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*
Biochemical Pharmacology, University of Konstanz, Konstanz, Germany; and
Institut für Mikrobiologie, Universitätsklinikum Charité, Medizinische Fakultät der Humboldt-Universität zu Berlin, Berlin, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast to the endotoxin of Gram-negative bacteria, no single constituent has so far been identified as the major immunostimulatory element in Gram-positive bacteria. In the last years, increasing evidence has been provided that lipoteichoic acids (LTAs)3 and peptidoglycans could substitute for whole Gram-positive bacteria in activation of macrophages and induction of multiorgan dysfunction syndrome (13, 14). Recently, it has been shown that signal transduction and cytokine production in response to several Gram-positive bacteria, peptidoglycan, and lipopeptides from various bacterial species is mediated by a cellular transmembrane receptor termed Toll-like receptor (TLR)-2 (15, 16, 17, 18, 19, 20, 21). However, controversial data have been published regarding the involvement of TLR2 or TLR4 in LTA-induced signaling (16, 17). Although previous experiments with bacterial DNA (22), lipopeptides (23, 24), or whole bacteria (23) indicated that down-regulation of macrophage responsiveness after stimulation was not restricted to endotoxin from Gram-negative bacteria, it has not been studied whether and how macrophage responsiveness is modulated by LTA.
For this purpose, we studied the effect on cytokine production of low-dose pretreatment with LTA or LPS followed by a second LTA/LPS challenge in vivo and in primary murine macrophages in vitro. By using mice lacking functional TLR4 (C3H/HeJ) or TLR2 (TLR2 knockout) we demonstrate macrophage desensitization on preexposure to LTA via TLR2 but independent of TLR4.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C3H/HeN and C3H/HeJ and female CD1 mice were purchased from Charles River Laboratories (Sulzfeld, Germany). TLR2 knockout mice were generated by homologous recombination by Deltagen (Menlo Park, CA) and kindly provided by Tularik (South San Francisco, CA). Heterozygous mice were interbred with CD1 mice to obtain homozygotes. Female TLR2-deficient mice and CD1 control mice were used for experiments. They were kept at 24°C, 55% humidity, 12-h day-night rhythm on a diet of Altromin C 1310 (Altromin, Lage, Germany) and were used at 8–10 wk of age. All animals received humane care in accordance with the National Institutes of Health guidelines and the legal requirements in Germany.
Preparation of LTA
Staphylococcus aureus (DSM 20233) was grown in a 42 l fermentor (MBR BioReactor, Wetzikon, Switzerland) and harvested at an OD578 of 15. After resuspension in 0.1 M citrate buffer at pH 4.7, bacteria were disrupted with glass beads in a Braun disintegrator, washed, and stored at -80°C. A defrosted aliquot of bacteria (100 ml) was mixed with an equal volume of n-butanol (Merck, Darmstadt, Germany) under stirring for 30 min at room temperature. After centrifugation at 13,000 x g for 20 min, the aquatic phase was lyophilized, resuspended in 50 ml of chromatography start buffer (15% n-propanol in 0.1 M ammonium acetate, pH 4.7), and centrifuged at 45,000 x g for 15 min. The supernatant was subjected to hydrophobic interaction chromatography on an octyl-Sepharose column (2.5 x 11 cm) with a linear gradient from 15 to 60% of n-propanol in 0.1 M ammonium acetate, pH 4.7. This LTA preparation contained <0.08 endotoxin units per milligram of LTA (6 pg LPS/mg LTA), as assessed by Limulus amoebocyte lysate assay (BioWhittaker, Verviers, Belgium). No contamination with lipopeptides was detected by photometric measurements (UV absorption), silver staining on SDS-PAGE, amino acid sequencing (Edman degradation and HPLC), and nuclear magnetic resonance examination. A more detailed characterization of the LTA preparation has been published elsewhere (25).
In vitro experiments
Mice were killed by terminal pentobarbital anesthesia (Narcoren; Merial, Hallbergmoos, Germany), and 10 ml of ice-cold PBS (Life Technologies, Karlsruhe, Germany) was injected into the peritoneal cavity. Animals were shaken gently and the lavage liquid was transferred to siliconized glass tubes (Vacutainer; Becton Dickinson, Heidelberg, Germany) for isolation of peritoneal cells. After centrifugation, cells were resuspended in medium (RPMI 1640; BioWhittaker) containing 10% FCS (Boehringer Mannheim, Mannheim, Germany) and 100 IU/ml penicillin/streptamycin (Biochrom, Berlin, Germany) and transferred to 96-well cell culture plates (105 cells/well). For determination of cytokine induction by LPS or LTA, cells were stimulated immediately with pyrogen-free saline (Braun, Melsungen, Germany), increasing concentrations of LPS (Salmonella abortus equi; Metalon, Wustenhofen, Germany), or LTA (S. aureus), respectively, at 37°C, 5% CO2 in a humidified atmosphere for 6 h.
To study desensitization, cells from C3H/HeN and HeJ mice were incubated in medium with increasing concentrations of LPS or LTA for 20 h. Cells then were washed twice with PBS, and new medium was added. Cells were challenged with either 10 ng/ml LPS or 10 µg/ml LTA for 6 h.
To determine the involvement of soluble factors in tolerance induction, equal numbers of peritoneal cells from C3H/HeN and HeJ mice were pooled and preincubated with medium, 1 ng/ml LPS, or 10 µg/ml LTA for 20 h before restimulation with 10 µg/ml LTA for 6 h.
In analogy, equal cell numbers from CD-1 wild-type and TLR-2-/- mice were preexposed to medium, 10 ng/ml LPS, or 10 µg/ml LTA for 20 h and restimulated with 100 ng/ml LPS for 6 h. TNF was determined in supernatants by ELISA. Lavaged peritoneal cells did not differ in number and proportion of macrophages between the different strains of mice used. Furthermore, the cytokine release in response to LPS as well as LTA per cell was very homogenous, supporting the notion that differences were not attributable to a different composition of the cell population plated.
In vivo experiments
Mice were injected i.p. with pyrogen-free saline, 3 µg/kg LPS, or 15 mg/kg LTA in pyrogen-free saline 24 h before challenge. For induction of liver damage, mice were starved overnight and injected i.p. with 5 µg/kg LPS or 25 mg/kg LTA with 1 g/kg galactosamine (GalN; Roth Chemicals, Karlsruhe, Germany) diluted in saline. After 90 min, blood was obtained from the tail vein for determination of plasma TNF. The extent of liver damage was assessed 8 h after challenge by measuring plasma alanine aminotransferase activity with an EPOS 5060 analyzer (Netheler & Hinz, Hamburg, Germany; Ref. 26).
Cytokine ELISA
TNF-
in supernatants was determined by ELISA with specific
Abs purchased from BD PharMingen (Hamburg, Germany). For the detection
of TNF in plasma samples, the OptEia kit from BD PharMingen was used.
The detection limits were 5 pg/ml.
Statistics
Data are presented as means ± SEM. Statistical differences were determined by one-way ANOVA followed by Tukey’s multiple comparison test or Dunnett’s multiple comparison test of all groups vs the control group. Data derived from experiments with nonpooled cells from individual mice were analyzed by using Dunnett’s multiple comparison test after repeated-measures ANOVA to account for the interindividual differences. Statistical evaluation of results presented as percentage was performed with raw data. In case of unequal variances (Bartlett’s test p < 0.05), data were first log-transformed. p < 0.05 was considered significant. All tests were performed with GraphPad Prism, version 3.0 for Windows (GraphPad Software, San Diego, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Published results are controversial concerning the requirement of
TLRs for signal transduction in response to LTA from Gram-positive
bacteria (16, 17). To determine the involvement of TLR4 in
signaling on stimulation with LTA, we compared TNF- production by
peritoneal macrophages from C3H/HeJ mice lacking functional TLR4
(27, 28, 29) and wild-type C3H/HeN mice. Macrophages from
wild-type mice exhibited TNF release on LPS stimulation with
concentrations as low as 10 pg/ml, whereas no TNF was released from
cells of C3H/HeJ mice when LPS concentrations up to 100 ng/ml were
used, confirming the well-known status of LPS-hyporesponsiveness of
this strain (Fig. 1
A). In
contrast to stimulation with LPS, macrophages from HeJ mice were
equally responsive as compared with HeN mice in terms of LTA-induced
TNF production (Fig. 1B). To test the involvement of TLR2 in
LTA signaling, we compared TNF production by peritoneal cells from
TLR2-deficient and control mice stimulated with LPS or LTA. In contrast
to the previous experiments with cells from C3H/HeJ mice,
TLR2-/- cells were normoresponsive to
LPS-induced TNF release, whereas no TNF-production in response to LTA
could be observed (Fig. 2). These
observations were corroborated by in vitro studies with a number of
TLR2- and/or TLR4-carrying cell lines as well as anti-TLR4 Abs
showing that the LTA from S. aureus signals through the TLR2
receptor only.4
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Prior exposure to LPS renders cells hyporesponsive to subsequent
stimulation with LPS. We tested whether prior exposure of cells to
highly purified LTA induced refractoriness to subsequent stimulation
with LTA comparable to LPS tolerance. Release of TNF in response to 10
µg/ml LTA was decreased in a dose-dependent fashion when primary
murine peritoneal cells were pretreated with different concentrations
of LTA for 20 h before restimulation (Fig. 3A, right).
Previously, it has been shown that IL-1 and LPS could substitute for
each other in the induction of refractoriness in vitro (30, 31), suggesting that hyporesponsiveness was attributable to
impaired function or expression of signaling intermediates shared by
IL-1 and LPS. As many of these factors are involved also in signal
transduction via TLR2 (32, 33, 34), we sought to determine
whether, in analogy to IL-1, pretreatment with LTA had an inhibitory
effect on LPS-induced signaling and vice versa. Indeed, exposure of
cells to LTA also induced hyporesponsiveness to subsequent stimulation
with LPS (Fig. 3B, right). Similarly, LPS induced
cellular refractoriness to both LTA and LPS (Fig. 3, A,
left and B, left). The same
experiments, as controls, were performed with cells from
LPS-hyporesponsive C3H/HeJ mice. As expected, no cytokine release was
found on restimulation with 10 ng/ml LPS (Fig. 3D), whereas
LTA-induced release of TNF from saline-preexposed HeJ macrophages was
comparable to cells derived from HeN mice (Fig. 3C, left).
In contrast to wild-type cells, HeJ macrophages were not rendered
LTA-tolerant by preexposure to LPS, whereas pretreatment with LTA
inhibited cytokine release (Fig. 3C).
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B, right) identify TLR2 as the receptor transmitting
tolerance induction by LTA: TLR-2-deficient cells were not affected by
pretreatment with LTA with regards to subsequent LPS-inducible cytokine
release.
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Administration of endotoxin in vivo induces a state of tolerance to the toxicity of subsequent endotoxin challenge in models of LPS shock and LPS-induced liver injury (35). Although suppression of LPS-induced cytokine production, especially of TNF, in tolerant animals is often put forward to explain the protective effect of endotoxin tolerance and ex vivo data confirm hyporesponsiveness of macrophages isolated from LPS-pretreated animals (36), the relationship between in vitro desensitization of macrophages and in vivo tolerance induction has not been delineated fully (37).
To determine whether the phenomenon of cross-desensitization by LPS and
LTA observed in vitro can also be reproduced in vivo, we performed
animal studies, injecting LTA or LPS 24 h before induction of
liver damage by galactosamine plus LPS/LTA. Saline-pretreated mice
exhibited elevated TNF plasma levels in response to GalN + LPS (5
µg/kg; only C3H/HeN mice; Fig. 4A) or GalN + LTA (25 mg/kg;
C3H/HeN, Fig. 4B and C3H/HeJ mice, Fig. 4C) and
developed liver injury as assessed by plasma transaminase activity
8 h after challenge. In contrast, TNF levels and liver damage were
significantly lessened when animals were injected with LPS (3 µg/kg)
or LTA (15 mg/kg) 24 h before challenge. Similarly, as shown for
isolated macrophages in vitro, LPS pretreatment was ineffective in
C3H/HeJ mice challenged subsequently with GalN/LTA, confirming the
requirement of TLR4-mediated signaling in tolerance induction by LPS in
vivo (Fig. 4C).
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Earlier reports suggested that refractoriness after preexposure of
cells to endotoxin was mediated by endogenous factors such as IL-10,
TGF
, or IL-1 (31, 38). This led us to study the role of
soluble mediators in tolerance induction in a coculture system by using
mixed macrophages from wild-type and TLR-deficient mice. If
desensitization was mediated by soluble factors released on stimulation
with LPS, macrophages from TLR4-mutated C3H/HeJ mice cocultured
together with wild-type macrophages should be rendered LTA-tolerant by
LPS pretreatment. In cultures of macrophages from either C3H/HeN or HeJ
mice and in coculture of both cell types, LTA pretreatment completely
inhibited cytokine production in response to LTA challenge (Fig. 5
A). In contrast, preexposure
to LPS only partially suppressed cytokine release by 
50% in the
coculture system, whereas complete inhibition was found in HeN cells
(Fig. 5A). Similar results were obtained with coculture of
TLR2-/- and wild-type cells restimulated with
LPS. In this setting, LPS pretreatment suppressed TNF production in
wild-type, TLR2-/-, and mixed cells (Fig. 5B). LTA pretreatment impaired cytokine production by
wild-type cells but had no effect on TLR2-/-
cells, whereas a 50% reduction of TNF was found in supernatants of
cocultured cells (Fig. 5B). These results indicate that in
the coculture system, only the cells carrying functional TLR were
desensitized, whereas the TLR4- or TLR2-deficient cells were unaffected
by the LPS/LTA pretreatment. These findings suggest that soluble
factors such as IL-10, TGF, or IL-1 that are released on contact
with LPS or LTA are not responsible for suppression of TNF formation on
secondary stimulation. Hence, direct signaling via the adequate TLR
seems to be necessary for in vitro desensitization by LPS or
LTA.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-mediated liver damage as
well as fulminant infection with high numbers of bacteria, suppression
of cytokine production, and prevention of tissue damage as well as of
mortality were observed when a nontoxic dose of LPS was administered
several hours or days before challenge (37, 41). We
demonstrate here that acquired tolerance to the immunostimulatory
activity of a bacterial component is not restricted to LPS, but also is
found in response to LTA from Gram-positive bacteria. Moreover, our
data showing cross-desensitization of LPS and LTA suggest a general
mechanism of suppressing proinflammatory responses after repeated
contact with components of Gram-positive or Gram-negative bacteria. Our findings are in line with a previous report showing suppressed cytokine production on stimulation of LPS-pretreated human monocytes with whole S. aureus (42). However, contrasting results were obtained by others showing unaltered or even increased cytokine production upon stimulation with muramyl dipeptide or whole S. aureus after LPS-tolerance induction (11, 43). These discrepancies may be attributable to species differences, as guinea pig and rabbit macrophages were used there, or to overall different experimental settings. The results presented here confirm and extend recent findings by Sato et al. (24) who demonstrated cross-desensitization of murine macrophages by LPS and the mycoplasmal lipopeptide macrophage activating protein 2 (MALP-2), which has been shown to signal also via TLR2 (21). As a major difference, in our setting, LPS pretreatment completely inhibited TNF release in response to subsequent LTA stimulation, whereas only a partial reduction of MALP-2 induced TNF production by LPS-desensitized macrophages was found by Sato et al. (24).
It recently has been shown that lipopeptides contaminating commercial
LPS preparations signal via TLR-2 (44). Such contamination
might contribute to the cross-desensitization with LTA, although a
highly purified endotoxin was used. However, we demonstrate in Fig. 3
that preexposure of wild-type C3H/HeN macrophages with 1 ng LPS/ml
already induced significant cross-desensitization to LTA restimulation,
whereas no significant reduction of LTA-induced TNF release was
observed in TLR4-mutated macrophages from C3H/HeJ mice pretreated with
LPS up to 10 ng/ml. This strongly argues for a TLR4-dependent mechanism
of cross-desensitization in response to the LPS concentrations used
throughout the study (1–10 ng LPS/ml).
In the last years, our understanding of the molecular mechanisms
underlying desensitization of macrophages by exposure to LPS has
increased considerably. Expression of CD14 is unaffected or even
increased after LPS stimulation, thus it is highly unlikely that
tolerance is mediated via expression of this LPS receptor (45, 46). Refractoriness in response to LPS preexposure has been
shown to be associated with altered G protein content (47, 48), phospholipase D and phosphatidylinositol-3 kinase
expression (49), and compromised protein kinase C
activation (50). Others described suppressed signal
transduction via both the mitogen-activated protein kinase cascade
(30, 51, 52, 53) and I-
B kinases, resulting in impaired
transcription of NF-B- and AP-1-regulated genes (30, 54). A predominance of transactivation-inactive p50/p50
homodimers of NF-B also has been found in LPS tolerance (55, 56). Recent data showing suppression of IL-1R-associated kinase
activation and association with myeloid differentiation protein 88
(57) and decreased surface expression of TLR4 on
LPS-tolerized cells (58) support the notion that very
early steps in LPS signaling are altered after LPS exposure. Further
evidence for this was provided by Medvedev et al. (30) who
reevaluated in vitro desensitization by IL-1 and TNF, showing induction
of cross-tolerance to LPS via the IL-1 receptor but not the TNF
receptor. Intriguingly, signal transduction of the IL-1R, the LPS
receptor TLR4, and TLR2 use similar signaling molecules (32, 34, 59). Our findings that preexposure to LTA inducing signaling via
TLR2 results in hyporesponsiveness to TLR4-mediated LPS signaling and
vice versa add further indirect evidence for a suppression of common
signaling molecules shared by TLR2 and TLR4 and IL-1R, i.e., myeloid
differentiation protein 88, IL-1R-associated kinase, TNF
receptor-activated factor 6, or NF-B-inducing kinase in desensitized
macrophages. Alternatively, activation of the IL-1R/TLR signaling
pathway could result in formation of a specific nuclear suppressor of
LPS-induced gene transcription, as suggested previously (60, 61).
Previous studies suggested that hyporesponsiveness after pretreatment
with LPS was mediated by the action of endogenous mediators such as
IL-10, TGF, or IL-1 produced on primary or secondary LPS
stimulation (31, 38, 42). Others postulated the existence
of soluble yet unidentified suppressor molecules of TNF expression
during LPS tolerance (62, 63). Our findings that
macrophages from mice deficient in TLR2 or carrying a nonfunctional
mutant of TLR4 were not rendered refractory by LTA or LPS pretreatment,
respectively, when cocultured with wild-type macrophages argue against
soluble mediators of desensitization unless factors requiring the
presence of TLR2 or TLR4 (i.e., yet unknown soluble ligands of TLR2 or
TLR4) are involved. However, we cannot rule out that the effects of
LPS/LTA pretreatment in vivo, i.e., protection against LPS shock and
liver injury, are mediated in part by endogenously produced cytokines.
Thus, macrophage-derived products such as TNF and IL-1, which are
released during the LPS/LTA pretreatment, might contribute to the
desensitization of target cells (e.g., hepatocytes) against the
toxicity of subsequent LPS/LTA challenge in vivo, e.g., by inducing
heat-shock and other acute phase proteins (64, 65, 66).
In conclusion, in the present study, we demonstrate cross-desensitization of primary murine macrophages by highly purified LTA and LPS in vitro and cross-tolerance to LTA/LPS-induced TNF production and liver damage in vivo. Our data provide evidence that macrophage desensitization is not a LPS-specific phenomenon but that common signaling pathways shared by TLR4 and TLR2 are impaired during macrophage refractoriness. Finally, our findings suggest that endogenously produced soluble factors do not suffice for macrophage desensitization in vitro.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas Hartung, Biochemical Pharmacology, University of Konstanz, P.O. Box M655, D-78457 Konstanz, Germany.
3 Abbreviations used in this paper: LTA, lipoteichoic acid; TLR, Toll-like receptor; GalN, D-galactosamine.
4 B. Opitz, N. W. J. Schroeder, I. Spreitzer, K. S. Michelsen, C. J. Kirschning, W. Hallatschek, U. Zaehringe, T. Hartung, U. B. Goebel, and, R. R., and Schumann. Toll-like receptor (TLR)-2 mediates treponema glycolipid and lipoteichoic acid (LTA)-induced NF-B translocation. Submitted for publication.
Received for publication December 8, 2000. Accepted for publication February 13, 2001.
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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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S. Traub, S. von Aulock, T. Hartung, and C. Hermann Invited review: MDP and other muropeptides direct and synergistic effects on the immune system Innate Immunity, April 1, 2006; 12(2): 69 - 85. [Abstract] [PDF]
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S. Morath, S. von Aulock, and T. Hartung Structure/function relationships of lipoteichoic acids Innate Immunity, December 1, 2005; 11(6): 348 - 356. [Abstract] [PDF]
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L. Romics Jr, A. Dolganiuc, A. Velayudham, K. Kodys, P. Mandrekar, D. Golenbock, E. Kurt-Jones, and G. Szabo Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni- bacterium acnes J. Leukoc. Biol., December 1, 2005; 78(6): 1255 - 1264. [Abstract] [Full Text] [PDF]
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J.-M. Cavaillon, C. Adrie, C. Fitting, and M. Adib-Conquy Reprogramming of circulatory cells in sepsis and SIRS Innate Immunity, October 1, 2005; 11(5): 311 - 320. [Abstract] [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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 T. A. Pham-Marcou, M. Gentili, K. Asehnoune, D. Fletcher, and J.-X. Mazoit Effect of neurolytic nerve block on systemic carrageenan-induced inflammatory response in mice Br. J. Anaesth., August 1, 2005; 95(2): 243 - 246. [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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 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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E. Lorenz, D. C. Chemotti, A. L. Jiang, and L. D. McDougal Differential Involvement of Toll-Like Receptors 2 and 4 in the Host Response to Acute Respiratory Infections with Wild-Type and Mutant Haemophilus influenzae Strains Infect. Immun., April 1, 2005; 73(4): 2075 - 2082. [Abstract] [Full Text] [PDF]
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M. W. Hornef and C. Bogdan The role of epithelial Toll-like receptor expression in host defense and microbial tolerance Innate Immunity, April 1, 2005; 11(2): 124 - 128. [Abstract] [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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A. Baetz, M. Frey, K. Heeg, and A. H. Dalpke Suppressor of Cytokine Signaling (SOCS) Proteins Indirectly Regulate Toll-like Receptor Signaling in Innate Immune Cells J. Biol. Chem., December 24, 2004; 279(52): 54708 - 54715. [Abstract] [Full Text] [PDF]
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C. S. Boutlis, J. B. Weinberg, J. Baker, M. J. Bockarie, C. S. Mgone, Q. Cheng, and N. M. Anstey Nitric Oxide Production and Nitric Oxide Synthase Activity in Malaria-Exposed Papua New Guinean Children and Adults Show Longitudinal Stability and No Association with Parasitemia Infect. Immun., December 1, 2004; 72(12): 6932 - 6938. [Abstract] [Full Text] [PDF]
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H.-Y. Hsu, K.-F. Hua, C.-C. Lin, C.-H. Lin, J. Hsu, and C.-H. Wong Extract of Reishi Polysaccharides Induces Cytokine Expression via TLR4-Modulated Protein Kinase Signaling Pathways J. Immunol., November 15, 2004; 173(10): 5989 - 5999. [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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M. Triantafilou, M. Manukyan, A. Mackie, S. Morath, T. Hartung, H. Heine, and K. Triantafilou Lipoteichoic Acid and Toll-like Receptor 2 Internalization and Targeting to the Golgi Are Lipid Raft-dependent J. Biol. Chem., September 24, 2004; 279(39): 40882 - 40889. [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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I. A. Clark, L. M. Alleva, A. C. Mills, and W. B. Cowden Pathogenesis of Malaria and Clinically Similar Conditions Clin. Microbiol. Rev., July 1, 2004; 17(3): 509 - 539. [Abstract] [Full Text] [PDF]
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R. Silverstein Review: D-Galactosamine lethality model: scope and limitations Innate Immunity, June 1, 2004; 10(3): 147 - 162. [Abstract] [PDF]
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S. von Aulock, N. W. J. Schroder, S. Traub, K. Gueinzius, E. Lorenz, T. Hartung, R. R. Schumann, and C. Hermann Heterozygous Toll-Like Receptor 2 Polymorphism Does Not Affect Lipoteichoic Acid-Induced Chemokine and Inflammatory Responses Infect. Immun., March 1, 2004; 72(3): 1828 - 1831. [Abstract] [Full Text] [PDF]
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T. J. Murphy, H. M. Paterson, J. A. Mannick, and J. A. Lederer Injury, sepsis, and the regulation of Toll-like receptor responses J. Leukoc. Biol., March 1, 2004; 75(3): 400 - 407. [Abstract] [Full Text] [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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J. Branger, S. Knapp, S. Weijer, J. C. Leemans, J. M. Pater, P. Speelman, S. Florquin, and T. van der Poll Role of Toll-Like Receptor 4 in Gram-Positive and Gram-Negative Pneumonia in Mice Infect. Immun., February 1, 2004; 72(2): 788 - 794. [Abstract] [Full Text] [PDF]
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M. P. Gould, J. A. Greene, V. Bhoj, J. L. DeVecchio, and F. P. Heinzel Distinct Modulatory Effects of LPS and CpG on IL-18-Dependent IFN-{gamma} Synthesis J. Immunol., February 1, 2004; 172(3): 1754 - 1762. [Abstract] [Full Text] [PDF]
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 F. C. Neuhaus and J. Baddiley A Continuum of Anionic Charge: Structures and Functions of D-Alanyl-Teichoic Acids in Gram-Positive Bacteria Microbiol. Mol. Biol. Rev., December 1, 2003; 67(4): 686 - 723. [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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 I. I. Salles, A. E. Tucker, D. E. Voth, and J. D. Ballard Toxin-induced resistance in Bacillus anthracis lethal toxin-treated macrophages PNAS, October 14, 2003; 100(21): 12426 - 12431. [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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C. S. Boutlis, E. Tjitra, H. Maniboey, M. A. Misukonis, J. R. Saunders, S. Suprianto, J. B. Weinberg, and N. M. Anstey Nitric Oxide Production and Mononuclear Cell Nitric Oxide Synthase Activity in Malaria-Tolerant Papuan Adults Infect. Immun., July 1, 2003; 71(7): 3682 - 3689. [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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S. Deininger, A. Stadelmaier, S. von Aulock, S. Morath, R. R. Schmidt, and T. Hartung Definition of Structural Prerequisites for Lipoteichoic Acid-Inducible Cytokine Induction by Synthetic Derivatives J. Immunol., April 15, 2003; 170(8): 4134 - 4138. [Abstract] [Full Text] [PDF]
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J.-M. Cavaillon, C. Adrie, C. Fitting, and M. Adib-Conquy Endotoxin tolerance: is there a clinical relevance? Innate Immunity, April 1, 2003; 9(2): 101 - 107. [Abstract] [PDF]
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Y. Asai, T. Jinno, and T. Ogawa Oral Treponemes and Their Outer Membrane Extracts Activate Human Gingival Epithelial Cells through Toll-Like Receptor 2 Infect. Immun., February 1, 2003; 71(2): 717 - 725. [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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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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A. E. Medvedev and S. N. Vogel Overexpression of CD14, TLR4, and MD-2 in HEK 293T cells does not prevent induction of in vitro endotoxin tolerance Innate Immunity, February 1, 2003; 9(1): 60 - 64. [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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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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A. E. Medvedev, A. Lentschat, L. M. Wahl, D. T. Golenbock, and S. N. Vogel Dysregulation of LPS-Induced Toll-Like Receptor 4-MyD88 Complex Formation and IL-1 Receptor-Associated Kinase 1 Activation in Endotoxin-Tolerant Cells J. Immunol., November 1, 2002; 169(9): 5209 - 5216. [Abstract] [Full Text] [PDF]
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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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 A. UEHARA, S. SUGAWARA, and H. TAKADA Priming of human oral epithelial cells by interferon-{gamma} to secrete cytokines in response to lipopolysaccharides, lipoteichoic acids and peptidoglycans J. Med. Microbiol., August 1, 2002; 51(8): 626 - 634. [Abstract] [Full Text] [PDF]
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 K. Bieback, E. Lien, I. M. Klagge, E. Avota, J. Schneider-Schaulies, W. P. Duprex, H. Wagner, C. J. Kirschning, V. ter Meulen, and S. Schneider-Schaulies Hemagglutinin Protein of Wild-Type Measles Virus Activates Toll-Like Receptor 2 Signaling J. Virol., July 29, 2002; 76(17): 8729 - 8736. [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. Morath, A. Stadelmaier, A. Geyer, R. R. Schmidt, and T. Hartung Synthetic Lipoteichoic Acid from Staphylococcus aureus Is a Potent Stimulus of Cytokine Release J. Exp. Med., June 17, 2002; 195(12): 1635 - 1640. [Abstract] [Full Text] [PDF]
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R. Jacinto, T. Hartung, C. McCall, and L. Li Lipopolysaccharide- and Lipoteichoic Acid-Induced Tolerance and Cross-Tolerance: Distinct Alterations in IL-1 Receptor-Associated Kinase J. Immunol., June 15, 2002; 168(12): 6136 - 6141. [Abstract] [Full Text] [PDF]
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B. G. Yipp, G. Andonegui, C. J. Howlett, S. M. Robbins, T. Hartung, M. Ho, and P. Kubes Profound Differences in Leukocyte-Endothelial Cell Responses to Lipopolysaccharide Versus Lipoteichoic Acid J. Immunol., May 1, 2002; 168(9): 4650 - 4658. [Abstract] [Full Text] [PDF]
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M. D. Lehner, F. Schwoebel, A. Kotlyarov, M. Leist, M. Gaestel, and T. Hartung Mitogen-Activated Protein Kinase-Activated Protein Kinase 2-Deficient Mice Show Increased Susceptibility to Listeria monocytogenes Infection J. Immunol., May 1, 2002; 168(9): 4667 - 4673. [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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M. W. Hornef, T. Frisan, A. Vandewalle, S. Normark, and A. Richter-Dahlfors Toll-like Receptor 4 Resides in the Golgi Apparatus and Colocalizes with Internalized Lipopolysaccharide in Intestinal Epithelial Cells J. Exp. Med., February 25, 2002; 195(5): 559 - 570. [Abstract] [Full Text] [PDF]
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S. Morath, A. Geyer, I. Spreitzer, C. Hermann, and T. Hartung Structural Decomposition and Heterogeneity of Commercial Lipoteichoic Acid Preparations Infect. Immun., February 1, 2002; 70(2): 938 - 944. [Abstract] [Full Text] [PDF]
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Y. Asai, Y. Ohyama, K. Gen, and T. Ogawa Bacterial Fimbriae and Their Peptides Activate Human Gingival Epithelial Cells through Toll-Like Receptor 2 Infect. Immun., December 1, 2001; 69(12): 7387 - 7395. [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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N. Kadowaki, S. Ho, S. Antonenko, R. de Waal Malefyt, R. A. Kastelein, F. Bazan, and Y.-J. Liu Subsets of Human Dendritic Cell Precursors Express Different Toll-like Receptors and Respond to Different Microbial Antigens J. Exp. Med., September 17, 2001; 194(6): 863 - 870. [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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) or
increasing concentrations of LPS (
), or LTA (
) for 20 h.
After washing, cells were restimulated with 10 µg/ml LTA
(A and C) or 10 ng/ml LPS
(B and D) for 6 h, and TNF was
determined in supernatants by ELISA. Representative data from one of
three independent experiments are presented as means ± SEM. *,
p < 0.05; **, p < 0.01 vs
respective control group (NaCl) based on repeated measurement ANOVA,
followed by Dunnett’s multiple comparison test.
