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The Journal of Immunology, 1999, 162: 3749-3752.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Toll-Like Receptor 4 (TLR4)-Deficient Mice Are Hyporesponsive to Lipopolysaccharide: Evidence for TLR4 as the Lps Gene Product1

Katsuaki Hoshino*,{dagger},§, Osamu Takeuchi*,§, Taro Kawai*,§, Hideki Sanjo*,§, Tomohiko Ogawa{ddagger}, Yoshifumi Takeda{dagger}, Kiyoshi Takeda*,§ and Shizuo Akira2,*,§

* Department of Biochemistry, Hyogo College of Medicine, Hyogo, Japan; {dagger} Research Institute, International Medical Center of Japan, Tokyo, Japan; {ddagger} 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
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The human homologue of Drosophila Toll (hToll), also called Toll-like receptor 4 (TLR4), is a recently cloned receptor of the IL-1/Toll receptor family. Interestingly, the TLR4 gene has been localized to the same region to which the Lps locus (endotoxin unresponsive gene locus) is mapped. To examine the role of TLR4 in LPS responsiveness, we have generated mice lacking TLR4. Macrophages and B cells from TLR4-deficient mice did not respond to LPS. All these manifestations were quite similar to those of LPS-hyporesponsive C3H/HeJ mice. Furthermore, C3H/HeJ mice have, in the cytoplasmic portion of TLR4, a single point mutation of the amino acid that is highly conserved among the IL-1/Toll receptor family. Overexpression of wild-type TLR4 but not the mutant TLR4 from C3H/HeJ mice activated NF-{kappa}B. Taken together, the present study demonstrates that TLR4 is the gene product that regulates LPS response.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
In adult Drosophila, the toll protein participates in host defense against fungal infection (1). The cytoplasmic region of Drosophila toll is homologous to that of the IL-1R family (2). Both Drosophila toll and IL-1R are known to signal through the NF-{kappa}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-{alpha}, 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 9q32–33; 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
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Reagents

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-{alpha} 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-{kappa}B reporter plasmid. After 24 h, the reporter gene activity was measured and normalized as described previously (15).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
We generated the mice deficient in TLR4 and examined the LPS responsiveness. The mouse TLR4 gene was disrupted by homologous recombination in E14.1 embryonic stem (ES) cells. A targeting vector was designed to replace both the transmembrane and cytoplasmic regions of TLR4 (amino acid residue 86–835) with neo (Fig. 1GoA). The targeted ES clones successfully transmitted the disrupted TLR4 gene through the germline (Fig. 1GoB). TLR4-/- mice were born normally, grew healthy, and showed no obvious abnormalities until 10 wk. Northern blot analysis using total RNA from splenocytes confirmed the absence of expression of TLR4 mRNA in TLR4-/- mice (Fig. 1GoC). FACS analysis of the expression of CD3, B220, CD4, CD8, IgM, I-Ab, and Fc{gamma}R on thymocytes, splenocytes, and peritoneal exclude cells showed normal composition in 6-wk-old TLR4-/- mice (data not shown).



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  		FIGURE 1. Targeted disruption of the mouse TLR4 gene. A, Targeting vector and restriction map of the Tlr4 locus. The restriction map of the wild-type allele, targeting vector and the mutated allele are shown. Filled boxes denote the coding exons. The orientation of neo and HSV-TK are indicated by the arrow. E, EcoRI; B, BamHI. B, Southern blot analysis of offspring from the heterozygote intercrosses. Genomic DNA was extracted from mouse tails, digested with BamHI, electrophoresed, and hybridized with the probe as shown in Fig. 1GoA. The approximate size of the wild-type band is 8.4 kbp, and the mutated band is 2.0 kbp. +/+, Wild-type; +/-, heterozygous mutant; -/-, homozygous mutant. C, Northern blot analysis of mouse TLR4 mRNA. Total RNA was isolated from the splenocytes of wild-type, TLR4-/-, and C3H/HeJ mice, electrophoresed and transferred to a nylon membrane. A mouse TLR4 cDNA probe was used for hybridization. The same membrane was rehybridized with a GAPDH probe.

 
We first examined the LPS response in macrophages from TLR4-/- mice. LPS contains polysaccharide and lipid A portion, and much of LPS responses are mediated by the lipid A portion (11). LPS (S. minnesota Re-595 or E. coli O55:B5), and synthetic E. coli-type lipid A (compound 506) were used in this study. It has been demonstrated that C3H/HeJ mice lack the responsiveness to LPS (Re-595) and synthetic lipid A (506) (13). Peritoneal macrophages were isolated from wild-type, TLR4-/-, and C3H/HeJ mice, cultured in the presence of various concentration of LPS from Re-595 or O55:B5, and production of TNF-{alpha} was measured (Fig. 2GoA). Wild-type macrophages produced an increased level of TNF-{alpha} 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-{alpha} in response to Re-595 LPS but did produce low levels of TNF-{alpha} 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-{gamma} for 24 h, and production of nitric oxide (NO2-) was measured (Fig. 2GoB). Wild-type macrophages produced NO2- in response to all LPS and lipid A as tested when cocultured with IFN-{gamma}. 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.



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  		FIGURE 2. Impaired LPS responsiveness in TLR4-/- macrophages. A, Peritoneal macrophages from wild-type, TLR4-/-, and C3H/HeJ mice were isolated 3 days after i.p. thioglycolate injection. The cells were cultured with the indicated concentrations of E. coli O55:B5 LPS or S. minnesota Re-595 LPS for 24 h. Concentrations of TNF-{alpha} in the culture supernatants were measured by ELISA. B, Peritoneal macrophages were isolated and cultured with 1.0 µg/ml S. minnesota Re-595 LPS (Re-595) or 1.0 µg/ml E. coli-type synthetic lipid A (506) in the presence or absence of 30 U/ml IFN-{gamma} for 24 h. Concentrations of NO2- in the culture supernatants were measured. Indicated values are means of duplicates. ND, Not detected.

 
We next analyzed LPS responsiveness of B cells. Splenic B cells were cultured in the presence of various concentrations of LPS (O55:B5, Re-595) or lipid A (506). Wild-type B cells showed an increased proliferative response to LPS and lipid A in a dose-dependent manner (Fig. 3GoA). In contrast, both TLR4-/- and C3H/HeJ B cells did not proliferate in response to O55:B5 LPS, Re-595, or lipid A 506. In addition, TLR4-/- B cells normally proliferated in response to IL-4 plus anti-IgM Ab or anti-CD40 Ab, indicating that the defective proliferative response is LPS specific (Fig. 3GoA). We further analyzed an augmentation of MHC class II expression on B cells in response to LPS (Re-595). Wild-type B cells showed the increased expression of MHC class II in response to LPS. However, LPS-induced augmentation of MHC class II expression on TLR4-/- and C3H/HeJ B cells was severely impaired (Fig. 3GoB). Both wild-type, TLR4-/-, and C3H/HeJ B cells expressed almost the same level of MHC class II in response to IL-4. Thus, B cells of TLR4-/- mice are specifically hyporesponsive to LPS. Taken together, all these findings demonstrate that TLR4-/- mice present almost the same phenotype with C3H/HeJ mice.



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  		FIGURE 3. Impaired LPS responsiveness in TLR4-/- B cells. A, Splenocytes (1 x 105) from wild-type, TLR4 and C3H/HeJ mice were cultured with the indicated concentrations of O55:B5 LPS, Re-595 LPS, or E. coli-type synthetic lipid A. Splenocytes were also cultured with 100 U/ml IL-4 plus 5 µg/ml anti-IgM Ab, or 500 ng/ml anti-CD40 Ab for 48 h. [3H]thymidine (37 kBq) was pulsed for the last 6 h. [3H] incorporation was measured with a scintillation counter. Indicated values are means ± SD of triplicates. B, Splenocytes (1 x 106) were cultured with the indicated concentrations of Re-595 LPS or 100 U/ml IL-4. At 48 h culture period, the cells were harvested and stained with biotin-conjugated anti-I-A Ab and phycoerythrin-conjugated anti-B220 Ab followed by streptavidin-FITC. Stained cells were analyzed on FACScalibur using Cell Quest software (Becton Dickinson, San Jose, CA).

 
We therefore examined whether there is any abnormality in the TLR4 gene of C3H/HeJ mice. As shown in Fig. 1GoC, expression of TLR4 mRNA was detected in splenocytes of C3H/HeJ mice at the similar level relative to the wild-type mice. We next searched for a mutation in the TLR4 gene of C3H/HeJ mice. Using a set of primers, we amplified the coding region of TLR4 gene from the spleen of LPS-responsive C3H/HeN and LPS-hyporesponsive C3H/HeJ mice after reverse transcription of mRNA, and the nucleotide sequences of the resultant PCR products were compared. TLR4 cDNA from C3H/HeN mice contained an open reading frame of 2508 bp, and predicted protein sequence produces an 835-aa residue. Murine TLR4 showed 86.0% and 64.5% overall amino acid similarity to rat and human TLR4, respectively (data not shown). The sequence analysis revealed one nucleotide difference in the cytoplasmic region of the TLR4 gene between C3H/HeN and C3H/HeJ mice (Fig. 4GoA). Transversion from C to A in C3H/HeJ mice resulted in an amino acid change from proline to histidine. As shown in Fig. 4GoB, this proline residue is highly conserved in the Toll receptor family. We next examined whether this mutation is the cause of defective LPS signaling in C3H/HeJ mice. We constructed two versions of expression vectors for TLR4 from C3H/HeN and C3H/HeJ mice. The extracellular portion of both constructs was replaced to that of CD4 because CD4-mediated aggregation may induce the activation of the downstream events, as in the case of the human TLR4 (5). As shown in Fig. 4GoC, CD4-TLR4 from C3H/HeN (wild-type) significantly induced the activation of NF-{kappa}B-dependent reporter gene expression. In contrast, TLR4 from C3H/HeJ failed to activate NF-{kappa}B, suggesting that this portion is critical for its signaling leading to the activation of NF-{kappa}B.



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  		FIGURE 4. A point mutation of the TLR4 gene in C3H/HeJ mice. A, Sequence comparison of mouse TLR4 cDNA obtained from C3H/HeJ and C3H/HeN mice. C3H/HeJ mice had one amino acid replacement (aa residue 712) in intracellular domain compared with wild-type mice. This amino acid residue is thought to be a critical for TLR signaling. B, The amino acid sequences of mouse TLR4 cytoplasmic domain obtained from wild-type and C3H/HeJ mice are aligned to those of other TLR family members (8). C, Two hundred ninety-three cells were transiently cotransfected with the expression plasmid for CD4-TLR4 from C3H/HeN or C3H/HeJ together with NF-{kappa}B-dependent reporter gene plasmid. The expression plasmid for MyD88 was used as a positive control (4). A similar result was obtained from another independent experiment.

 
In the present study we have generated mice deficient in TLR4 and examined LPS responsiveness, comparing with C3H/HeJ mice. TLR4-deficient mice showed hyporesponsiveness to LPS to an extent similar to that of C3H/HeJ mice. We also detected a missense mutation in the cytoplasmic portion of TLR4 in C3H/HeJ mice. Although there was a slight difference in the LPS response between TLR4-/- and C3H/HeJ mice, this may be due to a difference in the mutation (null mutation in TLR4-/- but a point mutation in C3H/HeJ mice), as well as in the strain. Taken together, these results demonstrate that TLR4 is the gene product of Lps locus, the defect of which results in hyporesponsiveness to LPS in C3H/HeJ mice. During preparation of our manuscript, a similar finding was published through the analyses of genetic and physical mapping of the Lps locus (16).


   Acknowledgments
 
We thank Dr. T. Kaisho for helpful discussion, Ms. A. Maekawa for technical assistance, Ms. T. Aoki, Ms. M. Hyuga and Ms. E. Nakatani for secretarial assistance, and all member of our laboratory for their helpful advice for the preparation of this manuscript.


   Footnotes
 
1 This work was supported by grants from the Ministry of Education of Japan. Back

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: Back

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. Back

Received for publication December 15, 1998. Accepted for publication January 19, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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  4. Muzio, M., J. Ni, P. Feng, V. M. Dixit. 1997. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL- 1 signaling. Science 278:1612.[Abstract/Free Full Text]
  5. Medzhitov, R., P. Preston-Hurlburt, Jr C. A. Janeway. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394.[Medline]
  6. Medzhitov, R., Jr C. A. Janeway. 1997. Innate immunity: the virtues of a nonclonal system of recognition. Cell 91:295.[Medline]
  7. O’Neill, L. A., C. Greene. 1998. Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J. Leukocyte Biol. 63:650.[Abstract]
  8. Rock, F. L., G. Hardiman, J. C. Timans, R. A. Kastelein, J. F. Bazan. 1998. A family of human receptors structurally related to Drosophila Toll. Proc. Natl. Acad. Sci. USA 95:588.[Abstract/Free Full Text]
  9. Yang, R. B., M. R. Mark, A. Gray, A. Huang, M. H. Xie, M. Zhang, A. Goddard, W. I. Wood, A. L. Gurney, P. J. Godowski. 1998. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signaling. Nature 395:284.[Medline]
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  15. Adachi, O., T. Kawai, K. Takeda, M. Matsumoto, H. Tsutsui, M. Sakagami, K. Nakanishi, S. Akira. 1998. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9:143.[Medline]
  16. Poltorak, A., X. He, I. Smirnova, M. Y. Liu, C. V. Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton, B. Beutler. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085.[Abstract/Free Full Text]



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Infect. Immun., July 1, 2009; 77(7): 2925 - 2931.
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I. Tirapu, B. Giquel, L. Alexopoulou, S. Uematsu, R. Flavell, S. Akira, and S. S. Diebold
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K. Ilg, K. Endt, B. Misselwitz, B. Stecher, M. Aebi, and W.-D. Hardt
O-Antigen-Negative Salmonella enterica Serovar Typhimurium Is Attenuated in Intestinal Colonization but Elicits Colitis in Streptomycin-Treated Mice
Infect. Immun., June 1, 2009; 77(6): 2568 - 2575.
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Myeloid Differentiation Protein-2-Dependent and -Independent Neutrophil Accumulation during Escherichia coli Pneumonia
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R Sharif, R Dawra, K Wasiluk, P Phillips, V Dudeja, E Kurt-Jones, R Finberg, and A Saluja
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Therapeutic Targeting of Toll-Like Receptors for Infectious and Inflammatory Diseases and Cancer
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Uric Acid Is a Danger Signal Activating NALP3 Inflammasome in Lung Injury Inflammation and Fibrosis
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Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis
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The roles of TLRs, RLRs and NLRs in pathogen recognition
Int. Immunol., April 1, 2009; 21(4): 317 - 337.
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Modulation of TLR Signaling by Multiple MyD88-Interacting Partners Including Leucine-Rich Repeat Fli-I-Interacting Proteins
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S. Kang, S.-P. Lee, K. E. Kim, H.-Z. Kim, S. Memet, and G. Y. Koh
Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages
Blood, March 12, 2009; 113(11): 2605 - 2613.
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J. Zhang, M. R. Chaluvadi, R. Reddy, M. S. Motika, T. A. Richardson, J. R. Cashman, and E. T. Morgan
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D. A. Schwartz
Gene-Environment Interactions and Airway Disease in Children
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T. Roger, C. Froidevaux, D. Le Roy, M. K. Reymond, A.-L. Chanson, D. Mauri, K. Burns, B. M. Riederer, S. Akira, and T. Calandra
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M. P. Sepulcre, F. Alcaraz-Perez, A. Lopez-Munoz, F. J. Roca, J. Meseguer, M. L. Cayuela, and V. Mulero
Evolution of Lipopolysaccharide (LPS) Recognition and Signaling: Fish TLR4 Does Not Recognize LPS and Negatively Regulates NF-{kappa}B Activation
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A. T. Vaughan, A. Gorringe, V. Davenport, N. A. Williams, and R. S. Heyderman
Absence of Mucosal Immunity in the Human Upper Respiratory Tract to the Commensal Bacteria Neisseria lactamica but Not Pathogenic Neisseria meningitidis during the Peak Age of Nasopharyngeal Carriage
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H.-J. Ko, J.-Y. Yang, D.-H. Shim, H. Yang, S.-M. Park, R. Curtiss III, and M.-N. Kweon
Innate Immunity Mediated by MyD88 Signal Is Not Essential for Induction of Lipopolysaccharide-Specific B Cell Responses but Is Indispensable for Protection against Salmonella enterica serovar Typhimurium infection
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M. R. Chaluvadi, R. D. Kinloch, B. A. Nyagode, T. A. Richardson, M. J. Raynor, M. Sherman, L. Antonovic, H. W. Strobel, D. L. Dillehay, and E. T. Morgan
Regulation of Hepatic Cytochrome P450 Expression in Mice with Intestinal or Systemic Infections of Citrobacter rodentium
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E. B. Thorgersen, A. Pharo, K. Haverson, A. K. Axelsen, P. Gaustad, G. J. Kotwal, G. Sfyroera, and T. E. Mollnes
Inhibition of Complement and CD14 Attenuates the Escherichia coli-Induced Inflammatory Response in Porcine Whole Blood
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T. Chen, J. Guo, C. Han, M. Yang, and X. Cao
Heat Shock Protein 70, Released from Heat-Stressed Tumor Cells, Initiates Antitumor Immunity by Inducing Tumor Cell Chemokine Production and Activating Dendritic Cells via TLR4 Pathway
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TLR4 Ligands Induce IFN-{alpha} Production by Mouse Conventional Dendritic Cells and Human Monocytes after IFN-{beta} Priming
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M. J. Karbarz, D. A. Six, and C. R. H. Raetz
Purification and Characterization of the Lipid A 1-Phosphatase LpxE of Rhizobium leguminosarum
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H. Komura, M. Miksa, R. Wu, S. M. Goyert, and P. Wang
Milk Fat Globule Epidermal Growth Factor-Factor VIII Is Down-Regulated in Sepsis via the Lipopolysaccharide-CD14 Pathway
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W. Chao
Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart
Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H1 - H12.
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T. A. Stephens, E. Nikoopour, B. J. Rider, M. Leon-Ponte, T. A. Chau, S. Mikolajczak, P. Chaturvedi, E. Lee-Chan, R. A. Flavell, S. M. M. Haeryfar, et al.
Dendritic Cell Differentiation Induced by a Self-Peptide Derived from Apolipoprotein E
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D. S. Spinner, I. S. Cho, S. Y. Park, J. I. Kim, H. C. Meeker, X. Ye, G. LaFauci, D. J. Kerr, M. J. Flory, B. S. Kim, et al.
Accelerated Prion Disease Pathogenesis in Toll-Like Receptor 4 Signaling-Mutant Mice
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C. Calcaterra, L. Sfondrini, A. Rossini, M. Sommariva, C. Rumio, S. Menard, and A. Balsari
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C. C. Toledo, T. J. Rogers, M. Svensson, R. Tati, H. Fischer, C. Svanborg, and D. Karpman
Shiga Toxin-Mediated Disease in MyD88-Deficient Mice Infected with Escherichia coli O157:H7
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R. T. Robinson, S. A. Khader, R. M. Locksley, E. Lien, S. T. Smiley, and A. M. Cooper
Yersinia pestis Evades TLR4-dependent Induction of IL-12(p40)2 by Dendritic Cells and Subsequent Cell Migration
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E Raschi, M. Borghi, C Grossi, V Broggini, S Pierangeli, and P. Meroni
Toll-like receptors: another player in the pathogenesis of the anti-phospholipid syndrome
Lupus, October 1, 2008; 17(10): 938 - 943.
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E Cockrell, R. Espinola, and K. McCrae
Annexin A2: biology and relevance to the antiphospholipid syndrome
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A. L. F. Bernardino, T. A. Myers, X. Alvarez, A. Hasegawa, and M. T. Philipp
Toll-Like Receptors: Insights into Their Possible Role in the Pathogenesis of Lyme Neuroborreliosis
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M. Miettinen, V. Veckman, S. Latvala, T. Sareneva, S. Matikainen, and I. Julkunen
Live Lactobacillus rhamnosus and Streptococcus pyogenes differentially regulate Toll-like receptor (TLR) gene expression in human primary macrophages
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E. T. Cadman, A. Y. Abdallah, C. Voisine, A.-M. Sponaas, P. Corran, T. Lamb, D. Brown, F. Ndungu, and J. Langhorne
Alterations of Splenic Architecture in Malaria Are Induced Independently of Toll-Like Receptors 2, 4, and 9 or MyD88 and May Affect Antibody Affinity
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Y. Gwack, S. Srikanth, M. Oh-hora, P. G. Hogan, E. D. Lamperti, M. Yamashita, C. Gelinas, D. S. Neems, Y. Sasaki, S. Feske, et al.
Hair Loss and Defective T- and B-Cell Function in Mice Lacking ORAI1
Mol. Cell. Biol., September 1, 2008; 28(17): 5209 - 5222.
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R. Lizundia, K.-S. Sauter, G. Taylor, and D. Werling
Host species-specific usage of the TLR4-LPS receptor complex
Innate Immunity, August 1, 2008; 14(4): 223 - 231.
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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
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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
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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
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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
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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
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Lipopolysaccharide-induced myocardial protection against ischaemia/reperfusion injury is mediated through a PI3K/Akt-dependent mechanism
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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
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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
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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
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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
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Cutting Edge: Overlapping Functions of TLR7 and TLR9 for Innate Defense against a Herpesvirus Infection
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TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity
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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
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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
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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
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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
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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
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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
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The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation
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Lipoteichoic Acid-Induced Lung Inflammation Depends on TLR2 and the Concerted Action of TLR4 and the Platelet-Activating Factor Receptor
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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
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Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria
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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
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Folimycin (concanamycin A) inhibits LPS-induced nitric oxide production and reduces surface localization of TLR4 in murine macrophages
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Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent
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Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages.
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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.
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 J. Physiol.Home page
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.
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 Infect. Immun.Home page
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.
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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.
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 Am. J. Respir. Cell Mol. Bio.Home page
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.
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 Am. J. Pathol.Home page
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
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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.
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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.
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