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CUTTING EDGE |

*
Department of Immunology, Saga Medical School, Nabeshima, Japan; and
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| Abstract |
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B activation, which was clearly inhibited by MTS510.
Thioglycolate-elicited peritoneal macrophages expressed TLR4-MD-2,
which was rapidly down-regulated in the presence of LPS. Moreover,
LPS-induced TNF-
production by peritoneal macrophages was inhibited
by MTS510. Collectively, the TLR4-MD-2 complex is expressed on
macrophages in vivo and senses and signals the presence of
LPS. | Introduction |
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,
IL-1, and IL-6. The defense programs are then activated, and invading
bacteria are eliminated. Excessive amount of the cytokines, however,
may result in fatal endotoxin shock. LPS signaling must be kept under
the control during immune responses. It is therefore of particular
importance to understand the molecular mechanisms underlying LPS
recognition and signaling for the control of immune responses and
endotoxin shock. LPS-binding protein is the plasma protein that first interacts with and recruits LPS from bacterial membrane to another protein CD14 (2, 3). CD14, which is present in plasma as well as on the monocyte cell surface binds to LPS and facilitates LPS signaling (4, 5). CD14 is a glycosylphosphatidylinositol-anchored protein and does not have a cytoplasmic signaling domain. Another molecule therefore must transmit the LPS signal across the plasma membrane (3, 5).
Toll-like receptors (TLRs)3 are mammalian homologues of the Drosophila Toll receptor and are thought to have a role in innate recognition of bacteria or fungi (6, 7, 8, 9). TLR4 is now identified as a signaling receptor for LPS. The TLR4 gene is mutated in the LPS low responder mouse strains C3H/HeJ and C57BL/10ScCr (10, 11, 12). Human TLR4 alone, however, is not capable of sensing the presence of LPS (13, 14). Another molecule, MD-2, which is physically associated with TLR4, is required for LPS recognition (14). The TLR4-MD-2 complex thus serves as the LPS signaling receptor. These conclusions are drawn from the results using stable transfectants expressing human TLR4 and/or MD-2. It is not clear as to mouse TLR4-MD-2 complex, or about in vivo expression and LPS signaling of the TLR4-MD-2 complex. The present study deals with these issues.
| Materials and Methods |
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A partial sequence of mouse MD-2 cDNA was obtained through the EST database at the National Center for Biological Information (accession number AA109204). Because the sequence did not contain the 3'-end of the coding region, 3'-RACE system (Life Technologies, Rockville, MD) was conducted to obtain the full length cDNA from BALB/c mouse kidneys with a forward primer: TCCGATGGTCTTCCTGGCGAG. The full length cDNA encoding mouse TLR4 was obtained from a BALB/c spleen cDNA library with the human TLR4 probe (accession number H48602) that was obtained from Genome Systems (St. Louis, MO).
Expression constructs and stable transfectants
The cDNAs were cloned into an expression vector, pEFBOS (15). The DNA fragment encoding the flag epitope followed by the His tag epitope had been introduced into the pEFBOS vector such that all expressed proteins bear the flag epitope at the C termini.
The plasmids were transfected into Ba/F3 cells (16) by
electroporation. An NF-
B reporter construct, p55Ig
Luc
(17), was also introduced. Expression of TLR4 or MD-2 was
confirmed by flow cytometry staining with cell permeabilization and
immunoprecipitation and probing with the anti-flag mAb (Fig. 2
, B and C, and data not shown).
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The following reagents were purchased from Sigma (St. Louis, MO): a mAb against the flag epitope M2; LPS from Escherichia coli (0111:B4 or 055:B5); LPS or lipid A from Salmonella minnesota (Re595). Ba/F3 cells were fed in 10% FCS-RPMI 1640 supplemented with IL-3 and 50 µM 2-ME. Mice and rats were obtained from Japan SLC (Shizuoka, Japan). Thioglycolate-elicited peritoneal macrophages were obtained from mice that had been injected 4 days before with 2 ml 4% thioglycolate i.p. (Difco, Detroit, MI).
Establishment of a mAb to mouse TLR4
A rat was immunized with Ba/F3 cells expressing mouse TLR4 and MD-2 and used for hybridoma production. The MTS510 mAb (rat IgG2a/k) that specifically reacted with the immunized transfectant but not with the original Ba/F3 line was selected for further analyses. The mAb was purified from ascites obtained from SCID mice.
Immunoprecipitation and immunoprobing
Cells were washed and lysed in lysis buffer consisting of 50 mM
Tris-HCl (pH 7.5), 150 mM NaCl, 1% Triton X-100, 50 mM iodoacetamide,
1 mM PMSF, 10 µg/ml soybean trypsin inhibitor, 2 mM
MgCl2, and 2 mM CaCl2.
After 30 min of incubation on ice, lysate was centrifuged and nuclei
were removed. The N-hydroxysuccinimide-activated Sepharose
4FF beads (Amersham Pharmacia Biotech, Piscataway, NJ) coupled with
MTS510 (4 mg/ml) were added to cell lysate and rotated for 4
h at 4°C. Beads were washed in the lysis buffer and bound proteins
were subjected to SDS-PAGE (9% acrylamide under nonreduced conditions)
and Western blotting. TLR4 and MD-2 were detected with the
anti-flag mAb M2 (Sigma) and Supersignal chemiluminescent substrate
(Pierce, Rockford, IL). To detect LPS-induced
phosphorylation of I
B-
, the
PhosphoPlus I
B-
Ab Kit (NEB, Beverly, MA) was
used.
Luciferase assay
Stable transfectants derived from Ba/F3 were inoculated onto 96-well plates at 5 x 104/well. After 4 h stimulation, cells were harvested, washed, and lysed in 100 µl lysis buffer, and luciferase activity was measured using 10 µl lysate and 50 µl luciferase substrate (Nippon Gene, Toyama, Japan). The luminescence was quantitated as a relative light unit on a luminometer (Berthold Japan, Tokyo, Japan).
Cell surface staining
Cells were stained with an FITC-conjugated mAb to Mac-1 (M1/70) or to CD19 (1D3) and biotinylated MTS510 followed by streptavidin-PE (PharMingen, San Diego, CA). Cells were analyzed on a FACScan (Becton Dickinson, Mountain View, CA).
ELISA
TNF-
production from peritoneal macrophages was measured by
ELISA according to the manufacturers instruction (Genzyme,
Cambridge, MA).
| Results |
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The whole sequence of mouse MD-2 was determined and shown in Fig. 1
. The longest coding region encodes 160
aa. Mouse MD-2 has 64% (103 aa) identity to human MD-2 in amino acid
sequence. The identity (64%) is similar to that between human and
mouse MD-1 (66%). Stable transfectants were next derived from Ba/F3
cells by transfecting expression vectors encoding mouse MD-2 or mouse
TLR4. Expression of TLR4 and/or MD-2 was confirmed by cytoplasmic or
cell surface staining or by immunoprecipitation and subsequent probing
of the flag epitope (Fig. 2
).
|
We then used the MTS510 mAb to see whether the physical association of TLR4 and MD-2, which had been previously shown in human (14), is conserved in mice. TLR4 was immunoprecipitated from Ba/F3 cells expressing TLR4 and MD-2 with the MTS510 mAb. TLR4 and MD-2 were probed with the anti-flag mAb. The MTS510 mAb was able to precipitate, in addition to TLR4, additional signals around 30 kDa (lane 4). These 30-kDa signals were similar in size to MD-2 that was precipitated with an anti-flag mAb from Ba/F3 cells expressing MD-2 alone or TLR4-MD-2 (lanes 6 and 8). Similar signals around 30 kDa were not detected with the MTS510 immunoprecipitation from Ba/F3 cells expressing TLR4 alone (lane 3) or from Ba/F3 cells expressing TLR4 with the flag epitope and MD-2 with another epitope tag (data not shown), as was shown in the previous human study (14). Mouse MD-2 was thus coprecipitated with mouse TLR4.
We noticed that an even larger amount of TLR4 was precipitated with
MTS510 from Ba/F3 cells expressing TLR4 and MD-2 than from those
expressing TLR4 alone (lanes 3 and 4).
Expression of TLR4 protein in these Ba/F3 lines was shown by
immunoprecipitation and probing with the anti-flag mAb
(lanes 7 and 8). The Ba/F3 line expressing
TLR4 alone was comparable with that expressing TLR4 and MD-2 with
respect to TLR4 protein expression. MTS510 mAb seemed to react
better with TLR4-MD-2 than with TLR4 alone. Flow cytometry analyses
further revealed poor reactivity of the MTS510 mAb with TLR4 alone. In
cell surface staining, MTS510 easily detected TLR4 on Ba/F3 cells
expressing TLR4 and MD-2, but not on those expressing TLR4 alone (Fig. 2
A, a and b). We also conducted
cell-permeabilized staining of Ba/F3 cells expressing TLR4 alone, to
detect intracellular TLR4 that might account for the majority of TLR4
protein expressed. MTS510 did not show significant binding to TLR4
alone (Fig. 2
Ad), abundant expression of which was seen with
the anti-flag mAb (Fig. 2
Ac). Taken together with the
immunoprecipitation results, the MTS510 mAb preferentially reacts,
especially in flow cytometry, with TLR4 that is associated with
MD-2.
LPS signaling via mouse TLR4 is augmented by MD-2
A role for MD-2 in the LPS signaling via TLR4 was addressed. The
Ba/F3 transfectants were stimulated with LPS. NF-
B activation was
examined by measuring luciferase activity from a reporter construct
that had been transfected (Fig. 3
A) or by immunoprobing with
the Ab specific for phosphorylated I
B-
(Fig. 3
B). The transfectant expressing mouse MD-2 alone did not
respond to LPS even at 10 µg/ml, whereas the TLR4-expresing
transfectant showed a significant response to LPS as judged by
phosphorylation of I
B-
as well as by luciferase
activity (Fig. 3
, A and B). In the luciferase
assay, the TLR4-MD-2-expressing transfectant showed one or two orders
of magnitude higher sensitivity and 2- to 3-fold stronger LPS
response than the cells expressing TLR4 alone to all LPS and lipid A
(Fig. 3
A). Moreover, LPS-induced NF-
B activation was
specifically inhibited by the MTS510 mAb (Fig. 3
C). The
enhancing effect by MD-2 coexpression was also demonstrated by
increased phosphorylation of I
B-
(Fig. 3
B). MD-2 thus enhances LPS signaling via TLR4 in an in
vitro cell line.
|
The mAb MTS510 allowed us to examine expression of the TLR4-MD-2
complex on cells in vivo as well as in vitro. Among in vitro cell
lines, TLR4-MD-2 was detected on B cell lymphomas such as
BCL1 and a macrophage line J774, but not on T
cell lines or fibroblast lines (data not shown). Cell surface TLR4-MD-2
was hardly detectable on CD19-positive B cells in spleen, bone marrow
cells, or thymocytes (Fig. 4
A
and data not shown). Intracellular staining by the saponin detergent
did not make any difference (data not shown). Apparent expression was
observed on thioglycolate-elicited peritoneal macrophages (Fig. 4
Ab). The expression was not observed on peritoneal
macrophages from mice lacking TLR4, confirming the specificity of
MTS510 (18). Interestingly, TLR4-MD-2 was rapidly
down-regulated by 2 h stimulation with LPS (Fig. 4
Ac).
Interestingly, the down-regulation of TLR4-MD-2 was similarly observed
in C3H/HeJ mice, which harbor the mutated TLR4 gene
(18).
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production from peritoneal macrophages,
and the mAb was included during LPS stimulation. MTS510 alone was not
agonistic. As was seen with the stable transfectant, MTS510 acted
antagonistically to LPS on peritoneal macrophages (Fig. 4| Discussion |
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As was shown with human MD-2, mouse MD-2 enhanced LPS signaling via
TLR4. Two, not mutually exclusive mechanisms would account for the
enhancing effect of MD-2. First, the TLR4-MD-2 complex is more
sensitive than TLR4 alone with regard to LPS responses. Ba/F3 cells
expressing human TLR4 alone, despite apparent expression on the cell
surface, does not signal LPS, whereas TLR4-MD-2 does (14).
Similarly, association of mouse MD-2 may augment the ability of mouse
TLR4 to signal LPS. The MTS510 mAb suggested that a conformational
change occurs to TLR4 with MD-2 association. Such a conformation may
correlate with higher sensitivity and stronger response to LPS. The
second possibility is that augmentation of LPS signaling by MD-2 may be
attributed to increased expression of cell surface TLR4. This
possibility is based on the fact that mouse TLR4 alone, in contrast to
the human counterpart, is able to signal LPS (Fig. 3
). Unfortunately,
the MTS510 mAb failed to detect TLR4 alone in flow cytometry (Fig. 2
, A and B). Although human MD-2 does not change
cell surface expression of human TLR4 (14), we do not know
whether mouse MD-2 influences cell surface expression of TLR4. In
either mechanism, the present study clearly demonstrated that mouse
MD-2, as the human counterpart does, enhances the LPS signaling
via TLR4.
The MTS510 mAb allowed us to see TLR4-MD-2 expression in vivo with flow
cytometry staining. TLR4-MD-2 was demonstrated on peritoneal
macrophages and, interestingly, rapidly down-regulated in the presence
of LPS. Moreover, LPS-induced TNF-
production was pronouncedly
inhibited by MTS510. TLR4-MD-2 is thus expressed in vivo on peritoneal
macrophages and signals LPS.
Down-regulation of TLR4-MD-2 can be attributed to disrupted association of TLR4 and MD-2, shedding from the cell surface, or internalization. In this regard, recent studies showed that LPS is rapidly internalized and transported to the Golgi apparatus (19, 20). Rapid down-regulation of TLR4-MD-2 therefore may be due to colocalization and cointernalization with LPS. Interestingly, C3H/HeJ mice, which are defective in LPS internalization (21), did not reveal a defect in down-regulation of TLR4-MD-2 (18). We must directly compare the distribution of TLR4-MD-2 and LPS in peritoneal macrophages.
B cells in spleen hardly expressed TLR4-MD-2 (Fig. 4
A). This
does not necessarily deny expression of TLR4 on B cells. Considering
that C3H/HeJ B cells show hyporesponsiveness to LPS, TLR4 must be
expressed and signal LPS in B cells. In keeping with this, one of our
mAbs to human TLR4 demonstrated expression of TLR4 on a subpopulation
of B cells in peripheral blood or a tonsil (our unpublished
observation). Preliminary studies with Northern hybridization revealed
that most B cell lymphomas as well as spleen cells express mRNA
transcripts encoding mouse MD-2 as well as TLR4 (Ref. 14
and data not shown). It must be determined whether B cells express
the MD-2 protein. The B cell sensitivity to LPS is about two orders of
magnitude lower than that of macrophages. It would be interesting to
learn whether low LPS responsiveness in B cells is due to low
expression of the MD-2 protein or to a lack of association with TLR4.
We are currently examining this issue with newly established mAbs to
mouse MD-2.
| Footnotes |
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2 Address correspondence and reprint requests to Dr. Kensuke Miyake, Department of Immunology, Saga Medical School, Nabeshima, Saga 849-8501, Japan. E-mail address: ![]()
3 Abbreviation used in this paper: TLR, Toll-like receptor. ![]()
Received for publication November 18, 1999. Accepted for publication February 2, 2000.
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D. Huugen, H. Xiao, A. van Esch, R. J. Falk, C. J. Peutz-Kootstra, W. A. Buurman, J. W. C. Tervaert, J. C. Jennette, and P. Heeringa Aggravation of Anti-Myeloperoxidase Antibody-Induced Glomerulonephritis by Bacterial Lipopolysaccharide: Role of Tumor Necrosis Factor-{alpha} Am. J. Pathol., July 1, 2005; 167(1): 47 - 58. [Abstract] [Full Text] [PDF] |
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R. L. Chelvarajan, S. M. Collins, J. M. Van Willigen, and S. Bondada The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function J. Leukoc. Biol., April 1, 2005; 77(4): 503 - 512. [Abstract] [Full Text] [PDF] |
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S. Jeyaseelan, H. W. Chu, S. K. Young, M. W. Freeman, and G. S. Worthen Distinct Roles of Pattern Recognition Receptors CD14 and Toll-Like Receptor 4 in Acute Lung Injury Infect. Immun., March 1, 2005; 73(3): 1754 - 1763. [Abstract] [Full Text] [PDF] |
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P. Tobias and L. K. Curtiss Thematic review series: The Immune System and Atherogenesis. Paying the price for pathogen protection: toll receptors in atherogenesis J. Lipid Res., March 1, 2005; 46(3): 404 - 411. [Abstract] [Full Text] [PDF] |
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D. Preciado, E. Caicedo, R. Jhanjee, R. Silver, G. Harris, S. K. Juhn, D. I. Choo, and F. Ondrey Pseudomonas aeruginosa Lipopolysaccharide Induction of Keratinocyte Proliferation, NF-{kappa}B, and Cyclin D1 Is Inhibited by Indomethacin J. Immunol., March 1, 2005; 174(5): 2964 - 2973. [Abstract] [Full Text] [PDF] |
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A. De Creus, M. Abe, A. H. Lau, H. Hackstein, G. Raimondi, and A. W. Thomson Low TLR4 Expression by Liver Dendritic Cells Correlates with Reduced Capacity to Activate Allogeneic T Cells in Response to Endotoxin J. Immunol., February 15, 2005; 174(4): 2037 - 2045. [Abstract] [Full Text] [PDF] |
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M. Triantafilou and K. Triantafilou Invited review: The dynamics of LPS recognition: complex orchestration of multiple receptors Innate Immunity, February 1, 2005; 11(1): 5 - 11. [Abstract] [PDF] |
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G. C. O'Brien, J. H. Wang, and H. P. Redmond Bacterial Lipoprotein Induces Resistance to Gram-Negative Sepsis in TLR4-Deficient Mice via Enhanced Bacterial Clearance J. Immunol., January 15, 2005; 174(2): 1020 - 1026. [Abstract] [Full Text] [PDF] |
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K. Takeda and S. Akira Toll-like receptors in innate immunity Int. Immunol., January 1, 2005; 17(1): 1 - 14. [Abstract] [Full Text] [PDF] |
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J. Pugin, S. Stern-Voeffray, B. Daubeuf, M. A. Matthay, G. Elson, and I. Dunn-Siegrist Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock Blood, December 15, 2004; 104(13): 4071 - 4079. [Abstract] [Full Text] [PDF] |
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N. Nilsen, U. Nonstad, N. Khan, C. F. Knetter, S. Akira, A. Sundan, T. Espevik, and E. Lien Lipopolysaccharide and Double-stranded RNA Up-regulate Toll-like Receptor 2 Independently of Myeloid Differentiation Factor 88 J. Biol. Chem., September 17, 2004; 279(38): 39727 - 39735. [Abstract] [Full Text] [PDF] |
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F.H. Nociti Jr., B.L. Foster, S.P. Barros, R.P. Darveau, and M.J. Somerman Cementoblast Gene Expression is Regulated by Porphyromonas gingivalis Lipopolysaccharide Partially via Toll-like Receptor-4/MD-2 Journal of Dental Research, August 1, 2004; 83(8): 602 - 607. [Abstract] [Full Text] [PDF] |
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A. Punturieri, R. S. Alviani, T. Polak, P. Copper, J. Sonstein, and J. L. Curtis Specific Engagement of TLR4 or TLR3 Does Not Lead to IFN-{beta}-Mediated Innate Signal Amplification and STAT1 Phosphorylation in Resident Murine Alveolar Macrophages J. Immunol., July 15, 2004; 173(2): 1033 - 1042. [Abstract] [Full Text] [PDF] |
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S. Ishihara, M. A. K. Rumi, Y. Kadowaki, C. F. Ortega-Cava, T. Yuki, N. Yoshino, Y. Miyaoka, H. Kazumori, N. Ishimura, Y. Amano, et al. Essential Role of MD-2 in TLR4-Dependent Signaling during Helicobacter pylori-Associated Gastritis J. Immunol., July 15, 2004; 173(2): 1406 - 1416. [Abstract] [Full Text] [PDF] |
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H. Matsushima, N. Yamada, H. Matsue, and S. Shimada TLR3-, TLR7-, and TLR9-Mediated Production of Proinflammatory Cytokines and Chemokines from Murine Connective Tissue Type Skin-Derived Mast Cells but Not from Bone Marrow-Derived Mast Cells J. Immunol., July 1, 2004; 173(1): 531 - 541. [Abstract] [Full Text] [PDF] |
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S.-i. Saitoh, S. Akashi, T. Yamada, N. Tanimura, M. Kobayashi, K. Konno, F. Matsumoto, K. Fukase, S. Kusumoto, Y. Nagai, et al. Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization Int. Immunol., July 1, 2004; 16(7): 961 - 969. [Abstract] [Full Text] [PDF] |
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R. L. Chelvarajan, S. M. Collins, I. E. Doubinskaia, S. Goes, J. Van Willigen, D. Flanagan, W. J. S. de Villiers, J. S. Bryson, and S. Bondada Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens J. Leukoc. Biol., June 1, 2004; 75(6): 982 - 994. [Abstract] [Full Text] [PDF] |
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M. Okamoto, G. Oh-e, T. Oshikawa, S. Furuichi, T. Tano, S. U. Ahmed, S. Akashi, K. Miyake, O. Takeuchi, S. Akira, et al. Toll-Like Receptor 4 Mediates the Antitumor Host Response Induced by a 55-Kilodalton Protein Isolated from Aeginetia indica L., a Parasitic Plant Clin. Vaccine Immunol., May 1, 2004; 11(3): 483 - 495. [Abstract] [Full Text] [PDF] |
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S. Kato, Y. Yuzawa, N. Tsuboi, S. Maruyama, Y. Morita, T. Matsuguchi, and S. Matsuo Endotoxin-Induced Chemokine Expression in Murine Peritoneal Mesothelial Cells: The Role of Toll-Like Receptor 4 J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1289 - 1299. [Abstract] [Full Text] [PDF] |
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K. A. Ryan, M. F. Smith Jr., M. K. Sanders, and P. B. Ernst Reactive Oxygen and Nitrogen Species Differentially Regulate Toll-Like Receptor 4-Mediated Activation of NF-{kappa}B and Interleukin-8 Expression Infect. Immun., April 1, 2004; 72(4): 2123 - 2130. [Abstract] [Full Text] [PDF] |
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D. S. Weiss, B. Raupach, K. Takeda, S. Akira, and A. Zychlinsky Toll-Like Receptors Are Temporally Involved in Host Defense J. Immunol., April 1, 2004; 172(7): 4463 - 4469. [Abstract] [Full Text] [PDF] |
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T. L. Gioannini, A. Teghanemt, D. Zhang, N. P. Coussens, W. Dockstader, S. Ramaswamy, and J. P. Weiss Isolation of an endotoxin-MD-2 complex that produces Toll-like receptor 4-dependent cell activation at picomolar concentrations PNAS, March 23, 2004; 101(12): 4186 - 4191. [Abstract] [Full Text] [PDF] |
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E. Andreakos, S. M. Sacre, C. Smith, A. Lundberg, S. Kiriakidis, T. Stonehouse, C. Monaco, M. Feldmann, and B. M. Foxwell Distinct pathways of LPS-induced NF-{kappa}B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP Blood, March 15, 2004; 103(6): 2229 - 2237. [Abstract] [Full Text] [PDF] |
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A. Shiratsuchi, I. Watanabe, O. Takeuchi, S. Akira, and Y. Nakanishi Inhibitory Effect of Toll-Like Receptor 4 on Fusion between Phagosomes and Endosomes/Lysosomes in Macrophages J. Immunol., February 15, 2004; 172(4): 2039 - 2047. [Abstract] [Full Text] [PDF] |
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S. H. Kim, V. J. Johnson, T.-Y. Shin, and R. P. Sharma Selenium Attenuates Lipopolysaccharide-Induced Oxidative Stress Responses Through Modulation of p38 MAPK and NF-{kappa}B Signaling Pathways Experimental Biology and Medicine, February 1, 2004; 229(2): 203 - 213. [Abstract] [Full Text] [PDF] |
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R. K. Ernst, A. M. Hajjar, J. H. Tsai, S. M. Moskowitz, C. B. Wilson, and S. I. Miller Pseudomonas aeruginosa lipid A diversity and its recognition by Toll-like receptor 4 Innate Immunity, December 1, 2003; 9(6): 395 - 400. [Abstract] [PDF] |
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F. Re and J. L. Strominger Separate Functional Domains of Human MD-2 Mediate Toll-Like Receptor 4-Binding and Lipopolysaccharide Responsiveness J. Immunol., November 15, 2003; 171(10): 5272 - 5276. [Abstract] [Full Text] [PDF] |
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M. Hashimoto, Y. Asai, and T. Ogawa Treponemal Phospholipids Inhibit Innate Immune Responses Induced by Pathogen-associated Molecular Patterns J. Biol. Chem., November 7, 2003; 278(45): 44205 - 44213. [Abstract] [Full Text] [PDF] |
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M. W. Hornef, B. H. Normark, A. Vandewalle, and S. Normark Intracellular Recognition of Lipopolysaccharide by Toll-like Receptor 4 in Intestinal Epithelial Cells J. Exp. Med., October 20, 2003; 198(8): 1225 - 1235. [Abstract] [Full Text] [PDF] |
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S. Akashi, S.-i. Saitoh, Y. Wakabayashi, T. Kikuchi, N. Takamura, Y. Nagai, Y. Kusumoto, K. Fukase, S. Kusumoto, Y. Adachi, et al. Lipopolysaccharide Interaction with Cell Surface Toll-like Receptor 4-MD-2: Higher Affinity than That with MD-2 or CD14 J. Exp. Med., October 6, 2003; 198(7): 1035 - 1042. [Abstract] [Full Text] [PDF] |
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K. Kawasaki, K. Gomi, Y. Kawai, M. Shiozaki, and M. Nishijima Molecular basis for lipopolysaccharide mimetic action of TaxolTM and flavolipin Innate Immunity, October 1, 2003; 9(5): 301 - 307. [Abstract] [PDF] |
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S. C. Higgins, E. C. Lavelle, C. McCann, B. Keogh, E. McNeela, P. Byrne, B. O'Gorman, A. Jarnicki, P. McGuirk, and K. H. G. Mills Toll-Like Receptor 4-Mediated Innate IL-10 Activates Antigen-Specific Regulatory T Cells and Confers Resistance to Bordetella pertussis by Inhibiting Inflammatory Pathology J. Immunol., September 15, 2003; 171(6): 3119 - 3127. [Abstract] [Full Text] [PDF] |
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H. M. Paterson, T. J. Murphy, E. J. Purcell, O. Shelley, S. J. Kriynovich, E. Lien, J. A. Mannick, and J. A. Lederer Injury Primes the Innate Immune System for Enhanced Toll-Like Receptor Reactivity J. Immunol., August 1, 2003; 171(3): 1473 - 1483. [Abstract] [Full Text] [PDF] |
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N. Qureshi, P.-Y. Perera, J. Shen, G. Zhang, A. Lenschat, G. Splitter, D. C. Morrison, and S. N. Vogel The Proteasome as a Lipopolysaccharide-Binding Protein in Macrophages: Differential Effects of Proteasome Inhibition on Lipopolysaccharide-Induced Signaling Events J. Immunol., August 1, 2003; 171(3): 1515 - 1525. [Abstract] [Full Text] [PDF] |
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S. Okugawa, Y. Ota, T. Kitazawa, K. Nakayama, S. Yanagimoto, K. Tsukada, M. Kawada, and S. Kimura Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages Am J Physiol Cell Physiol, August 1, 2003; 285(2): C399 - C408. [Abstract] [Full Text] [PDF] |
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C. E. O. Baleeiro, S. E. Wilcoxen, S. B. Morris, T. J. Standiford, and R. Paine III Sublethal Hyperoxia Impairs Pulmonary Innate Immunity J. Immunol., July 15, 2003; 171(2): 955 - 963. [Abstract] [Full Text] [PDF] |
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D. Dory, H. Echchannaoui, M. Letiembre, F. Ferracin, J. Pieters, Y. Adachi, S. Akashi, W. Zimmerli, and R. Landmann Generation and functional characterization of a clonal murine periportal Kupffer cell line from H-2Kb -tsA58 mice J. Leukoc. Biol., July 1, 2003; 74(1): 49 - 59. [Abstract] [Full Text] [PDF] |
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F. Bihl, L. Salez, M. Beaubier, D. Torres, L. Lariviere, L. Laroche, A. Benedetto, D. Martel, J.-M. Lapointe, B. Ryffel, et al. Overexpression of Toll-Like Receptor 4 Amplifies the Host Response to Lipopolysaccharide and Provides a Survival Advantage in Transgenic Mice J. Immunol., June 15, 2003; 170(12): 6141 - 6150. [Abstract] [Full Text] [PDF] |
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R. Tamai, S. Sugawara, O. Takeuchi, S. Akira, and H. Takada Synergistic effects of lipopolysaccharide and interferon-{gamma} in inducing interleukin-8 production in human monocytic THP-1 cells is accompanied by up-regulation of CD14, Toll-like receptor 4, MD-2 and MyD88 expression Innate Immunity, June 1, 2003; 9(3): 145 - 153. [Abstract] [PDF] |
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T. Pedron, R. Girard, and R. Chaby TLR4-dependent Lipopolysaccharide-induced Shedding of Tumor Necrosis Factor Receptors in Mouse Bone Marrow Granulocytes J. Biol. Chem., May 30, 2003; 278(23): 20555 - 20564. [Abstract] [Full Text] [PDF] |
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T. Ohnishi, M. Muroi, and K.-i. Tanamoto MD-2 Is Necessary for the Toll-Like Receptor 4 Protein To Undergo Glycosylation Essential for Its Translocation to the Cell Surface Clin. Vaccine Immunol., May 1, 2003; 10(3): 405 - 410. [Abstract] [Full Text] [PDF] |
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C. F. Ortega-Cava, S. Ishihara, M. A. K. Rumi, K. Kawashima, N. Ishimura, H. Kazumori, J. Udagawa, Y. Kadowaki, and Y. Kinoshita Strategic Compartmentalization of Toll-Like Receptor 4 in the Mouse Gut J. Immunol., April 15, 2003; 170(8): 3977 - 3985. [Abstract] [Full Text] [PDF] |
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T. Roger, C. Froidevaux, C. Martin, and T. Calandra Macrophage migration inhibitory factor (MIF) regulates host responses to endotoxin through modulation of Toll-like receptor 4 (TLR4) Innate Immunity, April 1, 2003; 9(2): 119 - 123. [Abstract] [PDF] |
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M. Okamoto, T. Oshikawa, T. Tano, G. Ohe, S. Furuichi, H. Nishikawa, S. U. Ahmed, S. Akashi, K. Miyake, O. Takeuchi, et al. Involvement of Toll-Like Receptor 4 Signaling in Interferon-{gamma} Production and Antitumor Effect by Streptococcal Agent OK-432 J Natl Cancer Inst, February 19, 2003; 95(4): 316 - 326. [Abstract] [Full Text] [PDF] |
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I. Caramalho, T. Lopes-Carvalho, D. Ostler, S. Zelenay, M. Haury, and J. Demengeot Regulatory T Cells Selectively Express Toll-like Receptors and Are Activated by Lipopolysaccharide J. Exp. Med., February 17, 2003; 197(4): 403 - 411. [Abstract] [Full Text] [PDF] |
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L. A. Augusto, M. Synguelakis, J. Johansson, T. Pedron, R. Girard, and R. Chaby Interaction of Pulmonary Surfactant Protein C with CD14 and Lipopolysaccharide Infect. Immun., January 1, 2003; 71(1): 61 - 67. [Abstract] [Full Text] [PDF] |
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K. Kawasaki, H. Nogawa, and M. Nishijima Identification of Mouse MD-2 Residues Important for Forming the Cell Surface TLR4-MD-2 Complex Recognized by Anti-TLR4-MD-2 Antibodies, and for Conferring LPS and Taxol Responsiveness on Mouse TLR4 by Alanine-Scanning Mutagenesis J. Immunol., January 1, 2003; 170(1): 413 - 420. [Abstract] [Full Text] [PDF] |
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T. L. Gioannini, D. Zhang, A. Teghanemt, and J. P. Weiss An Essential Role for Albumin in the Interaction of Endotoxin with Lipopolysaccharide-binding Protein and sCD14 and Resultant Cell Activation J. Biol. Chem., November 27, 2002; 277(49): 47818 - 47825. [Abstract] [Full Text] [PDF] |
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K. Yamamoto, T. Shimokawa, H. Yi, K.-i. Isobe, T. Kojima, D. J. Loskutoff, and H. Saito Aging Accelerates Endotoxin-Induced Thrombosis : Increased Responses of Plasminogen Activator Inhibitor-1 and Lipopolysaccharide Signaling with Aging Am. J. Pathol., November 1, 2002; 161(5): 1805 - 1814. [Abstract] [Full Text] [PDF] |
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N. Tsuboi, Y. Yoshikai, S. Matsuo, T. Kikuchi, K.-I. Iwami, Y. Nagai, O. Takeuchi, S. Akira, and T. Matsuguchi Roles of Toll-Like Receptors in C-C Chemokine Production by Renal Tubular Epithelial Cells J. Immunol., August 15, 2002; 169(4): 2026 - 2033. [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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S. B. Mizel and J. A. Snipes Gram-negative Flagellin-induced Self-tolerance Is Associated with a Block in Interleukin-1 Receptor-associated Kinase Release from Toll-like Receptor 5 J. Biol. Chem., June 14, 2002; 277(25): 22414 - 22420. [Abstract] [Full Text] [PDF] |
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J. Fan, A. Kapus, P. A. Marsden, Y. H. Li, G. Oreopoulos, J. C. Marshall, S. Frantz, R. A. Kelly, R. Medzhitov, and O. D. Rotstein Regulation of Toll-Like Receptor 4 Expression in the Lung Following Hemorrhagic Shock and Lipopolysaccharide J. Immunol., May 15, 2002; 168(10): 5252 - 5259. [Abstract] [Full Text] [PDF] |
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S. Li, V. M. Holers, S. A. Boackle, and C. M. Blatteis Modulation of Mouse Endotoxic Fever by Complement Infect. Immun., May 1, 2002; 70(5): 2519 - 2525. [Abstract] [Full Text] [PDF] |
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N. Tuaillon, D. F. Shen, R. B. Berger, B. Lu, B. J. Rollins, and C.-C. Chan MCP-1 Expression in Endotoxin-Induced Uveitis Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1493 - 1498. [Abstract] [Full Text] [PDF] |
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K. Dabbagh, M. E. Dahl, P. Stepick-Biek, and D. B. Lewis Toll-Like Receptor 4 Is Required for Optimal Development of Th2 Immune Responses: Role of Dendritic Cells J. Immunol., May 1, 2002; 168(9): 4524 - 4530. [Abstract] [Full Text] [PDF] |
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K. Gomi, K. Kawasaki, Y. Kawai, M. Shiozaki, and M. Nishijima Toll-Like Receptor 4-MD-2 Complex Mediates the Signal Transduction Induced by Flavolipin, an Amino Acid-Containing Lipid Unique to Flavobacterium meningosepticum J. Immunol., March 15, 2002; 168(6): 2939 - 2943. [Abstract] [Full Text] [PDF] |
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J. J. Watters, J. A. Sommer, Z. A. Pfeiffer, U. Prabhu, A. N. Guerra, and P. J. Bertics A Differential Role for the Mitogen-activated Protein Kinases in Lipopolysaccharide Signaling. THE MEK/ERK PATHWAY IS NOT ESSENTIAL FOR NITRIC OXIDE AND INTERLEUKIN 1beta PRODUCTION J. Biol. Chem., March 8, 2002; 277(11): 9077 - 9087. [Abstract] [Full Text] [PDF] |
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T. Vasselon and P. A. Detmers Toll Receptors: a Central Element in Innate Immune Responses Infect. Immun., March 1, 2002; 70(3): 1033 - 1041. [Full Text] [PDF] |
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R. Tamai, T. Sakuta, K. Matsushita, M. Torii, O. Takeuchi, S. Akira, S. Akashi, T. Espevik, S. Sugawara, and H. Takada Human Gingival CD14+ Fibroblasts Primed with Gamma Interferon Increase Production of Interleukin-8 in Response to Lipopolysaccharide through Up-Regulation of Membrane CD14 and MyD88 mRNA Expression Infect. Immun., March 1, 2002; 70(3): 1272 - 1278. [Abstract] [Full Text] [PDF] |
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N. Iovine, J. Eastvold, P. Elsbach, J. P. Weiss, and T. L. Gioannini The Carboxyl-terminal Domain of Closely Related Endotoxin-binding Proteins Determines the Target of Protein-Lipopolysaccharide Complexes J. Biol. Chem., March 1, 2002; 277(10): 7970 - 7978. [Abstract] [Full Text] [PDF] |
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R. N. Fichorova, A. O. Cronin, E. Lien, D. J. Anderson, and R. R. Ingalls Response to Neisseria gonorrhoeae by Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling J. Immunol., March 1, 2002; 168(5): 2424 - 2432. [Abstract] [Full Text] [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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