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CUTTING EDGE |
German Diabetes Research Institute, Heinrich-Heine-University, Düsseldorf, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and NO formation were found dependent on a
functional Tlr4 whereas stimulation of macrophages by CpG DNA was Tlr4
independent. We conclude that Tlr4 mediates hsp60 signaling. This is
the first report of a putative endogenous ligand of the Tlr4
complex. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. In addition, human hsp60 induced gene
expression of IL-12 and IL-15 (2). These two cytokines are
essential in driving the Th1 response. Since autologous hsp60 may be
aberrantly expressed on the cell surface in response to stress
(3, 4) and will be set free from the cell interior during
necrosis, these findings point to a role of hsp60 in initiating or
sustaining Th1-dependent tissue inflammation (2).
Interestingly, microbial hsp60/65 also induces a proinflammatory
response in innate immune cells (5, 6, 7), suggesting that
damaged autologous cells and microbial pathogens may alert innate
immunity via the same recognition system. In search for a possible receptor for hsp60 on the macrophage cell surface, we were led by the striking similarity of innate immune responses to hsp60 and LPS although a role of contaminations of hsp60 with endotoxin could be excluded (1, 2). Since the stimulatory action of mycobacterial hsp65 was not inhibited by an Ab to CD14 (5), we tested for a role of Toll-like receptor 4 (Tlr4). The latter has recently been identified as product of the lps gene and to mediate LPS signaling in mouse cells (8, 9, 10). In human cells, Tlr2 rather than Tlr4 appears to be important in LPS binding and signaling, but the situation is less clear (11, 12, 13).
Toll-like receptors are the human homologue of the
Drosophila Toll protein. They belong to the IL-1 receptor
family containing repeated leucine-rich motifs in their extracellular
portion and are linked to a signaling pathway that involves the
IL-1-receptor-associated kinase and NF-
B (14, 15).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recombinant human hsp60 was obtained from StressGen Biotechnologies (Victoria, Canada). The two immunostimulatory oligonucleotides 5'-ACC GAT AAC GTT GCC GGT GAC G-3' (Pal+) (16) and 5'-TCC ATG ACG TTC CTG ATG CT-3' (ODN1668) (17, 18) containing a CpG motif and the corresponding nonstimulatory oligonucleotide 5'-TCC ATG AGC TTC CTG ATG CT-3' (ODN1720) (17, 18) lacking a CpG motif were purchased from Life Technologies (Karlsruhe, Germany). LPS from Escherichia coli B 0.26 was obtained from Sigma (Deisenhofen, Germany).
Mouse bone marrow-derived macrophages
C3H/HeN and C3H/HeJ mice were purchased from Charles River (Sulzfeld, Germany), and C57BL/6JBom mice were from Breeding & Research Center A/S (Bomholtgård, Ry, Denmark). Bone marrow cells were obtained by flushing femurs and tibias of 8- to 12-wk-old mice with ice-cold PBS. After washing, 2.5 x 106 bone marrow cells were incubated (37°C, 5% CO2) in tissue culture dishes with 10 ml of Pluznik medium containing 5% heat-inactivated horse serum, 15% FCS (Life Technologies), 15% L929 cell-conditioned medium (19), and 65% RPMI 1640 supplemented with ampicillin (25 mg/L), penicillin (120 mg/L), streptomycin (270 mg/L), 1 mM sodium pyruvate, 2 mM L-glutamine, nonessential amino acids (10 ml/L, 100x), 24 mM NaHCO3, and 10 mM HEPES. After 7 days of cultivation, adherent bone marrow-derived macrophages were detached by incubation with ice-cold Ca2+-, Mg2+-free HBSS (Life Technologies) for 10 min followed by two washes with HBSS (500 g, 5 min). By nonspecific esterase stain (20), >98% of cells exhibited macrophage characteristics.
Stimulation of macrophages
Cells were seeded in 96-well flat-bottom microtiter plates (Falcon/Becton Dickinson, Franklin Lakes, NJ) (2 x 105 cells in 200 µl per well). After 24 h of preincubation (37°C, 5% CO2), various concentrations of hsp60, LPS, and oligonucleotides were added to the cultures, and the incubation was continued for different time intervals.
TNF- measurements
The amounts of TNF- released from the macrophages were
quantified by sandwich ELISA (2). The TNF- was
quantified using a standard curve obtained with the recombinant
cytokine (Genzyme, Kent, U.K.) vs medium alone as blank. The results
were expressed as pg TNF- per ml.
Measurement of nitrite production
The amount of NO released by macrophages was assessed by determining the concentration of nitrite (NO2-) accumulated in the culture supernatant using the colorimetric Griess reaction as described previously (2). The results show micromoles of NO2- per milliliter.
Statistical analysis
Data were expressed as mean + SD. Statistical analysis was performed using the Student t test, two-sided. Differences were considered statistically significant with p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in macrophages by human hsp60 is Tlr4
dependent
Bone marrow-derived macrophages of mouse strains C57BL/6 and
C3H/HeN responded to LPS or human hsp60 with rapid secretion of large
amounts of TNF- (Fig. 1
). A parallel
study of macrophages from C3H/HeJ mice showed no response to either LPS
or hsp60. However, these cells were not completely refractory to
inflammatory stimuli. An oligodeoxynucleotide derived from
mycobacterial sequences (ODN1668) and containing a potent
immunostimulatory CpG motif induced a strong TNF- response in the
LPS nonresponder strain. A second CpG containing oligonucleotide
(Pal+) was less stimulatory whereas a
CpG-deficient oligonucleotide (ODN1720) did not provoke a response
(Fig. 1).
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response
was obtained in C3H/HeN macrophages with 3 µg/ml hsp60 (0.05
µmol/L) whereas no such was response was seen in C3H/HeJ macrophages
even at ten times higher hsp60 levels (Fig. 2A). An analysis of the
kinetics revealed peak levels of secreted TNF- between 6 and 12
h in C3H/HeN macrophages. In the Tlr4-defective macrophages, TNF-
production was absent throughout the observation period of 72 h
(Fig. 2B).
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Macrophage cultures were analyzed for their ability to respond
with the production of NO to the various stimuli, by measuring the
stable end product nitrite in supernatants. Macrophages of C57BL/6,
C3H/HeN but not of C3H/HeJ mice responded to LPS challenge with NO
production, which indicates that endotoxin induced NO formation is Tlr4
dependent (Fig. 3). The same outcome was
obtained when hsp60 was taken as stimulus, with a complete lack of a NO
response in Tlr4-defective macrophages. In contrast, the two macrophage
types showed a very similar NO response when the strongly stimulatory
CpG DNA ODN1668 was used as stimulus whereas the less stimulatory CpG
oligonucleotide Pal+ failed to induce NO
formation, as was the case for the CpG deficient ODN1720 (Fig. 3).
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production. Increasing the hsp60 concentration
10-fold yielded about five times higher nitrite levels in C3H/HeN
macrophages whereas Tlr4-defective macrophages remained completely
refractory (Fig. 4A). Nitrite
accumulation in the supernatant reached maximum levels between 48 and
72 h of culture. There was no indication of NO production in
C3H/HeJ macrophages throughout this period (Fig. 4B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Indeed, macrophages from C3H/HeJ
(lpsd) mice were found clearly
refractory to LPS-induced TNF- production. Interestingly, inducible
NO formation was also found strictly dependent on a functional Tlr4
although signaling requirements differ from that of TNF- (24, 25). Exposure of lpsd
macrophages to immunostimulatory CpG DNA did stimulate both TNF- and
NO production, which shows that Tlr4-dependent and -independent
pathways for stimulating innate immune responses coexist in
macrophages. Also, these data demonstrate that CpG DNA signaling does
not occur via Tlr4.
Taken together, stimulation of TNF- or NO response by human hsp60
was found here as fully dependent on the presence of a functional Tlr4
membrane protein. Thus, the same transmembrane signaling receptor
appears to mediate the innate immune response to hsp60 and LPS.
Extensive controls were performed in two previous reports of the
immunostimulatory activity of extracellular mammalian hsp60 to exclude
a role of endotoxin contamination (1, 2). These controls
included the use of polymyxin B for neutralization of LPS, or
denaturing of protein by heat treatment, which suppressed hsp60 but not
LPS activity. Also, we were able to repeat the essential findings with
an endotoxin-free preparation from another source (Peptor, Rehovot,
Israel; less than 0.1 µEU of endotoxin contamination per µg hsp60;
D. Elias, personal communication). Finally, endotoxin-free bacterial
lipoproteins have been recently reported to mediate an innate immune
response via the Tlr-2 pathway (26, 27, 28). These
observations underscore that Tlr4 and T1r2 not only function as
receptors of LPS (8, 12, 28) but are also involved in the
recognition of protein ligands.
The previously described ligands for Toll-like receptors in mammalian cells are of microbial origin, which is in line with a function of these receptors in innate immune responses. We report here for the first time on a putative endogenous ligand of Toll-like receptors in mammals, the chaperone hsp60. This finding suggests that Toll-like receptors not only may have a function in innate immune defense against microbial pathogens but also may serve physiological functions by interacting with endogenous ligands. This is reminiscent of the situation in Drosophila where Toll controls dorsal-ventral patterning with Spätzle serving as endogenous ligand (29), whereas in adult insects Toll controls the antifungal and antibacterial response (30).
It is noteworthy that both Toll-like receptors and hsp60 are found early in phylogeny and both are of remarkably conserved structure. This indicates that their interaction is relevant and may also occur in more primitive organisms. Mammalian hsp60 usually is sequestered to the cell interior, in accordance with its ability to function as chaperone. However, hsp60 becomes accessible when it is set free during necrosis of tissue cells during inflammation or when hsp60 is partially translocated to the plasma membrane in response to diverse types of stress (3, 4). We therefore have proposed that autologous hsp60 may serve as danger Ag to the innate immune system (2).
The exact mechanism of interaction between mammalian hsp60 and the Tlr4 complex remains to be elucidated. With CD14 and MD-2, two members of the Tlr4 complex have been identified, both of which strongly potentiate LPS responsiveness of Tlr4 (31, 32). LPS appears to bind to Tlr4 via CD14 (31) as well as independent of CD14 (32). For human T1r2, direct binding to LPS was demonstrated in vitro (11), and efficient signaling appears to require serum CD14 (12). Similarly, the mechanism of interaction between bacterial lipoproteins and T1r2 has not been determined (26, 27, 28).
In summary, the proinflammatory signaling of human hsp60 was found dependent on a functional Tlr4. This finding suggests the existence of endogenous ligands of the Tlr4 complex, and a role of Toll-like receptors in innate immune discrimination of normal vs stressed or damaged tissue cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hubert Kolb, German Diabetes Research Institute, Auf’m Hennekamp 65, D-40225 Düsseldorf, Germany. E-mail address:
3 Abbreviations used in this paper: hsp, heat shock protein; Tlr, Toll-like receptor; ODN, oligodeoxynucleotide.
Received for publication October 14, 1999. Accepted for publication November 12, 1999.
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 X.-Y. Wang, J. Facciponte, X. Chen, J. R. Subjeck, and E. A. Repasky Scavenger Receptor-A Negatively Regulates Antitumor Immunity Cancer Res., May 15, 2007; 67(10): 4996 - 5002. [Abstract] [Full Text] [PDF]
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 N. Chaudhuri, M. K. B. Whyte, and I. Sabroe Reducing the Toll of Inflammatory Lung Disease Chest, May 1, 2007; 131(5): 1550 - 1556. [Abstract] [Full Text] [PDF]
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S. Tarang, A. Sodhi, and P. Chauhan Differential expression of Toll-like receptors in murine peritoneal macrophages in vitro on treatment with cisplatin Int. Immunol., May 1, 2007; 19(5): 635 - 643. [Abstract] [Full Text] [PDF]
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 A. Shamaei-Tousi, J. P. Halcox, and B. Henderson Stressing the obvious? Cell stress and cell stress proteins in cardiovascular disease Cardiovasc Res, April 1, 2007; 74(1): 19 - 28. [Abstract] [Full Text] [PDF]
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 J. R. Caso, J. M. Pradillo, O. Hurtado, P. Lorenzo, M. A. Moro, and I. Lizasoain Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke Circulation, March 27, 2007; 115(12): 1599 - 1608. [Abstract] [Full Text] [PDF]
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 P. Winkler, D. Ghadimi, J. Schrezenmeir, and J.-P. Kraehenbuhl Molecular and Cellular Basis of Microflora-Host Interactions J. Nutr., March 1, 2007; 137(3): 756S - 772S. [Abstract] [Full Text] [PDF]
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A. Osterloh, U. Kalinke, S. Weiss, B. Fleischer, and M. Breloer Synergistic and Differential Modulation of Immune Responses by Hsp60 and Lipopolysaccharide J. Biol. Chem., February 16, 2007; 282(7): 4669 - 4680. [Abstract] [Full Text] [PDF]
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 C. I. Maratheftis, E. Andreakos, H. M. Moutsopoulos, and M. Voulgarelis Toll-like Receptor-4 Is Up-Regulated in Hematopoietic Progenitor Cells and Contributes to Increased Apoptosis in Myelodysplastic Syndromes Clin. Cancer Res., February 15, 2007; 13(4): 1154 - 1160. [Abstract] [Full Text] [PDF]
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M. Pevsner-Fischer, V. Morad, M. Cohen-Sfady, L. Rousso-Noori, A. Zanin-Zhorov, S. Cohen, I. R. Cohen, and D. Zipori Toll-like receptors and their ligands control mesenchymal stem cell functions Blood, February 15, 2007; 109(4): 1422 - 1432. [Abstract] [Full Text] [PDF]
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M.-F. Tsan and Baochong Gao Review: Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors Innate Immunity, February 1, 2007; 13(1): 6 - 14. [Abstract] [PDF]
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 F. Cao, A. Castrillo, P. Tontonoz, F. Re, and G. I. Byrne Chlamydia pneumoniae-Induced Macrophage Foam Cell Formation Is Mediated by Toll-Like Receptor 2 Infect. Immun., February 1, 2007; 75(2): 753 - 759. [Abstract] [Full Text] [PDF]
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 G. Ramesh, S. R. Kimball, L. S. Jefferson, and W. B. Reeves Endotoxin and cisplatin synergistically stimulate TNF-{alpha} production by renal epithelial cells Am J Physiol Renal Physiol, February 1, 2007; 292(2): F812 - F819. [Abstract] [Full Text] [PDF]
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J. J. Lasarte, N. Casares, M. Gorraiz, S. Hervas-Stubbs, L. Arribillaga, C. Mansilla, M. Durantez, D. Llopiz, P. Sarobe, F. Borras-Cuesta, et al. The Extra Domain A from Fibronectin Targets Antigens to TLR4-Expressing Cells and Induces Cytotoxic T Cell Responses In Vivo J. Immunol., January 15, 2007; 178(2): 748 - 756. [Abstract] [Full Text] [PDF]
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T. Suganami, K. Tanimoto-Koyama, J. Nishida, M. Itoh, X. Yuan, S. Mizuarai, H. Kotani, S. Yamaoka, K. Miyake, S. Aoe, et al. Role of the Toll-like Receptor 4/NF-{kappa}B Pathway in Saturated Fatty Acid-Induced Inflammatory Changes in the Interaction Between Adipocytes and Macrophages Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 84 - 91. [Abstract] [Full Text] [PDF]
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Y. Sakata, J.-W. Dong, J. G. Vallejo, C.-H. Huang, J. S. Baker, K. J. Tracey, O. Tacheuchi, S. Akira, and D. L. Mann Toll-like receptor 2 modulates left ventricular function following ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H503 - H509. [Abstract] [Full Text] [PDF]
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J. H. Boyd, S. Mathur, Y. Wang, R. M. Bateman, and K. R. Walley Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-{kappa}B dependent inflammatory response Cardiovasc Res, December 1, 2006; 72(3): 384 - 393. [Abstract] [Full Text] [PDF]
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 J.E. den Hartog, S.A. Morre, and J.A. Land Chlamydia trachomatis-associated tubal factor subfertility: immunogenetic aspects and serological screening Hum. Reprod. Update, November 1, 2006; 12(6): 719 - 730. [Abstract] [Full Text] [PDF]
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R. M. Levy, J. M. Prince, R. Yang, K. P. Mollen, H. Liao, G. A. Watson, M. P. Fink, Y. Vodovotz, and T. R. Billiar Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4 Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R970 - R976. [Abstract] [Full Text] [PDF]
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X. Zhu, H. Zhao, A. R. Graveline, E. S. Buys, U. Schmidt, K. D. Bloch, A. Rosenzweig, and W. Chao MyD88 and NOS2 are essential for Toll-like receptor 4-mediated survival effect in cardiomyocytes Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1900 - H1909. [Abstract] [Full Text] [PDF]
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 I. K. Demedts, K. R. Bracke, T. Maes, G. F. Joos, and G. G. Brusselle Different Roles for Human Lung Dendritic Cell Subsets in Pulmonary Immune Defense Mechanisms Am. J. Respir. Cell Mol. Biol., September 1, 2006; 35(3): 387 - 393. [Abstract] [Full Text] [PDF]
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L. Kim, B. A. Butcher, C. W. Lee, S. Uematsu, S. Akira, and E. Y. Denkers Toxoplasma gondii Genotype Determines MyD88-Dependent Signaling in Infected Macrophages J. Immunol., August 15, 2006; 177(4): 2584 - 2591. [Abstract] [Full Text] [PDF]
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T. Warger, N. Hilf, G. Rechtsteiner, P. Haselmayer, D. M. Carrick, H. Jonuleit, P. von Landenberg, H.-G. Rammensee, C. V. Nicchitta, M. P. Radsak, et al. Interaction of TLR2 and TLR4 Ligands with the N-terminal Domain of Gp96 Amplifies Innate and Adaptive Immune Responses J. Biol. Chem., August 11, 2006; 281(32): 22545 - 22553. [Abstract] [Full Text] [PDF]
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K. Miyake Invited review: Roles for accessory molecules in microbial recognition by Toll-like receptors Innate Immunity, August 1, 2006; 12(4): 195 - 204. [Abstract] [PDF]
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 M. T. Borchers, N. L. Harris, S. C. Wesselkamper, M. Vitucci, and D. Cosman NKG2D ligands are expressed on stressed human airway epithelial cells Am J Physiol Lung Cell Mol Physiol, August 1, 2006; 291(2): L222 - L231. [Abstract] [Full Text] [PDF]
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O. Equils, D. Lu, M. Gatter, S. S. Witkin, C. Bertolotto, M. Arditi, J. A. McGregor, C. F. Simmons, and C. J. Hobel Chlamydia Heat Shock Protein 60 Induces Trophoblast Apoptosis through TLR4 J. Immunol., July 15, 2006; 177(2): 1257 - 1263. [Abstract] [Full Text] [PDF]
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A. Shimamoto, A. J. Chong, M. Yada, S. Shomura, H. Takayama, A. J. Fleisig, M. L. Agnew, C. R. Hampton, C. L. Rothnie, D. J. Spring, et al. Inhibition of Toll-like Receptor 4 With Eritoran Attenuates Myocardial Ischemia-Reperfusion Injury Circulation, July 4, 2006; 114(1_suppl): I-270 - I-274. [Abstract] [Full Text] [PDF]
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B. Henderson, E. Allan, and A. R. M. Coates Stress Wars: the Direct Role of Host and Bacterial Molecular Chaperones in Bacterial Infection Infect. Immun., July 1, 2006; 74(7): 3693 - 3706. [Full Text] [PDF]
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 S. F. Hussain, D. Yang, D. Suki, K. Aldape, E. Grimm, and A. B. Heimberger The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses Neuro-oncol, July 1, 2006; 8(3): 261 - 279. [Abstract] [Full Text] [PDF]
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P. Rallabhandi, J. Bell, M. S. Boukhvalova, A. Medvedev, E. Lorenz, M. Arditi, V. G. Hemming, J. C. G. Blanco, D. M. Segal, and S. N. Vogel Analysis of TLR4 Polymorphic Variants: New Insights into TLR4/MD-2/CD14 Stoichiometry, Structure, and Signaling J. Immunol., July 1, 2006; 177(1): 322 - 332. [Abstract] [Full Text] [PDF]
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M. K. Mohammad, M. Morran, B. Slotterbeck, D. W. Leaman, Y. Sun, H. v. Grafenstein, S.-C. Hong, and M. F. McInerney Dysregulated Toll-like receptor expression and signaling in bone marrow-derived macrophages at the onset of diabetes in the non-obese diabetic mouse Int. Immunol., July 1, 2006; 18(7): 1101 - 1113. [Abstract] [Full Text] [PDF]
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P. G. Tipping Toll-Like Receptors: The Interface between Innate and Adaptive Immunity J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1769 - 1771. [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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M. F. Roelofs, W. C. Boelens, L. A. B. Joosten, S. Abdollahi-Roodsaz, J. Geurts, L. U. Wunderink, B. W. Schreurs, W. B. van den Berg, and T. R. D. J. Radstake Identification of Small Heat Shock Protein B8 (HSP22) as a Novel TLR4 Ligand and Potential Involvement in the Pathogenesis of Rheumatoid Arthritis. J. Immunol., June 1, 2006; 176(11): 7021 - 7027. [Abstract] [Full Text] [PDF]
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Y. Zhai, L. Meng, F. Gao, Y. Wang, R. W. Busuttil, and J. W. Kupiec-Weglinski CD4+ T Regulatory Cell Induction and Function in Transplant Recipients after CD154 Blockade Is TLR4 Independent J. Immunol., May 15, 2006; 176(10): 5988 - 5994. [Abstract] [Full Text] [PDF]
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O. A. Harari, P. Alcaide, D. Ahl, F. W. Luscinskas, and J. K. Liao Absence of TRAM Restricts Toll-Like Receptor 4 Signaling in Vascular Endothelial Cells to the MyD88 Pathway Circ. Res., May 12, 2006; 98(9): 1134 - 1140. [Abstract] [Full Text] [PDF]
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 I. Jou, J. H. Lee, S. Y. Park, H. J. Yoon, E.-H. Joe, and E. J. Park Gangliosides Trigger Inflammatory Responses via TLR4 in Brain Glia Am. J. Pathol., May 1, 2006; 168(5): 1619 - 1630. [Abstract] [Full Text] [PDF]
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S.-i. Yokota, S. Minota, and N. Fujii Anti-HSP auto-antibodies enhance HSP-induced pro-inflammatory cytokine production in human monocytic cells via Toll-like receptors Int. Immunol., April 1, 2006; 18(4): 573 - 580. [Abstract] [Full Text] [PDF]
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L. Szalay, T. Shimizu, T. Suzuki, H.-P. Yu, M. A. Choudhry, M. G. Schwacha, L. W. Rue III, K. I. Bland, and I. H. Chaudry Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R812 - R818. [Abstract] [Full Text] [PDF]
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C. M. O'Connell, I. A. Ionova, A. J. Quayle, A. Visintin, and R. R. Ingalls Localization of TLR2 and MyD88 to Chlamydia trachomatis Inclusions: EVIDENCE FOR SIGNALING BY INTRACELLULAR TLR2 DURING INFECTION WITH AN OBLIGATE INTRACELLULAR PATHOGEN J. Biol. Chem., January 20, 2006; 281(3): 1652 - 1659. [Abstract] [Full Text] [PDF]
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E. F. Cohn, C. Nathan, D. Radzioch, H. Yu, Z. Xiang, and A. Ding Abrupt Expression of TLR4 in TLR4-Deficient Macrophages Imposes a Selective Disadvantage: Genetic Evidence for TLR4-Dependent Responses to Endogenous, Nonmicrobial Stimuli J. Immunol., January 15, 2006; 176(2): 1185 - 1194. [Abstract] [Full Text] [PDF]
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Y. Chen and R. W. Currie Small interfering RNA knocks down heat shock factor-1 (HSF-1) and exacerbates pro-inflammatory activation of NF-{kappa}B and AP-1 in vascular smooth muscle cells Cardiovasc Res, January 1, 2006; 69(1): 66 - 75. [Abstract] [Full Text] [PDF]
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Y. Ma, V. Temkin, H. Liu, and R. M. Pope NF-{kappa}B Protects Macrophages from Lipopolysaccharide-induced Cell Death: THE ROLE OF CASPASE 8 AND RECEPTOR-INTERACTING PROTEIN J. Biol. Chem., December 23, 2005; 280(51): 41827 - 41834. [Abstract] [Full Text] [PDF]
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T. Ha, Y. Li, F. Hua, J. Ma, X. Gao, J. Kelley, A. Zhao, G. E. Haddad, D. L. Williams, I. William Browder, et al. Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload Cardiovasc Res, November 1, 2005; 68(2): 224 - 234. [Abstract] [Full Text] [PDF]
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 S. Makino, G. G. Whitehead, C.-L. Lien, S. Kim, P. Jhawar, A. Kono, Y. Kawata, and M. T. Keating Heat-shock protein 60 is required for blastema formation and maintenance during regeneration PNAS, October 11, 2005; 102(41): 14599 - 14604. [Abstract] [Full Text] [PDF]
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C. A. Petersen, K. A. Krumholz, and B. A. Burleigh Toll-Like Receptor 2 Regulates Interleukin-1{beta}-Dependent Cardiomyocyte Hypertrophy Triggered by Trypanosoma cruzi Infect. Immun., October 1, 2005; 73(10): 6974 - 6980. [Abstract] [Full Text] [PDF]
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M. Cohen-Sfady, G. Nussbaum, M. Pevsner-Fischer, F. Mor, P. Carmi, A. Zanin-Zhorov, O. Lider, and I. R. Cohen Heat Shock Protein 60 Activates B Cells via the TLR4-MyD88 Pathway J. Immunol., September 15, 2005; 175(6): 3594 - 3602. [Abstract] [Full Text] [PDF]
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 M. J. Smyth, J. Swann, E. Cretney, N. Zerafa, W. M. Yokoyama, and Y. Hayakawa NKG2D function protects the host from tumor initiation J. Exp. Med., September 6, 2005; 202(5): 583 - 588. [Abstract] [Full Text] [PDF]
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I. Olsen, P. Boysen, S. Kulberg, J. C. Hope, G. Jungersen, and A. K. Storset Bovine NK Cells Can Produce Gamma Interferon in Response to the Secreted Mycobacterial Proteins ESAT-6 and MPP14 but Not in Response to MPB70 Infect. Immun., September 1, 2005; 73(9): 5628 - 5635. [Abstract] [Full Text] [PDF]
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A. M. McCord, A. W. O. Burgess, M. J. Whaley, and B. E. Anderson Interaction of Bartonella henselae with Endothelial Cells Promotes Monocyte/Macrophage Chemoattractant Protein 1 Gene Expression and Protein Production and Triggers Monocyte Migration Infect. Immun., September 1, 2005; 73(9): 5735 - 5742. [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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H. S. Youn, J. Y. Lee, K. A. Fitzgerald, H. A. Young, S. Akira, and D. H. Hwang Specific Inhibition of MyD88-Independent Signaling Pathways of TLR3 and TLR4 by Resveratrol: Molecular Targets Are TBK1 and RIP1 in TRIF Complex J. Immunol., September 1, 2005; 175(5): 3339 - 3346. [Abstract] [Full Text] [PDF]
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X. Yang, D. Coriolan, V. Murthy, K. Schultz, D. T. Golenbock, and D. Beasley Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signaling Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1069 - H1076. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
), and C3H/HeJ
mice (
) were incubated with medium, LPS (10 ng/ml), hsp60 (10
µg/ml), Pal+ (30 µg/ml), ODN1668 (30 µg/ml), or
ODN1720 (30 µg/ml). After 6 h, the TNF-
) and
C3H/HeJ mice (•) were incubated for 6 h with increasing
concentrations of hsp60 (A) or they were incubated for
different time intervals at a dose of 10 µg/ml hsp60
(B). The TNF-
