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CUTTING EDGE |
,§

*
Department of Biochemistry, Hyogo College of Medicine, Hyogo, Japan;
Research Institute, International Medical Center of Japan, Tokyo, Japan;
Department of Oral Microbiology, Asahi University School of Dentistry, Gifu, Japan; and
§
Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Japan.
| Abstract |
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B. Taken together, the present study demonstrates
that TLR4 is the gene product that regulates LPS
response. | Introduction |
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B pathway (3, 4). Recently, human homologues of
Drosophila toll, termed Toll-like receptors
(TLR)3, have been cloned, and
it is implicated that they activate both innate and adaptive immune
responses in vertebrates (5, 6, 7, 8). TLR2 has been shown to be a signaling
receptor that is activated by LPS (9, 10).
The C3H/HeJ mouse strain is characterized by hyporesponsiveness to LPS
(11). Macrophages from C3H/HeJ mice fail to induce inflammatory
cytokines, including TNF-
, IL-1, and IL-6. Their splenic B cells do
not proliferate after exposure to LPS. The molecular basis of this
hyporesponsiveness is unknown, but it may result from defective
membrane signal transduction after LPS binding. The hyporesponsive
phenotype of the C3H/HeJ mouse maps to the Lps locus
(endotoxin unresponsive gene locus) on mouse chromosome 4 (12). The
corresponding chromosomal location in the human genome is chromosome
9q3233; that is the same region to which human TLR4 has been mapped
(8). Recent genetic and physical mapping of the Lps locus
identifies TLR4 as a candidate gene in the critical region (12).
In the present study, we have generated TLR4-deficient (TLR4-/-) mice and examined the LPS responsiveness. TLR4-/- mice showed hyporesponsive to LPS to an extent similar to that of C3H/HeJ mice. We also detected a single point mutation in the TLR4 gene of C3H/HeJ mice. These results demonstrate that TLR4 is the gene product of the Lps locus.
| Materials and Methods |
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LPS from Escherichia coli serotype O55:B5 prepared by Westphal method and Salmonella minnesota Re-595 (R mutants) prepared by phenol-chloroform-petroleum ether extraction procedure were purchased from Sigma (St. Louis, MO). E. coli-type synthetic lipid A (compound 506) was described previously (13). Biotinylated anti-mouse I-A Ab were purchased from PharMingen (San Diego, CA).
Generation of murine TLR4-/- mice
The murine TLR4 genomic clone was screened from the 129/SvJ mouse genomic library (Stratagene, La Jolla, CA). A targeting vector was designed to replace a 2.54-kbp genomic fragment with neomycin resistance gene (neo) from pMC1-neo-poly(A) (Stratagene). A herpes simplex virus-thymidine kinase cassette (HSV-TK) was inserted into the 3' end of the vector. The resultant targeting vector was electroporated into E14.1 ES cells. Generation of chimeric mice and mutant mice was essentially as described previously (14).
B cell assay
Proliferative response of B cells and I-A expression on B cells were analyzed as described (14).
Cytokine production
Peritoneal macrophages were isolated 3 days after i.p.
thioglycolate injection, and then 5 x 104 cells were
cultured with various reagents for 24 h. Production of TNF-
was
measured by ELISA (Genzyme, Boston, MA), and production of
NO2- was measured by NO2/NO3
assay kit-C (Dojindo, Kumamoto, Japan).
Sequence analysis of mouse TLR4 cDNA
Total RNA was extracted from splenocytes of C3H/HeJ and C3H/HeN mice, reverse-transcribed, and amplified by PCR using a set of primers. The resulting DNA fragments were sequenced. The primer sequences were available upon request.
Reporter assay
The transmembrane and the cytoplasmic domain of murine TLR4
(amino acid residue 623 to 835) were fused to the extracellular domain
of murine CD4 (amino acid residue 1 to 384). The chimeras were ligated
into a mammalian expression vector pEF-BOS (15). Two hundred
ninety-three cells (1 x 105) seeded on 6-well plates
were transiently cotransfected with 2 µg of indicated expression
plasmids together with NF-
B reporter plasmid. After 24 h, the
reporter gene activity was measured and normalized as described
previously (15).
| Results and Discussion |
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R on thymocytes, splenocytes, and peritoneal
exclude cells showed normal composition in 6-wk-old
TLR4-/- mice (data not shown).
|
was measured (Fig. 2
in response to each LPS in a
dose-dependent manner. In contrast, TLR4-/- and C3H/HeJ
macrophages did not produce any detectable level of TNF-
in response
to Re-595 LPS but did produce low levels of TNF-
in response to a
high concentration of O55:B5 LPS. Next, the macrophages were cultured
with LPS or lipid A in the presence or absence of IFN-
for 24
h, and production of nitric oxide (NO2-) was measured
(Fig. 2
. In contrast, macrophages from
TLR4-/- and C3H/HeJ did not produce any detectable level
of NO2- in response to both Re-595 LPS and E.
coli-type lipid A 506.
|
|
B-dependent reporter gene
expression. In contrast, TLR4 from C3H/HeJ failed to activate NF-
B,
suggesting that this portion is critical for its signaling leading to
the activation of NF-
B.
|
| Acknowledgments |
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| Footnotes |
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2 Address correspondence and reprint requests to Dr. Shizuo Akira, Department of Biochemistry, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. E-mail address: ![]()
3 Abbreviations used in this paper: TLR, Toll-like receptor; TLR4-/- mice, TLR4-deficient mice; neo, neomycin resistance gene; HSV-TK, herpes simplex virus-thymidine kinase gene; ES cell, embryonic stem cell; NO2-, nitric oxide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. ![]()
Received for publication December 15, 1998. Accepted for publication January 19, 1999.
| References |
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T. Shimizu, Y. Kida, and K. Kuwano A Triacylated Lipoprotein from Mycoplasma genitalium Activates NF-{kappa}B through Toll-Like Receptor 1 (TLR1) and TLR2 Infect. Immun., August 1, 2008; 76(8): 3672 - 3678. [Abstract] [Full Text] [PDF] |
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J. M. Jordan, M. E. Woods, J. Olano, and D. H. Walker The Absence of Toll-Like Receptor 4 Signaling in C3H/HeJ Mice Predisposes Them to Overwhelming Rickettsial Infection and Decreased Protective Th1 Responses Infect. Immun., August 1, 2008; 76(8): 3717 - 3724. [Abstract] [Full Text] [PDF] |
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N. Gratz, M. Siller, B. Schaljo, Z. A. Pirzada, I. Gattermeier, I. Vojtek, C. J. Kirschning, H. Wagner, S. Akira, E. Charpentier, et al. Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9 J. Biol. Chem., July 18, 2008; 283(29): 19879 - 19887. [Abstract] [Full Text] [PDF] |
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T. Kobayashi, K. Takahashi, Y. Nagai, T. Shibata, M. Otani, S. Izui, S. Akira, Y. Gotoh, H. Kiyono, and K. Miyake Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice Int. Immunol., July 1, 2008; 20(7): 881 - 891. [Abstract] [Full Text] [PDF] |
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A. Lembo, M. Pelletier, R. Iyer, M. Timko, J. C. Dudda, T. E. West, C. B. Wilson, A. M. Hajjar, and S. J. Skerrett Administration of a Synthetic TLR4 Agonist Protects Mice from Pneumonic Tularemia J. Immunol., June 1, 2008; 180(11): 7574 - 7581. [Abstract] [Full Text] [PDF] |
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T. Ha, F. Hua, X. Liu, J. Ma, J. R. McMullen, T. Shioi, S. Izumo, J. Kelley, X. Gao, W. Browder, et al. Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism Cardiovasc Res, June 1, 2008; 78(3): 546 - 553. [Abstract] [Full Text] [PDF] |
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P. Gong, D. J. Angelini, S. Yang, G. Xia, A. S. Cross, D. Mann, D. D. Bannerman, S. N. Vogel, and S. E. Goldblum TLR4 Signaling Is Coupled to SRC Family Kinase Activation, Tyrosine Phosphorylation of Zonula Adherens Proteins, and Opening of the Paracellular Pathway in Human Lung Microvascular Endothelia J. Biol. Chem., May 9, 2008; 283(19): 13437 - 13449. [Abstract] [Full Text] [PDF] |
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T. Shimizu, Y. Kida, and K. Kuwano Ureaplasma parvum lipoproteins, including MB antigen, activate NF-{kappa}B through TLR1, TLR2 and TLR6 Microbiology, May 1, 2008; 154(5): 1318 - 1325. [Abstract] [Full Text] [PDF] |
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B. Pang, D. Winn, R. Johnson, W. Hong, S. West-Barnette, N. Kock, and W. E. Swords Lipooligosaccharides Containing Phosphorylcholine Delay Pulmonary Clearance of Nontypeable Haemophilus influenzae Infect. Immun., May 1, 2008; 76(5): 2037 - 2043. [Abstract] [Full Text] [PDF] |
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D. L. Trott, E. M. Hellestad, M. Yang, and M. E. Cook Additions of Killed Whole Cell Bacteria Preparations to Freund Complete Adjuvant Alter Laying Hen Antibody Response to Soluble Protein Antigen Poult. Sci., May 1, 2008; 87(5): 912 - 917. [Abstract] [Full Text] [PDF] |
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N. Zucchini, G. Bessou, S. Traub, S. H. Robbins, S. Uematsu, S. Akira, L. Alexopoulou, and M. Dalod Cutting Edge: Overlapping Functions of TLR7 and TLR9 for Innate Defense against a Herpesvirus Infection J. Immunol., May 1, 2008; 180(9): 5799 - 5803. [Abstract] [Full Text] [PDF] |
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B. Zhang, G. Ramesh, S. Uematsu, S. Akira, and W. B. Reeves TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity J. Am. Soc. Nephrol., May 1, 2008; 19(5): 923 - 932. [Abstract] [Full Text] [PDF] |
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V. Jain, A. Halle, K. A. Halmen, E. Lien, M. Charrel-Dennis, S. Ram, D. T. Golenbock, and A. Visintin Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling Blood, May 1, 2008; 111(9): 4637 - 4645. [Abstract] [Full Text] [PDF] |
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M. Leendertse, R. J. L. Willems, I. A. J. Giebelen, P. S. van den Pangaart, W. J. Wiersinga, A. F. de Vos, S. Florquin, M. J. M. Bonten, and T. van der Poll TLR2-Dependent MyD88 Signaling Contributes to Early Host Defense in Murine Enterococcus faecium Peritonitis J. Immunol., April 1, 2008; 180(7): 4865 - 4874. [Abstract] [Full Text] [PDF] |
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Y. Ren, Y. Xie, G. Jiang, J. Fan, J. Yeung, W. Li, P. K. H. Tam, and J. Savill Apoptotic Cells Protect Mice against Lipopolysaccharide-Induced Shock J. Immunol., April 1, 2008; 180(7): 4978 - 4985. [Abstract] [Full Text] [PDF] |
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M. C. Banas, B. Banas, K. L. Hudkins, T. A. Wietecha, M. Iyoda, E. Bock, P. Hauser, J. W. Pippin, S. J. Shankland, K. D. Smith, et al. TLR4 Links Podocytes with the Innate Immune System to Mediate Glomerular Injury J. Am. Soc. Nephrol., April 1, 2008; 19(4): 704 - 713. [Abstract] [Full Text] [PDF] |
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S. Lehnardt, E. Schott, T. Trimbuch, D. Laubisch, C. Krueger, G. Wulczyn, R. Nitsch, and J. R. Weber A Vicious Cycle Involving Release of Heat Shock Protein 60 from Injured Cells and Activation of Toll-Like Receptor 4 Mediates Neurodegeneration in the CNS J. Neurosci., March 5, 2008; 28(10): 2320 - 2331. [Abstract] [Full Text] [PDF] |
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A. Koneti, M. J. Linke, E. Brummer, and D. A. Stevens Evasion of Innate Immune Responses: Evidence for Mannose Binding Lectin Inhibition of Tumor Necrosis Factor Alpha Production by Macrophages in Response to Blastomyces dermatitidis Infect. Immun., March 1, 2008; 76(3): 994 - 1002. [Abstract] [Full Text] [PDF] |
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S. C. Gribar, R. J. Anand, C. P. Sodhi, and D. J. Hackam The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation J. Leukoc. Biol., March 1, 2008; 83(3): 493 - 498. [Abstract] [Full Text] [PDF] |
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S. Knapp, S. von Aulock, M. Leendertse, I. Haslinger, C. Draing, D. T. Golenbock, and T. van der Poll Lipoteichoic Acid-Induced Lung Inflammation Depends on TLR2 and the Concerted Action of TLR4 and the Platelet-Activating Factor Receptor J. Immunol., March 1, 2008; 180(5): 3478 - 3484. [Abstract] [Full Text] [PDF] |
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T. Kawasaki, M. A. Choudhry, M. G. Schwacha, S. Fujimi, J. A. Lederer, K. I. Bland, and I. H. Chaudry Trauma-hemorrhage inhibits splenic dendritic cell proinflammatory cytokine production via a mitogen-activated protein kinase process Am J Physiol Cell Physiol, March 1, 2008; 294(3): C754 - C764. [Abstract] [Full Text] [PDF] |
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P. Tissieres, I. Dunn-Siegrist, M. Schappi, G. Elson, R. Comte, V. Nobre, and J. Pugin Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria Blood, February 15, 2008; 111(4): 2122 - 2131. [Abstract] [Full Text] [PDF] |
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F. A. Amaral, D. Sachs, V. V. Costa, C. T. Fagundes, D. Cisalpino, T. M. Cunha, S. H. Ferreira, F. Q. Cunha, T. A. Silva, J. R. Nicoli, et al. Commensal microbiota is fundamental for the development of inflammatory pain PNAS, February 12, 2008; 105(6): 2193 - 2197. [Abstract] [Full Text] [PDF] |
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S. M. Eswarappa, N. Basu, O. Joy, and D. Chakravortty Folimycin (concanamycin A) inhibits LPS-induced nitric oxide production and reduces surface localization of TLR4 in murine macrophages Innate Immunity, February 1, 2008; 14(1): 13 - 24. [Abstract] [PDF] |
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T Watanabe, K Higuchi, A Kobata, H Nishio, T Tanigawa, M Shiba, K Tominaga, Y Fujiwara, N Oshitani, T Asahara, et al. Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent Gut, February 1, 2008; 57(2): 181 - 187. [Abstract] [Full Text] [PDF] |
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A. Miyake, Y. Murata, H. Okazawa, H. Ikeda, Y. Niwayama, H. Ohnishi, Y. Hirata, and T. Matozaki Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages. Genes Cells, February 1, 2008; 13(2): 209 - 219. [Abstract] [Full Text] [PDF] |
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I. Vaknin, L. Blinder, L. Wang, R. Gazit, E. Shapira, O. Genina, M. Pines, E. Pikarsky, and M. Baniyash A common pathway mediated through Toll-like receptors leads to T- and natural killer-cell immunosuppression Blood, February 1, 2008; 111(3): 1437 - 1447. [Abstract] [Full Text] [PDF] |
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E. Doz, N. Noulin, E. Boichot, I. Guenon, L. Fick, M. Le Bert, V. Lagente, B. Ryffel, B. Schnyder, V. F. J. Quesniaux, et al. Cigarette Smoke-Induced Pulmonary Inflammation Is TLR4/MyD88 and IL-1R1/MyD88 Signaling Dependent J. Immunol., January 15, 2008; 180(2): 1169 - 1178. [Abstract] [Full Text] [PDF] |
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A. Beck, R. Penner, and A. Fleig Lipopolysaccharide-induced down-regulation of Ca2+ release-activated Ca2+ currents (ICRAC) but not Ca2+-activated TRPM4-like currents (ICAN) in cultured mouse microglial cells J. Physiol., January 15, 2008; 586(2): 427 - 439. [Abstract] [Full Text] [PDF] |
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H. S. Seo, S. M. Michalek, and M. H. Nahm Lipoteichoic Acid Is Important in Innate Immune Responses to Gram-Positive Bacteria Infect. Immun., January 1, 2008; 76(1): 206 - 213. [Abstract] [Full Text] [PDF] |
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T. Shimizu, Y. Kida, and K. Kuwano Mycoplasma pneumoniae-Derived Lipopeptides Induce Acute Inflammatory Responses in the Lungs of Mice Infect. Immun., January 1, 2008; 76(1): 270 - 277. [Abstract] [Full Text] [PDF] |
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M. Cabanski, M. Steinmuller, L. M. Marsh, E. Surdziel, W. Seeger, and J. Lohmeyer PKR Regulates TLR2/TLR4-Dependent Signaling in Murine Alveolar Macrophages Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 26 - 31. [Abstract] [Full Text] [PDF] |
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W. Stenzel, S. Soltek, M. Sanchez-Ruiz, S. Akira, H. Miletic, D. Schluter, and M. Deckert Both TLR2 and TLR4 Are Required for the Effective Immune Response in Staphylococcus aureus-Induced Experimental Murine Brain Abscess Am. J. Pathol., January 1, 2008; 172(1): 132 - 145. [Abstract] [Full Text] [PDF] |
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Y. Asai, Y. Makimura, A. Kawabata, and T. Ogawa Soluble CD14 Discriminates Slight Structural Differences between Lipid As That Lead to Distinct Host Cell Activation J. Immunol., December 1, 2007; 179(11): 7674 - 7683. [Abstract] [Full Text] [PDF] |
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X. Tan, S. Essengue, J. Talreja, J. Reese, D. J. Stechschulte, and K. N. Dileepan Histamine Directly and Synergistically with Lipopolysaccharide Stimulates Cyclooxygenase-2 Expression and Prostaglandin I2 and E2 Production in Human Coronary Artery Endothelial Cells J. Immunol., December 1, 2007; 179(11): 7899 - 7906. [Abstract] [Full Text] [PDF] |
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