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The Journal of Immunology, 2002, 169: 6668-6672.
Copyright © 2002 by The American Association of Immunologists


Cutting Edge

Cutting Edge: A Novel Toll/IL-1 Receptor Domain-Containing Adapter That Preferentially Activates the IFN-{beta} Promoter in the Toll-Like Receptor Signaling1

Masahiro Yamamoto2, Shintaro Sato2, Kiyotoshi Mori, Katsuaki Hoshino, Osamu Takeuchi, Kiyoshi Takeda and Shizuo Akira3

Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Suita, Osaka, Japan


    Abstract
 Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 
MyD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MyD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MyD88 adapter-like, a second adapter harboring the TIR domain, is essential for MyD88-dependent TLR2 and TLR4 signaling pathways, but not for MyD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-{beta} (TRIF). As is the case in MyD88 and TIRAP, overexpression of TRIF activated the NF-{kappa}B-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-{kappa}B activation. Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-{beta} promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-{kappa}B-dependent and IFN-{beta} promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MyD88-independent pathway.


    Introduction
 Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 
A family of Toll-like receptors (TLRs)4 senses invasion of microorganisms by recognizing specific patterns of microbial components and triggers activation of innate immunity (1, 2, 3).

The TLR family harbors an extracellular leucine-rich repeat domain and a cytoplasmic domain (Toll/IL-1 receptor (TIR) domain) that is homologous to that of the IL-1R family (2). Analogous to the IL-1R, TLR recruits IL-1R-associated kinase via an adapter MyD88, and then induces activation of TNFR-associated factor 6 and finally NF-{kappa}B. TLR-mediated production of inflammatory cytokines is completely abrogated in MyD88-deficient cells. However, recent studies indicated that the signaling pathways through individual TLRs might differ from each other and thereby result in different biological responses (2). In fact, the TLR4 signaling contains MyD88-dependent and -independent pathways; the former is essential for cytokine production whereas the latter is involved in IFN regulatory factor (IRF)-3 activation and subsequent induction of IFN-{beta} and IFN-inducible genes (4, 5, 6). The MyD88-independent pathway is also observed in TLR3 signaling (7).

Recently, TIR domain-containing adapter protein (TIRAP)/MyD88 adapter-like (Mal) has been identified as a second adapter harboring the TIR domain (8, 9). In vitro studies indicated that TIRAP/Mal is involved in LPS-induced activation of the MyD88-independent pathway (7, 9). However, studies with TIRAP-deficient mice have revealed that TIRAP acts as an adapter in the MyD88-dependent signaling pathways via TLR2 and TLR4 (10). These studies suggest that several TIR domain-containing adapters are involved in the TLR-mediated signaling pathways and differential use of these adapters provides the specificity in the TLR signaling, and furthermore that the MyD88-independent signaling pathway is mediated by a molecule other than TIRAP.

To further clarify the signaling pathways via TLRs, we searched for adapters containing the TIR domain besides MyD88 and TIRAP. The database screening led to identification of a novel adapter we named TIR domain-containing adapter inducing IFN-{beta} (TRIF). Our present study shows that TRIF preferentially activates the promoter of the IFN-{beta}, and a dominant-negative (DN) form of TRIF, but not MyD88 or TIRAP, blocked polyinosine-polycytidylic acid (poly(I:C))-mediated TLR3 response, indicating the specific role of this novel adapter in TLR3 signaling.


    Materials and Methods
 Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 
Cell lines and reagents

293 cells were transfected with Flag-tagged human TLR3 expression vector together with pCMV-neo. G418-resistant clones were screened for expression of TLR3 by Western blot. Two independently isolated clones that stably express TLR3 were used in some experiments. We used LPS from Salmonella minnesota Re 595 (Sigma-Aldrich, St. Louis, MO) and poly(I:C) (Amersham Pharmacia Biotech, Piscataway, NJ). Macrophage-activating lipopeptide (2 kDa; MALP-2) and R-848 were described previously (11, 12).

Plasmids

The endothelial cell-leukocyte adhesion molecule (ELAM)-1 promoter-derived luciferase reporter plasmid (NF-{kappa}B luciferase reporter) was a kind gift from Dr. D. Golenbock. Murine IFN-{beta} promoter luciferase reporter was generated by PCR as described previously (13). Expression vectors for human TLR2 and human TLR4 were kind gifts from Dr. R. Medzhitov. The Flag-tagged human TLR3 was cloned into pEF-BOS vector. DN MyD88 has a deletion of death domain and DN TIRAP contains a proline to histidine mutation at amino acid 125. An expression vector for TLR7 was as described previously (11).

Luciferase reporter assay

293 cells were transiently transfected with reporter plasmids, together with the indicated expression vectors. Luciferase activity of total cell lysates was measured using Dual-luciferase reporter assay system (Promega, Madison, WI). The Renilla-luciferase reporter gene (50 ng) (Promega) was used as an internal control.

Immunoprecipitation and immunoblotting

293 cells were transiently transfected with the indicated expression vectors. Cells were lysed, and then immunoprecipitated with anti-Flag Ab (Sigma-Aldrich), anti-Myc Ab (MBL, Nagoya, Japan), or anti-human IRF-3 Ab (Santa Cruz Biotechnology, Santa Cruz, CA). Immunoprecipitants were washed, separated on SDS-PAGE, and transferred onto membrane. The membrane was blotted with anti-Flag Ab or anti-Myc Ab (Santa Cruz Biotechnology). Endogenous IRF-3 was identified with anti-human IRF-3 Ab. Then, the Abs were detected by the ECL system (PerkinElmer Life Sciences, Boston, MA).


    Results and Discussion
 Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 
Identification of TRIF

We suspected that, besides MyD88 and TIRAP, molecules with the TIR domain are involved in the TLR-mediated signaling pathways. Therefore, we searched for sequences that contain the TIR domain in expressed sequence tag databases and identified a novel human partial cDNA clone (GenBank accession number BC009860). This gene showed high similarity with smart00255 TIR domain obtained from a National Center for Biotechnology Information conserved domain search (Fig. 1GoA). Using this fragment as a probe, a full-length cDNA of this gene was isolated. This gene has a long open reading frame of 2136 bp that encodes 712 aa (Fig. 1GoB). The nucleotide sequence is available from GenBank (accession number AB093555). The deduced amino acid sequence of this cDNA showed 48% identities and 57% similarities with the mouse cDNA clone of unknown function (accession number XM110244). We referred to this gene product as TRIF for TIR domain-containing adapter inducing IFN-{beta} (see the next section for detail). The TIR domain of TRIF existed in the C-terminal side of this protein. The proline residue that is conserved among TLRs and essential for activation of the TLR-mediated signaling was observed (Fig. 1GoA) (14, 15, 16). Expression of the TRIF transcript was analyzed by Northern hybridization (Fig. 1GoC). The transcript was ubiquitously observed in all human tissues examined, among which the liver showed strong expression.



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FIGURE 1. Identification of TRIF that harbors the TIR domain. A, Alignment of the TIR domain of TRIF and smart00255 TIR domain from the National Center for Biotechnology Information conserved domain search. Asterisks indicate identical residues in both sequences, double dots indicate cognate amino acids, and underlining indicates the proline residue conserved among TLRs, MyD88, and TIRAP. B, Comparison of structures between human TRIF, MyD88, and TIRAP/Mal. Domains were determined using the BLAST program. Length in amino acids is indicated. C, Detection of TRIF transcripts in human adult tissues. Multitissue Northern blot membrane (Clontech Laboratories, Palo Alto, CA) was hybridized with 32P-labeled probe of TRIF. PBL, peripheral blood leukocyte.

 
TRIF is a potent activator of the IFN-{beta} promoter and the NF-{kappa}B-dependent promoter

As reported previously, ectopic expression of MyD88 and TIRAP significantly induced NF-{kappa}B activation in 293 cells as determined by the relative luciferase activity of the NF-{kappa}B-responsive promoter of the ELAM-1 gene (Fig. 2GoA, left). Expression of TRIF also induced activation of the NF-{kappa}B-dependent promoter, albeit at low level compared with MyD88- or TIRAP-mediated induction. Because LPS (TLR4 ligand) and dsRNA (TLR3 ligand) are shown to induce expression of IFN-{beta} in a MyD88-independent manner (5, 6, 7), we next examined activation of the IFN-{beta} promoter using the promoter-driven luciferase reporter gene (Fig. 2GoA, right). No promoter activation was observed when expression plasmid for MyD88 or TIRAP was introduced together with the reporter plasmid. However, expression of TRIF dramatically induced the IFN-{beta} promoter activity. This result showed that TRIF is unique as a potent activator of the IFN-{beta} promoter.



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FIGURE 2. TRIF activated the IFN-{beta} promoter and NF-{kappa}B. A, 293 cells were transiently transfected with TRIF, MyD88, TIRAP, or empty vector (-), together with NF-{kappa}B luciferase reporter (left) or the IFN-{beta} promoter luciferase reporter (right). Twenty-four hours after transfection, luciferase activity was measured. B, Schematic structures of TRIF deletion mutants (lower panel). 293 cells were transiently transfected with empty vector (-), full-length TRIF (full), TRIF lacking the N-terminal portion ({Delta}N) or the C-terminal portion ({Delta}C), or TRIF protein harboring only the TIR domain ({Delta}N{Delta}C), together with NF-{kappa}B luciferase reporter (left) or the IFN-{beta} promoter luciferase reporter (right). All of above data are representative of three independent experiments.

 
To identify the domain essential for the promoter activation in TRIF protein, we generated several truncated forms of TRIF: {Delta}N, which encompasses the C-terminal half including the TIR domain (amino acid 380 to the C-terminal end); {Delta}C, which encompasses the N-terminal half including the TIR domain (amino acids 1 to 541); and {Delta}N{Delta}C, which consists of the TIR domain only. When cotransfected with the NF-{kappa}B-responsive luciferase reporter, either {Delta}C or {Delta}N induced the luciferase activity, albeit reduced compared with full-length TRIF-mediated induction (Fig. 2GoB, left). In the case of the IFN-{beta} promoter-driven luciferase reporter, {Delta}C, but not {Delta}N, activated the promoter at the same level as full-length TRIF (Fig. 2GoB, right). {Delta}N{Delta}C did not activate the promoter activity of either luciferase reporter. These results showed that distinct domains of TRIF are responsible for activation of these two promoters: the N-terminal portion of TRIF is essential for activation of the IFN-{beta} promoter activity, whereas both N-terminal and C-terminal portions of TRIF are involved in the NF-{kappa}B-dependent activation.

DN form of TRIF blocks activation of signaling pathways via several TLRs

Full-length TRIF-induced activation of both the NF-{kappa}B-dependent and the IFN-{beta} promoters was significantly inhibited by coexpression of TRIF{Delta}N{Delta}C, showing that the TIR domain of TRIF acts as a dominant inhibitor like those of MyD88 and TIRAP (8, 9, 17) (Fig. 3GoA). Using TRIF{Delta}N{Delta}C, we examined whether TRIF is involved in TLR-dependent signaling pathways. Expression of TLR4/MD-2 in 293 cells enabled the cells to activate the NF-{kappa}B-dependent reporter in response to LPS (Fig. 3GoB). Coexpression of TRIF{Delta}N{Delta}C inhibited the TLR4-dependent activation of the NF-{kappa}B-dependent promoter. When 293 cells were ectopically expressed with TLR2 or TLR7, the cells showed NF-{kappa}B activation in response to mycoplasmal lipopeptide (MALP-2) or imidazoquinoline, respectively. The TLR2- and TLR7-dependent activation of the NF-{kappa}B-dependent promoter was prohibited by expression of TRIF{Delta}N{Delta}C (Fig. 3Go, C and D). Ectopic expression of MyD88 and TIRAP resulted in a ligand-independent activation of the NF-{kappa}B reporter. Coexpression of TRIF{Delta}N{Delta}C profoundly inhibited the NF-{kappa}B activity mediated by MyD88 and TIRAP (Fig. 3GoE). These findings suggest that TRIF is involved in signaling pathways via multiple TLRs at the level downstream of MyD88 and TIRAP.



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FIGURE 3. DN TRIF inhibited NF-{kappa}B activation via several TLRs, and activation of the IFN-{beta} promoter via TLR3. A, 293 cells were transfected with full-length TRIF plus empty vector (-) or TRIF{Delta}N{Delta}C, together with NF-{kappa}B luciferase reporter (left) or the IFN-{beta} promoter luciferase reporter (right). Twenty-four hours after transfection, luciferase activity was analyzed. B–D, 293 cells were transfected with TLR4 plus MD-2 (B), TLR2 (C), TLR7 (D), together with NF-{kappa}B luciferase reporter and, where indicated, TRIF{Delta}N{Delta}C. Cells were then stimulated with 100 ng/ml LPS (B), 30 ng/ml MALP-2 (C), or 100 nM R-848 (D) for 12 h and NF-{kappa}B-induced luciferase activity was measured. E, 293 cells were transfected with MyD88 or TIRAP, together with NF-{kappa}B luciferase reporter and empty vector (-) or TRIF{Delta}N{Delta}C. F, 293 cells expressing human TLR3 were transfected with TIRAP DN or MyD88 DN, together with NF-{kappa}B reporter and, where indicated, TLR2. Luciferase activity of cells after stimulation with 50 µg/ml poly(I:C) or MALP-2 was measured. G, 293 cells expressing human TLR3 were transfected with TIRAP DN or MyD88 DN, together with the IFN-{beta} promoter reporter. Luciferase activity of cells in response to poly(I:C) was measured. H and I, 293 cells stably expressing TLR3 were transfected with TRIF{Delta}N{Delta}C, together with NF-{kappa}B reporter (H) or the IFN-{beta} reporter (I). Luciferase activity in cells treated with poly(I:C) is shown. Two independently isolated 293 cell clones that express human TLR3 were used for the experiments, and the same results were obtained.

 
Compared with other TLR members, TLR3 uses a unique signaling pathway that induces IFN-{beta} more predominantly than other inflammatory cytokines such as IL-12 and TNF-{alpha} (18). When 293 cells stably expressing TLR3 were transfected with the reporter plasmid and then stimulated with poly(I:C), both the NF-{kappa}B-dependent and the IFN-{beta} promoters were activated (Fig. 3Go, F and G). Although expression of DN forms of MyD88 and TIRAP inhibited TLR2-dependent activation of NF-{kappa}B, they did not inhibit the poly(I:C)-dependent activation of either the IFN-{beta} promoter or the NF-{kappa}B-dependent ELAM-1 promoter, but enhanced activity of the NF-{kappa}B-dependent promoter (Fig. 3Go, F and G). These findings indicate that TLR3 signaling mainly consists of the MyD88-independent pathway. As ectopic expression of TRIF led to preferential activation of the IFN-{beta} promoter, we focused on the role of TRIF in TLR3 signaling. In sharp contrast to DN forms of MyD88 and TIRAP, TRIF{Delta}N{Delta}C inhibited poly(I:C)-dependent activation of both promoters in 293 cells stably expressing TLR3 (Fig. 3Go, H and I). These results indicated that TRIF is involved in the MyD88-independent activation of TLR3 signaling.

TRIF associates with TLR3 and IRF-3

We next addressed association of TRIF with TLR3 and TLR2. 293 cells were transfected with Myc-tagged TRIF together with Flag-tagged TLR2 or TLR3. Myc-TRIF was coimmunoprecipitated with Flag-TLR2 and TLR3 (Fig. 4GoA). The TIR domain of MyD88 and TIRAP was reportedly required for interaction with TLRs (8, 9, 17). We analyzed whether the TIR domain of TRIF ({Delta}N{Delta}C) associates with TLR3 (Fig. 4GoB). Myc-TRIF{Delta}N{Delta}C was coimmunoprecipitated with Flag-TLR3. These findings indicate that TRIF associates with TLR3 through the TIR domain and mediates the induction of IFN-{beta} in response to poly(I:C). poly(I:C) and LPS stimulation has been shown to activate IRF-3 (6, 19, 20). Therefore, we next examined association of TRIF and IRF-3 (Fig. 4GoC). 293 cells were transfected with Flag-tagged TRIF, and cell lysates were immunoprecipitated with anti-human IRF-3 Ab. Flag-TRIF was coimmunoprecipiated with IRF-3, indicating that TRIF interacts with IRF-3.



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FIGURE 4. Interaction of TRIF with TLR2, TLR3, and endogenous IRF-3. A, 293 cells were transiently transfected with Flag-TLR2, Flag-TLR3, and Myc-TRIF expression vectors. Thirty-six hours after transfection, cells were lysed, immunoprecipitated with anti-Flag Ab (IP), and then immunoblotted with anti-Flag or anti-Myc Ab (IB). B, 293 cells stably expressing Flag-TLR3 were transiently transfected with an empty vector (mock) or Myc-TRIF{Delta}N{Delta}C expression vector. Cell lysis, immunoprecipitation, and subsequent immunoblotting were performed as described in A. C, 293 cells were transiently transfected with Flag-GST or Flag-TRIF expression vector. Twenty-four hours later, cells were lysed, immunoprecipitated with anti-Flag Ab or anti-IRF-3 Ab, and then immunoblotted with anti-Flag Ab. Whole cell lysates (WCL) were immunoblotted by anti-IRF-3 Ab to detect endogenous (endo) IRF-3.

 
In the present study, we have identified and characterized a novel adapter containing the TIR domain, named TRIF. Overexpression of TRIF activated the NF-{kappa}B responsive promoter of the ELAM-1 gene as well as the promoter of the IFN-{beta} gene. Different from already published adapters such as MyD88 and TIRAP, TRIF activated the IFN-{beta} promoter much more strongly than the NF-{kappa}B responsive promoter. Noteworthy is that a DN form of TRIF, but not MyD88 or TIRAP, completely abolished the TLR3-mediated signaling. This indicates a special role of TRIF in the TLR3 signaling. Furthermore, the DN form of TRIF blocked the NF-{kappa}B activity mediated by TLR2, TLR4, and TLR7, indicating some roles in other TLR signaling pathways. Although the functional role of TRIF in individual TLR responses should be examined through generation of knockout mice, the fact that TRIF preferentially activates the IFN-{beta} promoter and TRIF associates with IRF-3 suggests the involvement of TRIF in the MyD88-independent pathway of TLR3 signaling.


    Acknowledgments
 
We thank Drs. Golenbock and Medzhitov for providing us with NF-{kappa}B reporter and expression vectors for TLR2 and TLR4, respectively. We also thank H. Sanjo, S. Uematsu, H. Hemmi, and T. Kaisho for helpful discussions, N. Okita for technical assistance, and E. Horita for secretarial assistance.


    Footnotes
 
1 This work was supported by grants from Special Coordination Funds, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Virtual Research Institute of Aging of Nippon Boehringer Ingelheim. Back

2 M.Y. and S.S. contributed equally to this work. Back

3 Address correspondence and reprint requests to Dr. Shizuo Akira, Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail address: sakira{at}biken.osaka-u.ac.jp Back

4 Abbreviations used in this paper: TLR, Toll-like receptor; MALP-2, macrophage-activating lipopeptide (2 kDa); poly(I:C), polyinosine-polycytidylic acid; IRF, IFN regulatory factor; TIR, Toll/IL-1 receptor; TIRAP, TIR domain-containing adapter protein; Mal, MyD88 adapter-like; TRIF, TIR domain-containing adapter inducing IFN-{beta}; ELAM, endothelial cell-leukocyte adhesion molecule; DN, dominant negative. Back

Received for publication September 20, 2002. Accepted for publication October 24, 2002.


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 Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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Infect. Immun.Home page
S. Kenzel, S. Santos-Sierra, S. D. Deshmukh, I. Moeller, B. Ergin, K. A. Fitzgerald, E. Lien, S. Akira, D. T. Golenbock, and P. Henneke
Role of p38 and Early Growth Response Factor 1 in the Macrophage Response to Group B Streptococcus
Infect. Immun., June 1, 2009; 77(6): 2474 - 2481.
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Infect. Immun.Home page
V. A. K. Rathinam, D. M. Appledorn, K. A. Hoag, A. Amalfitano, and L. S. Mansfield
Campylobacter jejuni-Induced Activation of Dendritic Cells Involves Cooperative Signaling through Toll-Like Receptor 4 (TLR4)-MyD88 and TLR4-TRIF Axes
Infect. Immun., June 1, 2009; 77(6): 2499 - 2507.
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Proc. Natl. Acad. Sci. USAHome page
Y. Li, C. Li, P. Xue, B. Zhong, A.-P. Mao, Y. Ran, H. Chen, Y.-Y. Wang, F. Yang, and H.-B. Shu
ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response
PNAS, May 12, 2009; 106(19): 7945 - 7950.
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J. Leukoc. Biol.Home page
S. Klaschik, D. Tross, and D. M. Klinman
Inductive and suppressive networks regulate TLR9-dependent gene expression in vivo
J. Leukoc. Biol., May 1, 2009; 85(5): 788 - 795.
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J. Biol. Chem.Home page
G. K. Radhakrishnan, Q. Yu, J. S. Harms, and G. A. Splitter
Brucella TIR Domain-containing Protein Mimics Properties of the Toll-like Receptor Adaptor Protein TIRAP
J. Biol. Chem., April 10, 2009; 284(15): 9892 - 9898.
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Clin. Microbiol. Rev.Home page
T. H. Mogensen
Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses
Clin. Microbiol. Rev., April 1, 2009; 22(2): 240 - 273.
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FASEB J.Home page
J. De Miranda, K. Yaddanapudi, M. Hornig, and W. I. Lipkin
Astrocytes recognize intracellular polyinosinic-polycytidylic acid via MDA-5
FASEB J, April 1, 2009; 23(4): 1064 - 1071.
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J. Immunol.Home page
S. Remy, P. Blancou, L. Tesson, V. Tardif, R. Brion, P. J. Royer, R. Motterlini, R. Foresti, M. Painchaut, S. Pogu, et al.
Carbon Monoxide Inhibits TLR-Induced Dendritic Cell Immunogenicity
J. Immunol., February 15, 2009; 182(4): 1877 - 1884.
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J. Immunol.Home page
A. K. Miyahira, A. Shahangian, S. Hwang, R. Sun, and G. Cheng
TANK-Binding Kinase-1 Plays an Important Role during In Vitro and In Vivo Type I IFN Responses to DNA Virus Infections
J. Immunol., February 15, 2009; 182(4): 2248 - 2257.
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J. Immunol.Home page
Y. Endoh, Y. M. Chung, I. A. Clark, C. L. Geczy, and K. Hsu
IL-10-Dependent S100A8 Gene Induction in Monocytes/Macrophages by Double-Stranded RNA
J. Immunol., February 15, 2009; 182(4): 2258 - 2268.
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J. Biol. Chem.Home page
S. Yanagimoto, K. Tatsuno, S. Okugawa, T. Kitazawa, K. Tsukada, K. Koike, T. Kodama, S. Kimura, Y. Shibasaki, and Y. Ota
A Single Amino Acid of Toll-like Receptor 4 That Is Pivotal for Its Signal Transduction and Subcellular Localization
J. Biol. Chem., February 6, 2009; 284(6): 3513 - 3520.
[Abstract] [Full Text] [PDF]


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J. Virol.Home page
M. R. Murawski, G. N. Bowen, A. M. Cerny, L. J. Anderson, L. M. Haynes, R. A. Tripp, E. A. Kurt-Jones, and R. W. Finberg
Respiratory Syncytial Virus Activates Innate Immunity through Toll-Like Receptor 2
J. Virol., February 1, 2009; 83(3): 1492 - 1500.
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J. Immunol.Home page
C. Richez, K. Yasuda, A. A. Watkins, S. Akira, R. Lafyatis, J. M. van Seventer, and I. R. Rifkin
TLR4 Ligands Induce IFN-{alpha} Production by Mouse Conventional Dendritic Cells and Human Monocytes after IFN-{beta} Priming
J. Immunol., January 15, 2009; 182(2): 820 - 828.
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J. Biol. Chem.Home page
W. Deng, M. Shi, M. Han, J. Zhong, Z. Li, W. Li, Y. Hu, L. Yan, J. Wang, Y. He, et al.
Negative Regulation of Virus-triggered IFN-{beta} Signaling Pathway by Alternative Splicing of TBK1
J. Biol. Chem., December 19, 2008; 283(51): 35590 - 35597.
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J. Leukoc. Biol.Home page
A. R. Ashtekar, P. Zhang, J. Katz, C. C. S. Deivanayagam, P. Rallabhandi, S. N. Vogel, and S. M. Michalek
TLR4-mediated activation of dendritic cells by the heat shock protein DnaK from Francisella tularensis
J. Leukoc. Biol., December 1, 2008; 84(6): 1434 - 1446.
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J. Biol. Chem.Home page
C.-S. Shi and J. H. Kehrl
MyD88 and Trif Target Beclin 1 to Trigger Autophagy in Macrophages
J. Biol. Chem., November 28, 2008; 283(48): 33175 - 33182.
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J. Immunol.Home page
S. Chen, R. Sorrentino, K. Shimada, Y. Bulut, T. M. Doherty, T. R. Crother, and M. Arditi
Chlamydia pneumoniae-Induced Foam Cell Formation Requires MyD88-Dependent and -Independent Signaling and Is Reciprocally Modulated by Liver X Receptor Activation
J. Immunol., November 15, 2008; 181(10): 7186 - 7193.
[Abstract] [Full Text] [PDF]


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J. Leukoc. Biol.Home page
Y. Hu, K.-H. Park-Min, A. Yarilina, and L. B. Ivashkiv
Regulation of STAT pathways and IRF1 during human dendritic cell maturation by TNF-{alpha} and PGE2
J. Leukoc. Biol., November 1, 2008; 84(5): 1353 - 1360.
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J. Immunol.Home page
N. Tamassia, V. Le Moigne, M. Rossato, M. Donini, S. McCartney, F. Calzetti, M. Colonna, F. Bazzoni, and M. A. Cassatella
Activation of an Immunoregulatory and Antiviral Gene Expression Program in Poly(I:C)-Transfected Human Neutrophils
J. Immunol., November 1, 2008; 181(9): 6563 - 6573.
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J. Biol. Chem.Home page
T. Kubota, M. Matsuoka, T.-H. Chang, P. Tailor, T. Sasaki, M. Tashiro, A. Kato, and K. Ozato
Virus Infection Triggers SUMOylation of IRF3 and IRF7, Leading to the Negative Regulation of Type I Interferon Gene Expression
J. Biol. Chem., September 12, 2008; 283(37): 25660 - 25670.
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J. Virol.Home page
J. R. Wilson, P. F. de Sessions, M. A. Leon, and F. Scholle
West Nile Virus Nonstructural Protein 1 Inhibits TLR3 Signal Transduction
J. Virol., September 1, 2008; 82(17): 8262 - 8271.
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Int ImmunolHome page
M. Shingai, M. Azuma, T. Ebihara, M. Sasai, K. Funami, M. Ayata, H. Ogura, H. Tsutsumi, M. Matsumoto, and T. Seya
Soluble G protein of respiratory syncytial virus inhibits Toll-like receptor 3/4-mediated IFN-beta induction
Int. Immunol., September 1, 2008; 20(9): 1169 - 1180.
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J. Biol. Chem.Home page
K. Fukuda, T. Watanabe, T. Tokisue, T. Tsujita, S. Nishikawa, T. Hasegawa, T. Seya, and M. Matsumoto
Modulation of Double-stranded RNA Recognition by the N-terminal Histidine-rich Region of the Human Toll-like Receptor 3
J. Biol. Chem., August 15, 2008; 283(33): 22787 - 22794.
[Abstract] [Full Text] [PDF]


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BloodHome page
R. T. Semnani, P. G. Venugopal, C. A. Leifer, S. Mostbock, H. Sabzevari, and T. B. Nutman
Inhibition of TLR3 and TLR4 function and expression in human dendritic cells by helminth parasites
Blood, August 15, 2008; 112(4): 1290 - 1298.
[Abstract] [Full Text] [PDF]


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IOVSHome page
Y. Liu, K. Kimura, R. Yanai, T.-i. Chikama, and T. Nishida
Cytokine, Chemokine, and Adhesion Molecule Expression Mediated by MAPKs in Human Corneal Fibroblasts Exposed to Poly(I:C)
Invest. Ophthalmol. Vis. Sci., August 1, 2008; 49(8): 3336 - 3344.
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Endocr. Rev.Home page
X. Huang, D. J. Moore, R. J. Ketchum, C. S. Nunemaker, B. Kovatchev, A. L. McCall, and K. L. Brayman
Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation
Endocr. Rev., August 1, 2008; 29(5): 603 - 630.
[Abstract] [Full Text] [PDF]


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J. Gen. Virol.Home page
D. Paulmann, T. Magulski, R. Schwarz, L. Heitmann, B. Flehmig, A. Vallbracht, and A. Dotzauer
Hepatitis A virus protein 2B suppresses beta interferon (IFN) gene transcription by interfering with IFN regulatory factor 3 activation
J. Gen. Virol., July 1, 2008; 89(7): 1593 - 1604.
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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. Hayashi, H. B. Cottam, M. Chan, G. Jin, R. I. Tawatao, B. Crain, L. Ronacher, K. Messer, D. A. Carson, and M. Corr
Mast cell-dependent anorexia and hypothermia induced by mucosal activation of Toll-like receptor 7
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R123 - R132.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
M. Abe, M. Matsuda, H. Kobayashi, Y. Miyata, Y. Nakayama, R. Komuro, A. Fukuhara, and I. Shimomura
Effects of Statins on Adipose Tissue Inflammation: Their Inhibitory Effect on MyD88-Independent IRF3/IFN-{beta} Pathway in Macrophages
Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 871 - 877.
[Abstract] [Full Text] [PDF]


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DiabetesHome page
Z. Dogusan, M. Garcia, D. Flamez, L. Alexopoulou, M. Goldman, C. Gysemans, C. Mathieu, C. Libert, D. L. Eizirik, and J. Rasschaert
Double-Stranded RNA Induces Pancreatic {beta}-Cell Apoptosis by Activation of the Toll-Like Receptor 3 and Interferon Regulatory Factor 3 Pathways
Diabetes, May 1, 2008; 57(5): 1236 - 1245.
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J. Immunol.Home page
S. Fan, S. Chen, Y. Liu, Y. Lin, H. Liu, L. Guo, B. Lin, S. Huang, and A. Xu
Zebrafish TRIF, a Golgi-Localized Protein, Participates in IFN Induction and NF-{kappa}B Activation
J. Immunol., April 15, 2008; 180(8): 5373 - 5383.
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J. Immunol.Home page
S. Bhushan, S. Tchatalbachev, J. Klug, M. Fijak, C. Pineau, T. Chakraborty, and A. Meinhardt
Uropathogenic Escherichia coli Block MyD88-Dependent and Activate MyD88-Independent Signaling Pathways in Rat Testicular Cells
J. Immunol., April 15, 2008; 180(8): 5537 - 5547.
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J. Immunol.Home page
P. Velazquez, B. Wei, M. McPherson, L. M. A. Mendoza, S. L. Nguyen, O. Turovskaya, M. Kronenberg, T. T. Huang, M. Schrage, L. N. Lobato, et al.
Villous B Cells of the Small Intestine Are Specialized for Invariant NK T Cell Dependence
J. Immunol., April 1, 2008; 180(7): 4629 - 4638.
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J. Leukoc. Biol.Home page
D. J. Kaczorowski, K. P. Mollen, R. Edmonds, and T. R. Billiar
Early events in the recognition of danger signals after tissue injury
J. Leukoc. Biol., March 1, 2008; 83(3): 546 - 552.
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J. Leukoc. Biol.Home page
K. Farhat, S. Riekenberg, H. Heine, J. Debarry, R. Lang, J. Mages, U. Buwitt-Beckmann, K. Roschmann, G. Jung, K.-H. Wiesmuller, et al.
Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling
J. Leukoc. Biol., March 1, 2008; 83(3): 692 - 701.
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J. Biol. Chem.Home page
A. C. Johnson, X. Li, and E. Pearlman
MyD88 Functions as a Negative Regulator of TLR3/TRIF-induced Corneal Inflammation by Inhibiting Activation of c-Jun N-terminal Kinase
J. Biol. Chem., February 15, 2008; 283(7): 3988 - 3996.
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J. Biol. Chem.Home page
W. Piao, C. Song, H. Chen, L. M. Wahl, K. A. Fitzgerald, L. A. O'Neill, and A. E. Medvedev
Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance
J. Biol. Chem., February 8, 2008; 283(6): 3109 - 3119.
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J. Gen. Virol.Home page
M. Sillanpaa, P. Kaukinen, K. Melen, and I. Julkunen
Hepatitis C virus proteins interfere with the activation of chemokine gene promoters and downregulate chemokine gene expression
J. Gen. Virol., February 1, 2008; 89(2): 432 - 443.
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J. Gen. Virol.Home page
R. E. Randall and S. Goodbourn
Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures
J. Gen. Virol., January 1, 2008; 89(1): 1 - 47.
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Drug Metab. Dispos.Home page
R. Ghose, D. White, T. Guo, J. Vallejo, and S. J. Karpen
Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein
Drug Metab. Dispos., January 1, 2008; 36(1): 95 - 101.
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J. Immunol.Home page
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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J. Immunol.Home page
J. P. McAleer, D. J. Zammit, L. Lefrancois, R. J. Rossi, and A. T. Vella
The Lipopolysaccharide Adjuvant Effect on T Cells Relies on Nonoverlapping Contributions from the MyD88 Pathway and CD11c+ Cells
J. Immunol., November 15, 2007; 179(10): 6524 - 6535.
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J. Immunol.Home page
K. Funami, M. Sasai, Y. Ohba, H. Oshiumi, T. Seya, and M. Matsumoto
Spatiotemporal Mobilization of Toll/IL-1 Receptor Domain-Containing Adaptor Molecule-1 in Response to dsRNA
J. Immunol., November 15, 2007; 179(10): 6867 - 6872.
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J. Biol. Chem.Home page
S. G. Devaraj, N. Wang, Z. Chen, Z. Chen, M. Tseng, N. Barretto, R. Lin, C. J. Peters, C.-T. K. Tseng, S. C. Baker, et al.
Regulation of IRF-3-dependent Innate Immunity by the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus
J. Biol. Chem., November 2, 2007; 282(44): 32208 - 32221.
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J. Immunol.Home page
M. Shingai, T. Ebihara, N. A. Begum, A. Kato, T. Honma, K. Matsumoto, H. Saito, H. Ogura, M. Matsumoto, and T. Seya
Differential Type I IFN-Inducing Abilities of Wild-Type versus Vaccine Strains of Measles Virus
J. Immunol., November 1, 2007; 179(9): 6123 - 6133.
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J. Virol.Home page
F. D. Gilfoy and P. W. Mason
West Nile Virus-Induced Interferon Production Is Mediated by the Double-Stranded RNA-Dependent Protein Kinase PKR
J. Virol., October 15, 2007; 81(20): 11148 - 11158.
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J. Immunol.Home page
Y. Hirata, A. H. Broquet, L. Menchen, and M. F. Kagnoff
Activation of Innate Immune Defense Mechanisms by Signaling through RIG-I/IPS-1 in Intestinal Epithelial Cells
J. Immunol., October 15, 2007; 179(8): 5425 - 5432.
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J. Leukoc. Biol.Home page
M. Loiarro, F. Capolunghi, N. Fanto, G. Gallo, S. Campo, B. Arseni, R. Carsetti, P. Carminati, R. De Santis, V. Ruggiero, et al.
Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound
J. Leukoc. Biol., October 1, 2007; 82(4): 801 - 810.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
K. D. McCall, N. Harii, C. J. Lewis, R. Malgor, W. Bae Kim, M. Saji, A. D. Kohn, R. T. Moon, and L. D. Kohn
High Basal Levels of Functional Toll-Like Receptor 3 (TLR3) and Noncanonical Wnt5a Are Expressed in Papillary Thyroid Cancer and Are Coordinately Decreased by Phenylmethimazole Together with Cell Proliferation and Migration
Endocrinology, September 1, 2007; 148(9): 4226 - 4237.
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J. Leukoc. Biol.Home page
F. J. Sheedy and L. A. J. O'Neill
The Troll in Toll: Mal and Tram as bridges for TLR2 and TLR4 signaling
J. Leukoc. Biol., August 1, 2007; 82(2): 196 - 203.
[Abstract] [Full Text] [PDF]


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BloodHome page
Y. Wang, T. Chen, C. Han, D. He, H. Liu, H. An, Z. Cai, and X. Cao
Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4
Blood, August 1, 2007; 110(3): 962 - 971.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
F. Diao, S. Li, Y. Tian, M. Zhang, L.-G. Xu, Y. Zhang, R.-P. Wang, D. Chen, Z. Zhai, B. Zhong, et al.
Negative regulation of MDA5- but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase
PNAS, July 10, 2007; 104(28): 11706 - 11711.
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JEMHome page
Z. J. Roberts, N. Goutagny, P.-Y. Perera, H. Kato, H. Kumar, T. Kawai, S. Akira, R. Savan, D. van Echo, K. A. Fitzgerald, et al.
The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis
J. Exp. Med., July 9, 2007; 204(7): 1559 - 1569.
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Mult SclerHome page
F. Mastronardi, H. Tsui, S. Winer, D. Wood, T. Selvanantham, C. Galligan, E. Fish, H-M. Dosch, and M. Moscarello
Synergy between paclitaxel plus an exogenous methyl donor in the suppression of murine demyelinating diseases
Multiple Sclerosis, June 1, 2007; 13(5): 596 - 609.
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J. Biol. Chem.Home page
A. E. Medvedev, W. Piao, J. Shoenfelt, S. H. Rhee, H. Chen, S. Basu, L. M. Wahl, M. J. Fenton, and S. N. Vogel
Role of TLR4 Tyrosine Phosphorylation in Signal Transduction and Endotoxin Tolerance
J. Biol. Chem., June 1, 2007; 282(22): 16042 - 16053.
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J. Immunol.Home page
T. Venkataraman, M. Valdes, R. Elsby, S. Kakuta, G. Caceres, S. Saijo, Y. Iwakura, and G. N. Barber
Loss of DExD/H Box RNA Helicase LGP2 Manifests Disparate Antiviral Responses
J. Immunol., May 15, 2007; 178(10): 6444 - 6455.
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Infect. Immun.Home page
M. Obonyo, M. Sabet, S. P. Cole, J. Ebmeyer, S. Uematsu, S. Akira, and D. G. Guiney
Deficiencies of Myeloid Differentiation Factor 88, Toll-Like Receptor 2 (TLR2), or TLR4 Produce Specific Defects in Macrophage Cytokine Secretion Induced by Helicobacter pylori
Infect. Immun., May 1, 2007; 75(5): 2408 - 2414.
[Abstract] [Full Text] [PDF]


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Int ImmunolHome page
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.
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J. Biol. Chem.Home page
H. Ishida, K. Li, M. Yi, and S. M. Lemon
p21-activated Kinase 1 Is Activated through the Mammalian Target of Rapamycin/p70 S6 Kinase Pathway and Regulates the Replication of Hepatitis C Virus in Human Hepatoma Cells
J. Biol. Chem., April 20, 2007; 282(16): 11836 - 11848.
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J. Immunol.Home page
C. Sullivan, J. H. Postlethwait, C. R. Lage, P. J. Millard, and C. H. Kim
Evidence for Evolving Toll-IL-1 Receptor-Containing Adaptor Molecule Function in Vertebrates
J. Immunol., April 1, 2007; 178(7): 4517 - 4527.
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Infect. Immun.Home page
W. A. Derbigny, S.-C. Hong, M. S. Kerr, M. Temkit, and R. M. Johnson
Chlamydia muridarum Infection Elicits a Beta Interferon Response in Murine Oviduct Epithelial Cells Dependent on Interferon Regulatory Factor 3 and TRIF
Infect. Immun., March 1, 2007; 75(3): 1280 - 1290.
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J. Immunol.Home page
S. A. Stanley, J. E. Johndrow, P. Manzanillo, and J. S. Cox
The Type I IFN Response to Infection with Mycobacterium tuberculosis Requires ESX-1-Mediated Secretion and Contributes to Pathogenesis
J. Immunol., March 1, 2007; 178(5): 3143 - 3152.
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J. Immunol.Home page
M. R. Power, B. Li, M. Yamamoto, S. Akira, and T.-J. Lin
A Role of Toll-IL-1 Receptor Domain-Containing Adaptor-Inducing IFN-beta in the Host Response to Pseudomonas aeruginosa Lung Infection in Mice
J. Immunol., March 1, 2007; 178(5): 3170 - 3176.
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J. Nutr.Home page
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.
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J. Immunol.Home page
S. M. Sacre, A. M. C. Lundberg, E. Andreakos, C. Taylor, M. Feldmann, and B. M. Foxwell
Selective Use of TRAM in Lipopolysaccharide (LPS) and Lipoteichoic Acid (LTA) Induced NF-{kappa}B Activation and Cytokine Production in Primary Human Cells: TRAM Is an Adaptor for LPS and LTA Signaling
J. Immunol., February 15, 2007; 178(4): 2148 - 2154.
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BloodHome page
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.
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Innate ImmunityHome page
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.
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Hum ReprodHome page
K. Nasu, H. Itoh, A. Yuge, M. Nishida, and H. Narahara
Human oviductal epithelial cells express Toll-like receptor 3 and respond to double-stranded RNA: Fallopian tube-specific mucosal immunity against viral infection
Hum. Reprod., February 1, 2007; 22(2): 356 - 361.
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J. Immunol.Home page
A. G. Hise, K. Daehnel, I. Gillette-Ferguson, E. Cho, H. F. McGarry, M. J. Taylor, D. T. Golenbock, K. A. Fitzgerald, J. W. Kazura, and E. Pearlman
Innate Immune Responses to Endosymbiotic Wolbachia Bacteria in Brugia malayi and Onchocerca volvulus Are Dependent on TLR2, TLR6, MyD88, and Mal, but Not TLR4, TRIF, or TRAM
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A. Bagchi, E. A. Herrup, H. S. Warren, J. Trigilio, H.-S. Shin, C. Valentine, and J. Hellman
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Am. J. Physiol. Heart Circ. Physiol.Home page
H. S. Hardarson, J. S. Baker, Z. Yang, E. Purevjav, C.-H. Huang, L. Alexopoulou, N. Li, R. A. Flavell, N. E. Bowles, and J. G. Vallejo
Toll-like receptor 3 is an essential component of the innate stress response in virus-induced cardiac injury
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H. Zhou, B. M. Lapointe, S. R. Clark, L. Zbytnuik, and P. Kubes
A Requirement for Microglial TLR4 in Leukocyte Recruitment into Brain in Response to Lipopolysaccharide
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Sci SignalHome page
H. Hacker and M. Karin
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H. Weighardt, S. Kaiser-Moore, S. Schlautkotter, T. Rossmann-Bloeck, U. Schleicher, C. Bogdan, and B. Holzmann
Type I IFN Modulates Host Defense and Late Hyperinflammation in Septic Peritonitis
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J. Immunol.Home page
W. Jiang and D. S. Pisetsky
The Role of IFN-{alpha} and Nitric Oxide in the Release of HMGB1 by RAW 264.7 Cells Stimulated with Polyinosinic-Polycytidylic Acid or Lipopolysaccharide.
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Hum ReprodHome page
V. M. Abrahams, T. M. Schaefer, J. V. Fahey, I. Visintin, J. A. Wright, P. B. Aldo, R. Romero, C. R. Wira, and G. Mor
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Am. J. Physiol. Renal Physiol.Home page
R. D. Pawar, P. S. Patole, M. Wornle, and H.-J. Anders
Microbial nucleic acids pay a Toll in kidney disease
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J. Gen. Virol.Home page
K. Hayashi, L. C. Hooper, M. S. Chin, C. N. Nagineni, B. Detrick, and J. J. Hooks
Herpes simplex virus 1 (HSV-1) DNA and immune complex (HSV-1-human IgG) elicit vigorous interleukin 6 release from infected corneal cells via Toll-like receptors.
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Innate ImmunityHome page
E. M. Pietras, S. K. Saha, and Genhong Cheng
The interferon response to bacterial and viral infections
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J. Immunol.Home page
J. D. Turner, R. S. Langley, K. L. Johnston, G. Egerton, S. Wanji, and M. J. Taylor
Wolbachia Endosymbiotic Bacteria of Brugia malayi Mediate Macrophage Tolerance to TLR- and CD40-Specific Stimuli in a MyD88/TLR2-Dependent Manner
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BloodHome page
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Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo
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I. Bekeredjian-Ding, S. I. Roth, S. Gilles, T. Giese, A. Ablasser, V. Hornung, S. Endres, and G. Hartmann
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Innate ImmunityHome page
A. E. Medvedev, I. Sabroe, J. D. Hasday, and S. N. Vogel
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Proc. Natl. Acad. Sci. USAHome page
G. Cheng, J. Zhong, and F. V. Chisari
Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms
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J. Virol.Home page
C. B. Lopez, J. S. Yount, T. Hermesh, and T. M. Moran
Sendai Virus Infection Induces Efficient Adaptive Immunity Independently of Type I Interferons
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Proc. Natl. Acad. Sci. USAHome page
D. C. Rowe, A. F. McGettrick, E. Latz, B. G. Monks, N. J. Gay, M. Yamamoto, S. Akira, L. A. O'Neill, K. A. Fitzgerald, and D. T. Golenbock
The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction
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