
increase mRNA expression; however, the second stimulation with LPS did
increase it in MALP-2-pretreated cells. Thus, in the case of iNOS and
IL-10 induction, the LPS tolerance was observed in LPS-pretreated cells
despite the fact that basal mRNA expression was increased, and whereas
MALP-2 tolerance was observed in MALP-2-pretreated cells, LPS tolerance
was not observed, unlike in induction of TNF- and IL-6.
MALP-2 pretreatment affects LPS-mediated signaling pathway
The signaling pathways of both LPS and MALP-2 have been shown to
depend on MyD88, leading to activation of NF-B and JNK (12, 13). We analyzed activation of NF-B and JNK in MALP-2- and
LPS-pretreated macrophages. We first investigated NF-B activation in
response to MALP-2 and LPS (Fig. 4A). Peritoneal macrophages
pretreated with MALP-2 or LPS for 24 h were stimulated with 100
ng/ml of S. minnesota Re595 LPS or 3 ng/ml MALP-2 for 20
min. Nuclear extracts from these cells were analyzed with EMSA using a
specific probe containing NF-B binding motif. In nontreated cells,
both MALP-2 and LPS stimulation induced a significant increase in
NF-B DNA binding activity. Both MALP-2 and LPS stimulation resulted
in the formation of two major DNA-protein complexes (* and ** in
Fig. 4A). To determine which subunits of NF-B comprised
these two complexes, we conducted supershift experiments using Abs to
p50 and p65 subunit of NF-B (Fig. 4B). Preincubation with
anti-p50 Ab resulted in supershifts of both upper (*) and lower
(**) bands. In contrast, anti-p65 Ab only induced supershift of
upper band. These demonstrate that the upper band represents p50/p65
heterodimer, and the lower band represents p50/p50 homodimer. When
cells were pretreated with LPS, augmentation of NF-B activity in
response to second stimulation with LPS was almost completely
suppressed (Fig. 4A). Likewise, MALP-2-induced NF-B
activation was not observed in MALP-2-pretreated cells. Thus, NF-B
activity was severely reduced in both MALP-2 and LPS tolerance. In
MALP-2-pretreated cells, not only MALP-2-induced but also LPS-induced
augmentation of NF-B activity were severely reduced, indicating that
MALP-2 treatment affected both MALP-2- and LPS-mediated signaling
pathways. In contrast, MALP-2 stimulation significantly increased
NF-B activity in LPS-pretreated cells; p50/p65 heterodimers
(upper band, *) was mainly induced (Fig. 4A)
Thus, MALP-2 treatment affected both MALP-2- and LPS-mediated NF-B
activity; in contrast, LPS treatment affected LPS-mediated, but less
effectively MALP-2-mediated, NF-B activity in macrophages.
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A). JNK
was activated in response to both LPS and MALP-2 in nontreated cells.
JNK activation was almost completely diminished when cells were
pretreated with the same stimulant. Furthermore, LPS-induced JNK
activation was not observed in MALP-2-pretreated cells; in contrast,
MALP-2-induced JNK activation was significantly observed, although at a
reduced level, in LPS-pretreated cells. Taken together, these results
indicate that signaling pathways of both MALP-2 and LPS were affected
in MALP-2-pretreated macrophages; in contrast, the LPS-mediated, but
not the MALP-2-mediated, signaling pathway was affected in
LPS-pretreated cells.
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B). In LPS- or MALP-2-pretreated cells, PMA-induced
phosphorylation of ERK-1 and 2 was observed at a level similar to that
in nontreated cells. Thus, LPS- or MALP-2-pretreated cells showed no
impaired response to an unrelated stimulation. Surface expression of theTLR4-MD2 complex was not reduced by MALP-2 stimulation
We next addressed expression of several components involved in the
signaling pathways for LPS and MALP-2. RT-PCR analysis showed that mRNA
expression of genes, such as TLR4, TLR2, MD2, MyD88, and IRAK-1, was
not reduced in LPS- and MALP-2-treated macrophages (Fig. 6A). Western blot analysis
further demonstrated that expression of IRAK-1 was not reduced in LPS-
and MALP-2-tretaed cells (Fig. 6B).
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C,
left). However, the surface expression of the TLR4-MD2
complex was not reduced, rather it was enhanced, in MALP-2-treated
macrophages. CD14 is another surface molecule responsible for the
recognition of LPS. MALP-2 stimulation did not reduce surface CD14
expression, as is the case in LPS stimulation (Fig. 6C,
right). These results suggest that MALP-2-induced tolerance
to LPS did not occur through down-regulation of the surface TLR4-MD2
complex and CD14 expression, indicating that MALP-2-induced tolerance
occurs through mechanisms other than LPS-induced tolerance. LPS- and MALP-2-induced tolerance was not mediated by IL-10
In LPS- and MALP-2-pretreated macrophages, IL-10 mRNA was
constitutively expressed (Fig. 3B). IL-10 is known to
suppress macrophage activity. Although LPS tolerance has been shown to
be induced independently of IL-10, there remains the possibility that
MALP-2-induced tolerance is dependent on IL-10 (22).
Therefore, we analyzed whether IL-10 was involved in LPS- and
MALP-2-induced tolerance using IL-10-deficient mice. Peritoneal
macrophages from wild-type and IL-10-deficient mice were pretreated
with LPS or MALP-2, then restimulated and analyzed for TNF-
production by ELISA (Fig. 7). In
LPS-pretreated IL-10-deficient macrophages, LPS did not but MALP-2 did
induce TNF- production. In MALP-2-pretreated IL-10-deficient
macrophages, neither MALP-2 nor LPS induced TNF- production, Thus,
macrophages from IL-10-deficient mice displayed the similar
cross-tolerance state as wild-type mice, indicating that MALP-2-induced
tolerance occurs independently of IL-10 induction.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first demonstrated that MALP-2 and LPS synergistically act on
peritoneal macrophages and induce production of inflammatory cytokines.
An adaptor molecule, MyD88, is involved in the signaling pathway via
TLR4 (19, 20). Upon stimulation, MyD88, which binds to
TLR4, recruits IRAK to the receptor. IRAK then activates TRAF6, leading
to activation of NF-B and JNK (23, 24). Indeed, both
MyD88- and TRAF6-deficient mice displayed hyporesponsiveness to LPS
(18, 25, 26). MyD88-deficient mice especially were almost
completely unresponsive to LPS, indicating that the MyD88-dependent
pathway is essential for inflammatory responses to LPS
(18). Furthermore, MyD88-deficient mice showed no
inflammatory response to several other bacterial components, including
peptidoglycan and MALP-2 (13, 27). Both peptidoglycan and
MALP-2 have been shown to be recognized by TLR2. Thus, MyD88 is the
adaptor molecule shared by TLR2- and TLR4-mediated signaling pathways.
Although the molecular mechanism of the synergistic action of MALP-2
and LPS is unknown, our present study indicates that the simultaneous
activation of different TLRs could exert the synergistic effects.
Indeed, bacterial lipopeptides and lipoprotein have been shown to
induce inflammatory cytokine production in synergy with LPS (4, 28). The mycoplasmal lipopeptide MALP-2 is structurally related
to bacterial lipopeptides and lipoprotein, all of which have been shown
recognized by TLR2 (29, 30, 31, 32, 33). Several other reports
demonstrated that bacterial DNA also synergistically acts with LPS for
induction of inflammatory cytokine production (34, 35, 36). A
responsible pattern recognition receptor of bacterial DNA has not been
identified. However, when we consider that bacterial DNA and LPS
synergistically act in a manner similar to MALP-2 and LPS, we can
hypothesize that bacterial DNA is recognized by a member of the TLR
family other than TLR4.
We next addressed the cross-tolerance between MALP-2 and LPS. MALP-2
induced tolerance to the second stimulation with MALP-2, like LPS
tolerance. In addition, when macrophages were treated with MALP-2,
these cells showed the reduced TNF- production in response to the
second LPS stimulation, demonstrating that MALP-2 treatment induced
tolerance to LPS as well as to MALP-2. Our previous study demonstrated
that a major cause of LPS tolerance is the down-regulation of the
TLR4-MD2 complex after LPS pretreatment. Reduction of surface
expression of the TLR4-MD2 complex was observed even in C3H/HeJ mice,
which are hyporesponsive to LPS (16). The rapid
down-regulation of TLR4-MD2 might occur by an internalization of LPS
along with the receptor complex. This hypothesis was supported by the
recent report demonstrating that surface TLR2 on macrophages was
rapidly internalized to phagosome after treatment with zymosan, a
component of the yeast cell wall (37). Therefore, in the
MALP-2-treated macrophages, surface TLR2 might be down-regulated, as is
the case in zymosan-treated macrophages. However, we cannot explain the
mechanism of the MALP-2-induced tolerance to LPS by down-regulation of
surface TLR2 expression, because TLR2-deficient mice showed the normal
response to LPS (12). Furthermore, macrophages treated
with MALP-2 did not show any decreased expression of the surface
TLR4-MD2 complex. Despite the normal TLR4 expression in MALP-2-treated
macrophages, LPS-induced NF-B and JNK activation was severely
reduced. These findings indicate that MALP-2-induced tolerance to LPS
is due to the affected LPS signaling pathway, but not to the reduced
surface expression of the TLR4-MD2 complex. Interestingly, when
macrophages were pretreated with LPS, induction of tolerance to MALP-2
was poor. Production of TNF- as well as activation of NF-B and
JNK in response to MALP-2 were significantly observed in LPS-pretreated
macrophages. A similar phenomenon has been reported in several
cross-tolerance models. Pretreatment with bacterial DNA induced LPS
tolerance; however, LPS pretreatment was less effective in induction of
tolerance to bacterial DNA (34, 38). Likewise, although
muramyl dipeptide pretreatment significantly reduced the serum level of
inflammatory cytokines after administration of LPS, LPS treatment did
not reduce inflammatory cytokine production after muramyl dipeptide
administration in guinea pig (2). Thus, LPS treatment has
been shown to be less effective in induction of tolerance to other
bacterial components. In this point our speculation is as follows. In
both LPS and MALP-2 pretreatment, tolerance occurs through
down-regulation of surface TLRs as well as inhibition of the downstream
signaling pathways. In the case of MALP-2 pretreatment, the shut-off of
the downstream signaling pathway takes place at a similar pace with the
down-regulation of TLR2. In contrast, when pretreated with LPS, the
down-regulation of surface TLR4 is dominant, and thereby the downstream
signaling pathway is not severely affected.
In LPS-pretreated macrophages, mRNA expression of iNOS and IL-10 was constitutively observed, but subsequent LPS stimulation did not enhance the mRNA expression, indicating that the cells were tolerant to LPS. Several previous studies reported that production of NO and IL-10 was induced by LPS even in the LPS-tolerant cells (19, 20). These data seem contradictory to our findings; however, in these papers macrophages were pretreated with a low concentration of LPS (<20 ng/ml). We previously reported that induction of LPS tolerance was not severe when stimulated with a low concentration of LPS (16). Thus, the low concentration of LPS might not effectively induce LPS tolerance.
In MALP-2-pretreated cells, LPS-induced expression of iNOS and IL-10
was not severely affected. In this regard we speculate as follows.
MALP-2 pretreatment affects mainly the TLR-MyD88-dependent signaling
pathway, which is essential for LPS-induced TNF- induction, as
demonstrated in MyD88-deficient mice (18). However, even
in MyD88-deficient mice, LPS-induced activation of the signaling
cascades and expression of several genes other than TNF- and IL-6
were observed (our unpublished observations). These indicate that an
unidentified MyD88-independent signaling pathway(s) does exist. In
MALP-2-pretreated macrophages, surface expression of the TLR4-MD2
complex was not reduced, which means that possibly LPS-induced
activation of the MyD88-independent signaling pathway occurs.
Therefore, we suspect that although LPS-induced activation of the
MyD88-dependent signaling pathway was affected, activation of the
MyD88-independent signaling pathway in MALP-2-pretreated cells might
account for the induction of iNOS and IL-10. Elucidation of precise
mechanisms of tolerance induction will require additional
experiments.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Shizuo Akira, Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
3 Abbreviations used in this paper: TLR, Toll-like receptor; MALP-2, macrophage-activating lipopeptides, 2 kDa; ERK, extracellular-regulated kinase; JNK, c-Jun NH2-terminal kinase; iNOS, inducible NO synthase; IRAK, IL-1 receptor-associated kinase.
Received for publication April 24, 2000. Accepted for publication September 18, 2000.
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 W. Chao Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H1 - H12. [Abstract] [Full Text] [PDF]
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 S. Epelman, B. Berenger, D. Stack, G. G. Neely, L. L. Ma, and C. H. Mody Microbial Products Activate Monocytic Cells through Detergent-Resistant Membrane Microdomains Am. J. Respir. Cell Mol. Biol., December 1, 2008; 39(6): 657 - 665. [Abstract] [Full Text] [PDF]
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 H. Mashimo, N. Ohguro, S. Nomura, N. Hashida, K. Nakai, and Y. Tano Neutrophil Chemotaxis and Local Expression of Interleukin-10 in the Tolerance of Endotoxin-Induced Uveitis Invest. Ophthalmol. Vis. Sci., December 1, 2008; 49(12): 5450 - 5457. [Abstract] [Full Text] [PDF]
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A. Draisma, M. Dorresteijn, P. Pickkers, and H. van der Hoeven The effect of systemic iNOS inhibition during human endotoxemia on the development of tolerance to different TLR-stimuli Innate Immunity, June 1, 2008; 14(3): 153 - 159. [Abstract] [PDF]
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 J. D. Coudert, L. Scarpellino, F. Gros, E. Vivier, and W. Held Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways Blood, April 1, 2008; 111(7): 3571 - 3578. [Abstract] [Full Text] [PDF]
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H. G. Kim, N.-R. Kim, M. G. Gim, J. M. Lee, S. Y. Lee, M. Y. Ko, J. Y. Kim, S. H. Han, and D. K. Chung Lipoteichoic Acid Isolated from Lactobacillus plantarum Inhibits Lipopolysaccharide-Induced TNF-{alpha} Production in THP-1 Cells and Endotoxin Shock in Mice J. Immunol., February 15, 2008; 180(4): 2553 - 2561. [Abstract] [Full Text] [PDF]
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J. Geisel, F. Kahl, M. Muller, H. Wagner, C. J. Kirschning, I. B. Autenrieth, and J.-S. Frick IL-6 and Maturation Govern TLR2 and TLR4 Induced TLR Agonist Tolerance and Cross-Tolerance in Dendritic Cells J. Immunol., November 1, 2007; 179(9): 5811 - 5818. [Abstract] [Full Text] [PDF]
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 M. Shinohara, K.-i. Hirata, T. Yamashita, T. Takaya, N. Sasaki, R. Shiraki, T. Ueyama, N. Emoto, N. Inoue, M. Yokoyama, et al. Local Overexpression of Toll-Like Receptors at the Vessel Wall Induces Atherosclerotic Lesion Formation: Synergism of TLR2 and TLR4 Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2384 - 2391. [Abstract] [Full Text] [PDF]
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J. C. Coffey, J. H. Wang, R. Kelly, L. Romics Jr., A. O'Callaghan, C. Fiuza, and H. P. Redmond Tolerization with BLP down-regulates HMGB1 a critical mediator of sepsis-related lethality J. Leukoc. Biol., October 1, 2007; 82(4): 906 - 914. [Abstract] [Full Text] [PDF]
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S. K. Biswas, P. Bist, M. K. Dhillon, T. Kajiji, C. del Fresno, M. Yamamoto, E. Lopez-Collazo, S. Akira, and V. Tergaonkar Role for MyD88-Independent, TRIF Pathway in Lipid A/TLR4-Induced Endotoxin Tolerance J. Immunol., September 15, 2007; 179(6): 4083 - 4092. [Abstract] [Full Text] [PDF]
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M. B. B. McCall, M. G. Netea, C. C. Hermsen, T. Jansen, L. Jacobs, D. Golenbock, A. J. A. M. van der Ven, and R. W. Sauerwein Plasmodium falciparum Infection Causes Proinflammatory Priming of Human TLR Responses J. Immunol., July 1, 2007; 179(1): 162 - 171. [Abstract] [Full Text] [PDF]
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Y. Yanagawa and K. Onoe Enhanced IL-10 Production by TLR4- and TLR2-Primed Dendritic Cells upon TLR Restimulation J. Immunol., May 15, 2007; 178(10): 6173 - 6180. [Abstract] [Full Text] [PDF]
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J. H. Chang, T. Hampartzoumian, B. Everett, A. Lloyd, P. J. McCluskey, and D. Wakefield Changes in Toll-like Receptor (TLR)-2 and TLR4 Expression and Function but Not Polymorphisms Are Associated with Acute Anterior Uveitis Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1711 - 1717. [Abstract] [Full Text] [PDF]
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 R. Graveline, M. Segura, D. Radzioch, and M. Gottschalk TLR2-dependent recognition of Streptococcus suis is modulated by the presence of capsular polysaccharide which modifies macrophage responsiveness Int. Immunol., April 1, 2007; 19(4): 375 - 389. [Abstract] [Full Text] [PDF]
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J. Sun, P. E. Fegan, A. S. Desai, J. L. Madara, and M. E. Hobert Flagellin-induced tolerance of the Toll-like receptor 5 signaling pathway in polarized intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, March 1, 2007; 292(3): G767 - G778. [Abstract] [Full Text] [PDF]
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A. Bagchi, E. A. Herrup, H. S. Warren, J. Trigilio, H.-S. Shin, C. Valentine, and J. Hellman MyD88-Dependent and MyD88-Independent Pathways in Synergy, Priming, and Tolerance between TLR Agonists J. Immunol., January 15, 2007; 178(2): 1164 - 1171. [Abstract] [Full Text] [PDF]
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J. M. Buckley, J. H. Wang, and H. P. Redmond Cellular reprogramming by gram-positive bacterial components: a review J. Leukoc. Biol., October 1, 2006; 80(4): 731 - 741. [Abstract] [Full Text] [PDF]
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J. D. Turner, R. S. Langley, K. L. Johnston, G. Egerton, S. Wanji, and M. J. Taylor Wolbachia Endosymbiotic Bacteria of Brugia malayi Mediate Macrophage Tolerance to TLR- and CD40-Specific Stimuli in a MyD88/TLR2-Dependent Manner J. Immunol., July 15, 2006; 177(2): 1240 - 1249. [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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C. H. Li, J. H. Wang, and H. P. Redmond Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation J. Leukoc. Biol., April 1, 2006; 79(4): 867 - 875. [Abstract] [Full Text] [PDF]
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 S Ramsey, A Ozinsky, A Clark, K.D Smith, P de Atauri, V Thorsson, D Orrell, and H Bolouri Transcriptional noise and cellular heterogeneity in mammalian macrophages Phil Trans R Soc B, March 29, 2006; 361(1467): 495 - 506. [Abstract] [Full Text] [PDF]
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Y. Sekine, T. Yumioka, T. Yamamoto, R. Muromoto, S. Imoto, K. Sugiyma, K. Oritani, K. Shimoda, M. Minoguchi, S. Akira, et al. Modulation of TLR4 Signaling by a Novel Adaptor Protein Signal-Transducing Adaptor Protein-2 in Macrophages J. Immunol., January 1, 2006; 176(1): 380 - 389. [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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 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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 H.-S. Mun, F. Aosai, K. Norose, L.-X. Piao, H. Fang, S. Akira, and A. Yano Toll-Like Receptor 4 Mediates Tolerance in Macrophages Stimulated with Toxoplasma gondii-Derived Heat Shock Protein 70 Infect. Immun., August 1, 2005; 73(8): 4634 - 4642. [Abstract] [Full Text] [PDF]
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C. Feterowski, A. Novotny, S. Kaiser-Moore, P. F. Muhlradt, T. Rossmann-Bloeck, M. Rump, B. Holzmann, and H. Weighardt Attenuated pathogenesis of polymicrobial peritonitis in mice after TLR2 agonist pre-treatment involves ST2 up-regulation Int. Immunol., August 1, 2005; 17(8): 1035 - 1046. [Abstract] [Full Text] [PDF]
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E. A. Hayashi, S. Akira, and A. Nobrega Role of TLR in B Cell Development: Signaling through TLR4 Promotes B Cell Maturation and Is Inhibited by TLR2 J. Immunol., June 1, 2005; 174(11): 6639 - 6647. [Abstract] [Full Text] [PDF]
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P. Henneke, S. Morath, S. Uematsu, S. Weichert, M. Pfitzenmaier, O. Takeuchi, A. Muller, C. Poyart, S. Akira, R. Berner, et al. Role of Lipoteichoic Acid in the Phagocyte Response to Group B Streptococcus J. Immunol., May 15, 2005; 174(10): 6449 - 6455. [Abstract] [Full Text] [PDF]
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J.-N. Tournier, A. Quesnel-Hellmann, J. Mathieu, C. Montecucco, W.-J. Tang, M. Mock, D. R. Vidal, and P. L. Goossens Anthrax Edema Toxin Cooperates with Lethal Toxin to Impair Cytokine Secretion during Infection of Dendritic Cells J. Immunol., April 15, 2005; 174(8): 4934 - 4941. [Abstract] [Full Text] [PDF]
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M. R. Power, Y. Peng, E. Maydanski, J. S. Marshall, and T.-J. Lin The Development of Early Host Response to Pseudomonas aeruginosa Lung Infection Is Critically Dependent on Myeloid Differentiation Factor 88 in Mice J. Biol. Chem., November 19, 2004; 279(47): 49315 - 49322. [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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S. Epelman, D. Stack, C. Bell, E. Wong, G. G. Neely, S. Krutzik, K. Miyake, P. Kubes, L. D. Zbytnuik, L. L. Ma, et al. Different Domains of Pseudomonas aeruginosa Exoenzyme S Activate Distinct TLRs J. Immunol., August 1, 2004; 173(3): 2031 - 2040. [Abstract] [Full Text] [PDF]
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L. C. Parker, M. K. B. Whyte, S. N. Vogel, S. K. Dower, and I. Sabroe Toll-Like Receptor (TLR)2 and TLR4 Agonists Regulate CCR Expression in Human Monocytic Cells J. Immunol., April 15, 2004; 172(8): 4977 - 4986. [Abstract] [Full Text] [PDF]
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Hongkuan Fan and J. A. Cook Review: Molecular mechanisms of endotoxin tolerance Innate Immunity, April 1, 2004; 10(2): 71 - 84. [Abstract] [PDF]
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K. S. Kobayashi and R. A. Flavell Shielding the double-edged sword: negative regulation of the innate immune system J. Leukoc. Biol., March 1, 2004; 75(3): 428 - 433. [Abstract] [Full Text] [PDF]
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K. Nakayama, S. Okugawa, S. Yanagimoto, T. Kitazawa, K. Tsukada, M. Kawada, S. Kimura, K. Hirai, Y. Takagaki, and Y. Ota Involvement of IRAK-M in Peptidoglycan-induced Tolerance in Macrophages J. Biol. Chem., February 20, 2004; 279(8): 6629 - 6634. [Abstract] [Full Text] [PDF]
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D. Frleta, R. J. Noelle, and W. F. Wade CD40-mediated up-regulation of Toll-like receptor 4-MD2 complex on the surface of murine dendritic cells J. Leukoc. Biol., December 1, 2003; 74(6): 1064 - 1073. [Abstract] [Full Text]
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M. Fujita, T. Into, M. Yasuda, T. Okusawa, S. Hamahira, Y. Kuroki, A. Eto, T. Nisizawa, M. Morita, and K.-i. Shibata Involvement of Leucine Residues at Positions 107, 112, and 115 in a Leucine-Rich Repeat Motif of Human Toll-Like Receptor 2 in the Recognition of Diacylated Lipoproteins and Lipopeptides and Staphylococcus aureus Peptidoglycans J. Immunol., October 1, 2003; 171(7): 3675 - 3683. [Abstract] [Full Text] [PDF]
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J. C. Leemans, M. Heikens, K. P. M. van Kessel, S. Florquin, and T. van der Poll Lipoteichoic Acid and Peptidoglycan from Staphylococcus aureus Synergistically Induce Neutrophil Influx into the Lungs of Mice Clin. Vaccine Immunol., September 1, 2003; 10(5): 950 - 953. [Abstract] [Full Text] [PDF]
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U. Deiters, M. Gumenscheimer, C. Galanos, and P. F. Muhlradt Toll-Like Receptor 2- and 6-Mediated Stimulation by Macrophage-Activating Lipopeptide 2 Induces Lipopolysaccharide (LPS) Cross Tolerance in Mice, Which Results in Protection from Tumor Necrosis Factor Alpha but in Only Partial Protection from Lethal LPS Doses Infect. Immun., August 1, 2003; 71(8): 4456 - 4462. [Abstract] [Full Text] [PDF]
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C. Ropert, M. Closel, A. C. L. Chaves, and R. T. Gazzinelli Inhibition of a p38/Stress-Activated Protein Kinase-2-Dependent Phosphatase Restores Function of IL-1 Receptor-Associated Kinase-1 and Reverses Toll-Like Receptor 2- and 4-Dependent Tolerance of Macrophages J. Immunol., August 1, 2003; 171(3): 1456 - 1465. [Abstract] [Full Text] [PDF]
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I. Diterich, C. Rauter, C. J. Kirschning, and T. Hartung Borrelia burgdorferi-Induced Tolerance as a Model of Persistence via Immunosuppression Infect. Immun., July 1, 2003; 71(7): 3979 - 3987. [Abstract] [Full Text] [PDF]
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G. J. Nau, A. Schlesinger, J. F. L. Richmond, and R. A. Young Cumulative Toll-Like Receptor Activation in Human Macrophages Treated with Whole Bacteria J. Immunol., May 15, 2003; 170(10): 5203 - 5209. [Abstract] [Full Text] [PDF]
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C. F. Ortega-Cava, S. Ishihara, M. A. K. Rumi, K. Kawashima, N. Ishimura, H. Kazumori, J. Udagawa, Y. Kadowaki, and Y. Kinoshita Strategic Compartmentalization of Toll-Like Receptor 4 in the Mouse Gut J. Immunol., April 15, 2003; 170(8): 3977 - 3985. [Abstract] [Full Text] [PDF]
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A. H. Dalpke and K. Heeg Synergistic and antagonistic interactions between LPS and superantigens Innate Immunity, February 1, 2003; 9(1): 51 - 54. [Abstract] [PDF]
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 K. Burns, S. Janssens, B. Brissoni, N. Olivos, R. Beyaert, and J. Tschopp Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4 J. Exp. Med., January 20, 2003; 197(2): 263 - 268. [Abstract] [Full Text] [PDF]
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 R. Girard, T. Pedron, S. Uematsu, V. Balloy, M. Chignard, S. Akira, and R. Chaby Lipopolysaccharides from Legionella and Rhizobium stimulate mouse bone marrow granulocytes via Toll-like receptor 2 J. Cell Sci., January 15, 2003; 116(2): 293 - 302. [Abstract] [Full Text] [PDF]
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S.-J. Yeo, J.-G. Yoon, S.-C. Hong, and A.-K. Yi CpG DNA Induces Self and Cross-Hyporesponsiveness of RAW264.7 Cells in Response to CpG DNA and Lipopolysaccharide: Alterations in IL-1 Receptor-Associated Kinase Expression J. Immunol., January 15, 2003; 170(2): 1052 - 1061. [Abstract] [Full Text] [PDF]
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A.-F. Petit-Bertron, C. Fitting, J.-M. Cavaillon, and M. Adib-Conquy Adherence influences monocyte responsiveness to interleukin-10 J. Leukoc. Biol., January 1, 2003; 73(1): 145 - 154. [Abstract] [Full Text] [PDF]
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J. H. Wang, M. Doyle, B. J. Manning, S. Blankson, Q. D. Wu, C. Power, R. Cahill, and H. P. Redmond Cutting Edge: Bacterial Lipoprotein Induces Endotoxin-Independent Tolerance to Septic Shock J. Immunol., January 1, 2003; 170(1): 14 - 18. [Abstract] [Full Text] [PDF]
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M. A. Dobrovolskaia, A. E. Medvedev, K. E. Thomas, N. Cuesta, V. Toshchakov, T. Ren, M. J. Cody, S. M. Michalek, N. R. Rice, and S. N. Vogel Induction of In Vitro Reprogramming by Toll-Like Receptor (TLR)2 and TLR4 Agonists in Murine Macrophages: Effects of TLR "Homotolerance" Versus "Heterotolerance" on NF-{kappa}B Signaling Pathway Components J. Immunol., January 1, 2003; 170(1): 508 - 519. [Abstract] [Full Text] [PDF]
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G. Hajishengallis, M. Martin, R. E. Schifferle, and R. J. Genco Counteracting Interactions between Lipopolysaccharide Molecules with Differential Activation of Toll-Like Receptors Infect. Immun., December 1, 2002; 70(12): 6658 - 6664. [Abstract] [Full Text] [PDF]
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E. Kopp and R. Medzhitov A Plague on Host Defense J. Exp. Med., October 21, 2002; 196(8): 1009 - 1012. [Full Text] [PDF]
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J. H. Wang, M. Doyle, B. J. Manning, Q. Di Wu, S. Blankson, and H. P. Redmond Induction of Bacterial Lipoprotein Tolerance Is Associated with Suppression of Toll-like Receptor 2 Expression J. Biol. Chem., September 20, 2002; 277(39): 36068 - 36075. [Abstract] [Full Text] [PDF]
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K. Ruckdeschel and K. Richter Lipopolysaccharide Desensitization of Macrophages Provides Protection against Yersinia enterocolitica-Induced Apoptosis Infect. Immun., September 1, 2002; 70(9): 5259 - 5264. [Abstract] [Full Text] [PDF]
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M. Adib-Conquy and J.-M. Cavaillon Gamma Interferon and Granulocyte/Monocyte Colony-stimulating Factor Prevent Endotoxin Tolerance in Human Monocytes by Promoting Interleukin-1 Receptor-associated Kinase Expression and Its Association to MyD88 and Not by Modulating TLR4 Expression J. Biol. Chem., July 26, 2002; 277(31): 27927 - 27934. [Abstract] [Full Text] [PDF]
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S. Sato, O. Takeuchi, T. Fujita, H. Tomizawa, K. Takeda, and S. Akira A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways Int. Immunol., July 1, 2002; 14(7): 783 - 791. [Abstract] [Full Text] [PDF]
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S. B. Mizel and J. A. Snipes Gram-negative Flagellin-induced Self-tolerance Is Associated with a Block in Interleukin-1 Receptor-associated Kinase Release from Toll-like Receptor 5 J. Biol. Chem., June 14, 2002; 277(25): 22414 - 22420. [Abstract] [Full Text] [PDF]
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A. S. Cross Invited review: Endotoxin tolerance -- current concepts in historical perspective Innate Immunity, April 1, 2002; 8(2): 83 - 98. [PDF]
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K. L. Davis and K. S. Wise Site-Specific Proteolysis of the MALP-404 Lipoprotein Determines the Release of a Soluble Selective Lipoprotein-Associated Motif-Containing Fragment and Alteration of the Surface Phenotype of Mycoplasma fermentans Infect. Immun., March 1, 2002; 70(3): 1129 - 1135. [Abstract] [Full Text] [PDF]
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A.-K. Yi, J.-G. Yoon, S.-C. Hong, T. W. Redford, and A. M. Krieg Lipopolysaccharide and CpG DNA synergize for tumor necrosis factor-{alpha} production through activation of NF-{kappa}B Int. Immunol., November 1, 2001; 13(11): 1391 - 1404. [Abstract] [Full Text] [PDF]
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M. Martin, J. Katz, S. N. Vogel, and S. M. Michalek Differential Induction of Endotoxin Tolerance by Lipopolysaccharides Derived from Porphyromonas gingivalis and Escherichia coli J. Immunol., November 1, 2001; 167(9): 5278 - 5285. [Abstract] [Full Text] [PDF]
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A. E. Medvedev, P. Henneke, A. Schromm, E. Lien, R. Ingalls, M. J. Fenton, D. T. Golenbock, and S. N. Vogel Induction of Tolerance to Lipopolysaccharide and Mycobacterial Components in Chinese Hamster Ovary/CD14 Cells Is Not Affected by Overexpression of Toll-Like Receptors 2 or 4 J. Immunol., August 15, 2001; 167(4): 2257 - 2267. [Abstract] [Full Text] [PDF]
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M. Wysocka, S. Robertson, H. Riemann, J. Caamano, C. Hunter, A. Mackiewicz, L. J. Montaner, G. Trinchieri, and C. L. Karp IL-12 Suppression During Experimental Endotoxin Tolerance: Dendritic Cell Loss and Macrophage Hyporesponsiveness J. Immunol., June 15, 2001; 166(12): 7504 - 7513. [Abstract] [Full Text] [PDF]
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M. D. Lehner, S. Morath, K. S. Michelsen, R. R. Schumann, and T. Hartung Induction of Cross-Tolerance by Lipopolysaccharide and Highly Purified Lipoteichoic Acid Via Different Toll-Like Receptors Independent of Paracrine Mediators J. Immunol., April 15, 2001; 166(8): 5161 - 5167. [Abstract] [Full Text] [PDF]
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F. Re and J. L. Strominger Toll-like Receptor 2 (TLR2) and TLR4 Differentially Activate Human Dendritic Cells J. Biol. Chem., September 28, 2001; 276(40): 37692 - 37699. [Abstract] [Full Text] [PDF]
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