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,
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* Program in Molecular Medicine and Departments of
Internal Medicine/Infectious Diseases,
Biochemistry, and
Microbiology and Immunology, Wake Forest University Medical Center, Winston-Salem, NC 27157; and
¶ Department of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-
are selectively repressed,
while certain anti-inflammatory genes such as secretory IL-1R
antagonist are still induced in LPS-adapted/tolerant cells. In this
report, we demonstrate that LPS-tolerized human promonocytic THP-1
cells develop cross-tolerance and no longer respond to LTA-induced
IL-1/TNF- production, indicating that disruption of common
intracellular signaling is responsible for the decreased
IL-1/TNF- production. We observe that down-regulation of
IL-1R-associated kinase (IRAK) protein level and kinase activity
closely correlates with the development of cross-tolerance. IRAK
protein levels and kinase activities in LPS-tolerized cells remain low
and hyporesponsive to subsequent LPS or LTA challenges. We also
demonstrate that THP-1 cells with prolonged LTA treatment develop LTA
tolerance and do not express IL-1/TNF- upon further LTA
challenge. Strikingly, cells tolerized with LTA are only refractory to
subsequent LTA challenge and can still respond to LPS stimulation.
Correspondingly, stimulation of TLR2 by LTA, although activating IRAK,
does not cause IRAK degradation. IRAK from LTA-tolerized cells can be
subsequently activated and degraded by further LPS challenge, but not
LTA treatment. Our studies reveal that LTA-induced tolerance is
distinct compared with that of LPS tolerance, and is likely due to
disruption of unique TLR2 signaling components upstream of
MyD88/IRAK. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-.
Recurrent multiple exposures to microbial products such as LPS during
infection result in an adaptive immune response, which is reflected by
repression of proinflammatory genes when blood leukocytes are
stimulated ex vivo with bacterial endotoxin (4). This
phenomenon is often referred to as endotoxin tolerance. Repression of
transcription and rapid degradation of proinflammatory cytokine mRNAs
contribute to decreased proinflammatory cytokine protein production in
LPS-tolerant cells as well as septic blood leukocytes (4, 5). However, tolerant cells are not totally unresponsive to
further LPS challenge. In contrast, LPS-tolerized cells continue to
produce several anti-inflammatory proteins such as secretory IL-1R
antagonist (sIL-1RA) (6). We have observed that efficient
translation of the stable sIL-1RA message contributes to the prolonged
induction of sIL-1RA protein in both septic blood leukocytes and
tolerant THP-1 cells (5). Therefore, selective and
specific disruption of certain TLR4 signaling component(s) is likely to
contribute to the altered LPS response in tolerant cells. It has been
reported that TLR4 receptor level decreases following LPS treatment in
mouse peritoneal macrophages, suggesting that TLR4 down-regulation may
disrupt the LPS signaling. However, the decrease of TLR4 receptor level
may not be the only cause of LPS signaling disruption. First, it is
observed that LPS and IL-1 can induce a state of cross-tolerance
against each other (7). IL-1-pretreated leukocytes do
not respond to LPS treatment and no longer express cytokine genes.
Second, induction of tolerance to LPS and mycobacterial components in
Chinese hamster ovary/CD14 cells is not affected by overexpression of
either TLR2 or TLR4 (8). Third, LPS-tolerized cells can
still respond to an additional dose of LPS challenge and produce
several anti-inflammatory proteins such as IL-1RA (6).
These studies suggest that repression of IL-1-like inflammatory
genes in leukocytes is due to impaired function of intracellular
signaling intermediate(s) of the TLR/IL-1 signaling pathway rather than
defect or down-regulation of the TLR receptor. Using the model human
promonocytic THP-1 cells, we have first observed that the protein level
of IRAK, one of the proximal TLR signaling components, is greatly
decreased in LPS-tolerant cells. In addition, IRAK kinase activity is
no longer responsive to further LPS challenge in tolerant cells. Our
results indicate that down-regulation of IRAK is at least in part
responsible for the development of LPS tolerance in which IL-1-like
gene expression is repressed.
Besides LPS, other Gram-positive bacterial toxins such as LTA can also
activate innate immune response and induce a wide array of gene
expressions. Resembling the effect of LPS, murine peritoneal macrophage
cells pretreated with LTA no longer express IL-1 or TNF- upon a
second dose of LTA stimulation (9). The molecular
mechanism of LTA-induced tolerance is not clear.
In this report, we intend to examine in detail LPS- and LTA-induced
homologous and heterologous tolerance phenotype in terms of repressed
IL-1 and TNF- production. Using human promonocytic THP-1 cells,
we observed that LTA-tolerized cells no longer produce IL-1 or
TNF- protein upon subsequent LTA challenge, while still maintaining
normal response to LPS stimulation. In contrast, LPS-tolerized THP-1
cells show severe hyporesponsiveness to subsequent LPS or LTA challenge
as reflected by decreased IL-1 and TNF- production.
Correspondingly, we show that only LPS treatment causes IRAK level
decrease, while LTA treatment can activate IRAK kinase activity, but
cannot cause a decrease in IRAK protein level. Our result indicates
that the mechanism for LTA-induced tolerance is distinct compared with
that of LPS tolerance and likely involves disruption of signaling
component(s) upstream of IRAK.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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THP-1 cells, an undifferentiated human promonocytic cell line, were obtained from the American Type Culture Collection (Manassas, VA) and maintained in RPMI 1640 medium (Life Technologies, Rockville, MD) supplemented with 10 U/ml penicillin G, 10 µg/ml streptomycin, 2 mM L-glutamine, and 10% FBS (HyClone Laboratories, Logan, UT) at 37°C and 5% CO2 in a humidified incubator. We chose to use the undifferentiated THP-1 cells to study the tolerance phenotype due to its resemblance to the human blood cells (5, 6). Log-phase cells were used in all experiments. Normal THP-1 cells were suspended in media at 1 x 107 cells/ml and stimulated with either 1.0 µg/ml LPS (Escherichia coli 0111:B4; Sigma-Aldrich, St. Louis, MO) or 1.0 µg/ml LTA (highly purified through butanol extraction as described previously (10)) for the times indicated in the figure legends. Thus obtained LPS and LTA have been shown to only signal through TLR4 and TLR2, respectively (11, 12).
Induction of homologous and cross-tolerance
THP-1 cells were rendered homologous tolerant by treating the cells with various concentrations of LPS (0.1–1000 ng/ml) or LTA (0.1–1000 ng/ml) for 16 h. The cells were centrifuged, washed once in medium, and resuspended in RPMI 1640. Cells were then restimulated by the identical microbial stimulus (1 µg/ml LPS or 1 µg/ml LTA) with which they were pretreated. Under cross-tolerant conditions, THP-1 cells were treated with LPS (0.1–1000 ng/ml) or LTA (1–1000 ng/ml) for 16 h, washed, resuspended, and stimulated with the different microbial stimulus (1000 ng/ml LPS or 1000 ng/ml LTA). For all assays, control cells were treated similarly but were not exposed to LPS or LTA.
TNF- and IL-1 enzyme immunoassays
TNF- and IL-1 levels in culture supernatants were assayed
in duplicate and quantified by ELISA with a Quantikine Enzyme
Immunoassay kit (R&D Systems, Minneapolis, MN) according to the
manufacturer’s instructions.
Western blot analysis
Normal and tolerant THP-cells (5 x
106 cells/condition) were collected at each time
described in the figure legends. Cells were pelleted at 1000 x
g for 10 min, lysed on ice for 20 min in 800 µl lysis
buffer (50 mM HEPES (pH 7.6), 150 mM NaCl, 1 mM EDTA. 1% Nonidet P-40,
20 mM -glycerophosphate, 1 mM sodium orthovanadate, 1 mM sodium
fluoride, 1 mM benzamidine, 5 mM p-nitrophenylphosphate, 1
mM DTT, 1 mM PMSF, and 1 µg/ml each of aprotinin, leupeptin, and
pepstatin). Cell debris was isolated at 4°C by centrifugation (14,000
rpm) for 20 min and supernatants were collected. The protein
concentration in the supernatants was determined using a Bio-Rad
protein assay kit (Bio-Rad, Hercules, CA) according to the
manufacturer’s instructions. One-third of the total protein extracts
was solubilized by SDS sample buffer (80 mM Tris-HCl (pH 6.8), 2% SDS,
50% glycerol, 0.05% bromphenol blue, and 0.2 M DTT), separated by
SDS-PAGE (10% acrylamide) along with a broad range molecular weight
markers (Bio-Rad), and transferred to Immuno-Blot polyvinylidene
difluoride membrane (Bio-Rad). The membranes were blocked
overnight at 4°C with 5% nonfat milk in 1x TBS/0.05% Tween 20 and
were probed with 0.7 µg/ml IRAK1 Ab (Upstate Biotechnology, Lake
Placid, NY). The membranes were washed four times in 1x
TBS/0.05% Tween 20 and incubated for 30 min with goat anti-rabbit
IgG conjugated to HRP (Upstate Biotechnology). The membranes were
washed four times in 1x TBS/0.05% Tween 20, and IRAK1 protein was
visualized by SuperSignal chemiluminescent reagent (Pierce,
Rockford, IL).
Immunoprecipitation and in vitro kinase assay
The remaining two-thirds of isolated protein cell extract were
treated with 5 µl anti-IRAK Ab (Upstate Biotechnology) for 1
h on a rotator at 4°C. Protein G-agarose beads (50 µl; Life
Technologies) were added to each sample, followed by overnight
incubation at 4°C. The beads were isolated by centrifugation
(2500 x g) and washed four times in lysis buffer
described above. The beads were then washed twice with kinase buffer
(20 mM HEPES (pH 7.6), 20 mM MgCl2, 20 mM
-glycerophosphate, 20 mM p-nitrophenylphosphate, 1 mM
EDTA, 1 mM sodium orthovanadate, and 1 mM benzamidine). Each sample was
incubated at 37°C for 30 min in 50 µl kinase buffer supplemented
with 5 µM ATP, 2 µg myelin basic protein (MBP), and 1 µl
[
-32P]ATP. SDS sample buffer was added after
incubation, and the samples were subjected to SDS-PAGE (15%
acrylamide) analysis. To quantify IRAK kinase activity, the gel was
dried and exposed to a Molecular Dynamics PhosphorImager 425 SI
(Sunnyvale, CA). Band intensity was quantified using the
ImageQuant 4.1 software (Molecular Dynamics, Sunnyvale, CA).
Statistical analysis
A mean constitutive activity or fold induction was determined for each experiment. Data are presented as the mean ± SEM. Statistics were performed using either two-tailed paired or nonpaired t tests to determine significant changes in activities. Data were analyzed using Microsoft Excel 97 software (Microsoft, Seattle, WA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Through distinct TLRs, diverse bacterial products trigger human
leukocyte innate immunity response and induce IL-1 as well as
TNF- production. As shown in Fig. 1
, fresh THP-1 cells treated with LPS or LTA express IL-1 and TNF-
proteins as measured by ELISA. We then examined the ability of LPS to
induce innate immunity tolerance. Undifferentiated THP-1 cells were
pretreated with various concentrations of LPS for 16 h. Pretreated
THP-1 cells were washed with LPS-free RPMI 1640 medium and subjected to
another LPS or LTA challenge for 6 h. The IL-1 and TNF-
protein levels were subsequently assayed using ELISA. We observed that
THP-1 cells with overnight LPS treatment develop cross-tolerance to
subsequent LPS or LTA challenge. Production of TNF- and IL-1 in
response to a second dose of LPS or LTA was decreased in a
dose-dependent fashion when THP-1 cells were pretreated with various
concentrations of LPS for 16 h before restimulation. (Fig. 1, A and C).
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, B and
D, pretreatment with 1 µg/ml LTA induced a statistically
significant hyporesponsive state to further LTA challenge as measured
by decreased IL-1 and TNF- production. Interestingly, unlike LPS
pretreatment, THP-1 cells pretreated with various concentrations of LTA
can still respond to further LPS challenge and express normal amounts
of IL-1 and TNF- comparable to fresh THP-1 cells (Fig. 1, B and D). These results indicate that LTA can
only induce tolerance to itself, while LPS can induce cross-tolerance
to LPS and LTA in human THP-1 cells. Both LPS and LTA activate IRAK in normal THP-1 cells
Only LPS, not LTA stimulation, results in IRAK degradation. The
activation of a common TLR intracellular signaling pathway contributes
to the innate immunity stimulation upon various microbial products.
IRAK is one of the proximal TLR intracellular signaling components. We
previously showed that LPS and bacterial flagellin protein FliC can
both induce endogenous IRAK protein kinase activation through TLR4 and
TLR5 (1, 2). To examine whether LTA could similarly
activate IRAK, we examined the IRAK protein kinase activity and protein
levels in THP-1 cells upon LTA challenge. Undifferentiated THP-1 cells
were subjected to either LPS or LTA treatment for various time periods.
IRAK protein levels were subsequently determined by Western blot
analysis using total protein extracts. To examine LPS- and LTA-induced
IRAK kinase activities, IRAK protein was immunoprecipitated from total
protein extracts and subjected to in vitro kinase assays using MBP as
described in Materials and Methods. As shown in Fig. 2B, IRAK kinase activity was
maximally induced following an 80-min stimulation with either LPS or
LTA. Interestingly, LPS stimulation resulted in a 2- to 3-fold greater
induction of IRAK kinase activity compared with LTA stimulation.
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A, we detected the occurrence of the upper
phosphorylated IRAK band following 20 min of LPS stimulation. IRAK
protein levels were markedly reduced at 80 min and remain low following
6 h of LPS challenge. In contrast, we observed that LTA
stimulation does not induce apparent IRAK phosphorylation and
degradation. IRAK remained as a single band and its intensity was not
altered at various times of LTA challenge (Fig. 2A).
We performed three independent experiments and obtained consistent
results. Our data indicate that LTA stimulation does activate IRAK
kinase in fresh nontolerant cells and suggest that LTA/TLR2 also
utilize IRAK in mediating innate immunity activation and inflammatory
gene expression. However, there are distinct differences regarding IRAK
protein regulation upon LPS/TLR4 and LTA/TLR2 stimulation. IRAK from LPS-tolerized cells exhibits no response to either LPS or LTA
In contrast, IRAK from LTA-tolerized cells fails to respond to
further LTA challenge, yet is capable of responding to further LPS
stimulation. We previously showed that IRAK protein and kinase levels
remain persistently low in LPS-tolerized cells and unresponsive to
further LPS challenge (1). Given the hypothesis that IRAK
is utilized by many TLR receptors in mediating responses to a variety
of microbial stimulants, we would predict that IRAK from LPS-tolerized
cells would no longer respond to further LTA challenge. To test this,
THP-1 cells were pretreated with 1 µg/ml LPS overnight followed by
washing with fresh RPMI 1640 medium. Pretreatment with such
concentrations of LPS was shown above to induce statistically
significant tolerance to subsequent LPS and LTA challenge (Fig. 1).
LPS-pretreated cells were subjected to subsequent LPS or LTA challenge
for various periods of time. Total protein extracts were prepared and
analyzed through SDS-PAGE. IRAK protein levels were detected by Western
blot. As shown in Fig. 3, IRAK levels in
LPS-pretreated cells remained low following subsequent LPS or LTA
challenge. In vitro IRAK kinase activity toward MBP was subsequently
assayed using immunoprecipitated IRAK from the total protein extracts
as described in Materials and Methods. As expected, neither
LPS nor LTA induced IRAK kinase activation in LPS-pretreated THP-1
cells (Fig. 4).
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Undifferentiated THP-1 cells were treated with 1 µg/ml LTA overnight
followed by washing with fresh RPMI 1640 medium. LTA-pretreated cells
were subsequently subjected to further LPS or LTA challenge for various
periods of time. IRAK protein levels and kinase activities were
subsequently determined as previously described. As shown in Fig. 3, there was no apparent IRAK protein level decrease in LTA-tolerant THP-1
cells challenged by an additional dose of LTA. Despite the presence of
high IRAK protein level in LTA-tolerant cells, subsequent LTA challenge
did not cause IRAK kinase activation (Fig. 4). This suggests that LTA
pretreatment causes disruption of the unique TLR2 signaling component
upstream of IRAK. Interestingly, we observed that IRAK protein from
LTA-tolerized cells still responded to further LPS challenge and
underwent rapid kinase activation as well as protein degradation (Figs. 3 and 4). These results indicate that the hyporesponsiveness of
LPS-tolerant cells to subsequent LPS or LTA challenge as seen by the
decrease in IL-1 and TNF- protein production (Fig. 1, A and C) can be attributed to, at least in part,
the down-regulation of IRAK protein levels and low IRAK kinase
activity. In contrast, LTA pretreatment may cause disruption upstream
of IRAK and therefore leaves IRAK unmodified and responsive to further
LPS challenge through the TLR4 receptor. LTA-tolerized THP-1 cells still retain some LPS/LTA response such as increased sIL-1RA production
Previous studies reported that the TLR4 receptor is down-regulated
in LPS-tolerant cells (13). It is therefore likely that
down-regulation of the TLR4 or TLR2 receptor would lead to cellular
hyporesponsiveness to LPS or LTA. In discordance to the above
hypothesis, others and our studies indicate that LPS-tolerized THP-1
cells and human blood cells still retain some responsiveness to LPS
such as elevated production of anti-inflammatory sIL-1RA protein
(6, 14). These studies suggest that the TLR4 receptor is
still functional in LPS-tolerized cells. The decreased IL-1 and
TNF- production is likely caused by selective disruption of
intracellular signaling component. To gain some insight regarding
whether the TLR2 receptor is functional in LTA-tolerized cells, we
tested whether LTA can similarly induce sIL-1RA protein in
LTA-tolerized THP-1 cells. THP-1 cells pretreated with 1 µg/ml LTA
for 16 h were washed with fresh RPMI 1640 medium and restimulated
with 1 mg/ml LTA for 6 h. As shown in Fig. 5, LTA-tolerized THP-1 cells are equally
responsive to both LTA and LPS compared with fresh THP-1 cells in terms
of sIL-1RA protein production.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B activation, which contribute
to the induction of IL-1 as well as TNF-. On the other hand,
TLR4, instead of TLR2 signaling may activate unique downstream
components (such as STAT1) and induce a subset of genes such as MCP5
and IP10 (15).
With regard to the common signaling pathway that leads to IL-1 and
TNF- production, it was shown that prolonged treatment with LPS or
LTA could induce a state of tolerance and decreased IL-1 and TNF-
production upon subsequent challenge (4, 9). The mechanism
of LPS-induced tolerance is complex and probably involves
down-regulation of multiple TLR signaling components, including
down-regulation of the TLR4 receptor, disruption and degradation of
IRAK kinase, as well as reduced activation of mitogen-activated
protein kinases (13, 16). However, total disruption
of the TLR4 receptor is unlikely during LPS tolerance, since
LPS-tolerant human macrophages/monocytes can still respond to further
LPS challenge and express many other genes and proteins
(6). Furthermore, induction of tolerance to LPS in Chinese
hamster ovary/CD14 cells is not affected by overexpression of TLR4
(8). We and others reported that LPS treatment induces
rapid degradation and inactivation of the intracellular signaling
molecule IRAK (1, 17). The timing of IRAK disruption
correlates well with the development of LPS tolerance (within 3 h
of LPS treatment). Our present study further confirms our conclusion
regarding the IRAK response upon LPS challenge and indicates that
disruption of the IRAK response may also be responsible for the
development of LPS-induced cross-tolerance (Fig. 6).
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/TNF- production (9). Although the TLR signaling
pathway between mouse and human bear similarities, there are also
striking differences (18, 19). To date, there has been no
report whether human monocyte/macrophages develop LTA tolerance. In
this report, we studied the innate immune response of human monocytic
THP-1 cells upon LTA challenge. We observed that, like LPS stimulation,
LTA stimulation similarly induces IRAK kinase activation and subsequent
IL-1 and TNF- protein production. Furthermore, we first observed
that THP-1 cells treated with LTA acquire hyporesponsiveness and
decreased IL-1/TNF- production upon subsequent LTA treatment.
Correspondingly, LTA no longer induces IRAK kinase activation nor
IL-1/TNF- protein production in LTA-tolerized cells.
Strikingly, we observed that LTA-tolerized THP-1 cells can still
respond normally to further LPS challenge and produce IL-1 as well
as TNF- proteins. This suggests that LTA-induced tolerance is caused
by disruption of the unique TLR2 signaling component not shared by
LPS/TLR4 signaling, and likely resides upstream of IRAK (Fig. 6). This
would enable LTA-tolerized cells to still maintain functional TLR
intracellular signaling response shared by other TLRs. In accordance
with this, we observed that the IRAK protein level is not decreased
following prolonged LTA treatment. Furthermore, we show that IRAK in
LTA-tolerized cells can still respond normally to subsequent LPS
challenge and exhibit kinase activation as well as protein degradation.
In sharp contrast, LPS-tolerized THP-1 cells exhibit severe
hyporesponsiveness to both LPS and LTA challenge.
The disruption of TLR2 signaling leading to decreased IL-1 and
TNF- production in LTA-tolerant cells is not due to inactivation of
the TLR2 receptor. LTA-tolerized THP-1 cells are not totally
unresponsive to subsequent LTA challenge. Instead, LTA-tolerized
cells can still respond to further LTA treatment and selectively
express sIL-1RA protein (Fig. 5). This indicates that the TLR2 receptor
is still functional in LTA-tolerant cells. The decreased expression of
inflammatory proteins such as IL-1 and TNF- is likely due to
disruption of intracellular signaling components downstream of the TLR2
receptor and upstream of IRAK. The candidate protein(s) include adaptor
protein MyD88, Tollip, TIRAP/MAL, as well as other enzymes such
as phosphatidylinositol 3-kinase (PI3). The LPS/TLR4 pathway has
been shown to utilize all of these adaptor proteins as well as PI3 in
the downstream signaling (1, 20, 15, 6). However, the TLR2
pathway was shown to use only the MyD88 and PI3 (15, 21).
One likely scenario is that the LPS/TLR4 signaling can recruit the
specific adaptor protein(s) that leads to IRAK phosphorylation and
subsequent degradation, whereas LTA/TLR2 signaling recruited adaptor(s)
could only lead to IRAK activation, but not
phosphorylation/degradation. Indeed, we observed that LTA cannot induce
IRAK phosphorylation (Fig. 2). It was previously reported that IRAK
phosphorylation is a prerequisite for subsequent degradation. The fact
that LTA can induce IRAK kinase activation indicates that IRAK
activation and phosphorylation is two independent events and may be
controlled by distinct upstream regulatory steps.
Taken together, our study reveals that cellular innate immunity
tolerance toward distinct microbial toxins may involve alteration of
distinct TLR signaling components. However, down-regulation of the
common TLR intracellular signaling factor IRAK will lead to a state of
cross-tolerance and decreased IL-1 and TNF- production upon
subsequent challenge with multiple microbial toxins.
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Footnotes |
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2 C.M. and L.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Liwu Li or Dr. Charles McCall, Department of Internal Medicine, Section of Infectious Diseases, Wake Forest University School of Medicine, Winston-Salem, NC 27157. E-mail addresses: lwli@wfubmc.edu or chmccall{at}wfubmc.edu
4 Abbreviations used in this paper: LTA, lipoteichoic acid; TLR, Toll-like receptor; IRAK, IL-1R-associated kinase; sIL-1RA, secretory IL-1R antagonist; MBP, myelin basic protein; PI3, phosphatidylinositol 3-kinase.
Received for publication November 21, 2001. Accepted for publication April 10, 2002.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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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G. E. Morris, M. K. B. Whyte, G. F. Martin, P. J. Jose, S. K. Dower, and I. Sabroe Agonists of Toll-like Receptors 2 and 4 Activate Airway Smooth Muscle via Mononuclear Leukocytes Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 814 - 822. [Abstract] [Full Text] [PDF]
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D. De Nardo, P. Masendycz, S. Ho, M. Cross, A. J. Fleetwood, E. C. Reynolds, J. A. Hamilton, and G. M. Scholz A Central Role for the Hsp90{middle dot}Cdc37 Molecular Chaperone Module in Interleukin-1 Receptor-associated-kinase-dependent Signaling by Toll-like Receptors J. Biol. Chem., March 18, 2005; 280(11): 9813 - 9822. [Abstract] [Full Text] [PDF]
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Y. Huang, T. Li, D. C. Sane, and L. Li IRAK1 Serves as a Novel Regulator Essential for Lipopolysaccharide-induced Interleukin-10 Gene Expression J. Biol. Chem., December 3, 2004; 279(49): 51697 - 51703. [Abstract] [Full Text] [PDF]
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M. Siedlar, M. Frankenberger, E. Benkhart, T. Espevik, M. Quirling, K. Brand, M. Zembala, and L. Ziegler-Heitbrock Tolerance Induced by the Lipopeptide Pam3Cys Is Due to Ablation of IL-1R-Associated Kinase-1 J. Immunol., August 15, 2004; 173(4): 2736 - 2745. [Abstract] [Full Text] [PDF]
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A. Bafica, C. A. Scanga, M. Schito, D. Chaussabel, and A. Sher Influence of Coinfecting Pathogens on HIV Expression: Evidence for a Role of Toll-Like Receptors J. Immunol., June 15, 2004; 172(12): 7229 - 7234. [Abstract] [Full Text] [PDF]
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A. Bafica, C. A. Scanga, O. Equils, and A. Sher The induction of Toll-like receptor tolerance enhances rather than suppresses HIV-1 gene expression in transgenic mice J. Leukoc. Biol., March 1, 2004; 75(3): 460 - 466. [Abstract] [Full Text] [PDF]
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S. Lotz, E. Aga, I. Wilde, G. van Zandbergen, T. Hartung, W. Solbach, and T. Laskay Highly purified lipoteichoic acid activates neutrophil granulocytes and delays their spontaneous apoptosis via CD14 and TLR2 J. Leukoc. Biol., March 1, 2004; 75(3): 467 - 477. [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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R. Haase, C. J. Kirschning, A. Sing, P. Schrottner, K. Fukase, S. Kusumoto, H. Wagner, J. Heesemann, and K. Ruckdeschel A Dominant Role of Toll-Like Receptor 4 in the Signaling of Apoptosis in Bacteria-Faced Macrophages J. Immunol., October 15, 2003; 171(8): 4294 - 4303. [Abstract] [Full Text] [PDF]
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 D. de Kleijn and G. Pasterkamp Toll-like receptors in cardiovascular diseases Cardiovasc Res, October 15, 2003; 60(1): 58 - 67. [Abstract] [Full Text] [PDF]
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 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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 Y. Yu, H. Zeng, S. Lyons, A. Carlson, D. Merlin, A. S. Neish, and A. T. Gewirtz TLR5-mediated activation of p38 MAPK regulates epithelial IL-8 expression via posttranscriptional mechanism Am J Physiol Gastrointest Liver Physiol, July 7, 2003; 285(2): G282 - G290. [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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Z. Jiang, M. Zamanian-Daryoush, H. Nie, A. M. Silva, B. R. G. Williams, and X. Li Poly(dI{middle dot}dC)-induced Toll-like Receptor 3 (TLR3)-mediated Activation of NFkappa B and MAP Kinase Is through an Interleukin-1 Receptor-associated Kinase (IRAK)-independent Pathway Employing the Signaling Components TLR3-TRAF6-TAK1-TAB2-PKR J. Biol. Chem., May 2, 2003; 278(19): 16713 - 16719. [Abstract] [Full Text] [PDF]
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Liwu Li, R. Jacinto, B. Yoza, and C. E. McCall Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes Innate Immunity, February 1, 2003; 9(1): 39 - 44. [Abstract] [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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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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D. van der Kleij, E. Latz, J. F. H. M. Brouwers, Y. C. M. Kruize, M. Schmitz, E. A. Kurt-Jones, T. Espevik, E. C. de Jong, M. L. Kapsenberg, D. T. Golenbock, et al. A Novel Host-Parasite Lipid Cross-talk. SCHISTOSOMAL LYSO-PHOSPHATIDYLSERINE ACTIVATES TOLL-LIKE RECEPTOR 2 AND AFFECTS IMMUNE POLARIZATION J. Biol. Chem., December 6, 2002; 277(50): 48122 - 48129. [Abstract] [Full Text] [PDF]
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