HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, R.-B. Articles by Godowski, P. J. Search for Related Content PubMed PubMed Citation Articles by Yang, R.-B. Articles by Godowski, P. J.

Signaling Events Induced by Lipopolysaccharide-Activated Toll-Like Receptor 2

Department of Molecular Biology, Genentech, Inc., San Francisco, CA 94080

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Human Toll-like receptor 2 (TLR2) is a signaling receptor that responds to LPS and activates NF-B. Here, we investigate further the events triggered by TLR2 in response to LPS. We show that TLR2 associates with the high-affinity LPS binding protein membrane CD14 to serve as an LPS receptor complex, and that LPS treatment enhances the oligomerization of TLR2. Concomitant with receptor oligomerization, the IL-1R-associated kinase (IRAK) is recruited to the TLR2 complex. Intracellular deletion variants of TLR2 lacking C-terminal 13 or 141 aa fail to recruit IRAK, which is consistent with the inability of these mutants to transmit LPS cellular signaling. Moreover, both deletion mutants could still form complexes with wild-type TLR2 and act in a dominant-negative (DN) fashion to block TLR2-mediated signal transduction. DN constructs of myeloid differentiation protein, IRAK, TNF receptor-associated factor 6, and NF-B-inducing kinase, when coexpressed with TLR2, abrogate TLR2-mediated NF-B activation. These results reveal a conserved signaling pathway for TLR2 and IL-1Rs and suggest a molecular mechanism for the inhibition of TLR2 by DN variants.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Members of the human Toll-like receptor (TLR)² family share a similar topography with an extracellular domain (ECD) containing multiple leucine rich-repeats, a single membrane-spanning domain, and an intracellular domain with significant sequence similarity to the IL-1R family (1). Toll was originally identified in Drosophila and is essential for the establishment of dorsoventral polarity in the embryo (2). Toll also plays an important role in innate immunity, inducing an antimicrobial response in the adult fly (3, 4).

Human sepsis is responsible for >20,000–50,000 deaths per year in the United States (5). In the case of sepsis induced by Gram-negative bacteria, host cells sense the presence of LPS (endotoxin), which is a major cell wall component of the invading pathogen, and mount a dysregulated innate immune response resulting in pathophysiological consequences (6). Macrophages and monocytes respond to LPS by inducing the expression of cytokines, cell adhesion molecules, and low-m.w. proinflammatory molecules. The activation of monocytes/macrophages by LPS requires a serum protein known as LPS-binding protein (LBP) and a GPI-anchored cell-surface protein, CD14 (7, 8). However, until recently, little was known about how the LPS signal is transduced across the plasma membrane (9). A role for TLRs in this process was initially suggested by the observation that a constitutively active form of one human TLR (TLR4) is capable of inducing NF-B activation as well as the expression of several proinflammatory cytokines (10). Thus, it was proposed that human TLRs may regulate innate immunity and signal the activation of adapted immunity (10, 11). Nevertheless, the precise functions of these TLRs remain unclear.

We and others showed recently that the expression of human TLR2 renders LPS responsiveness to otherwise LPS-unresponsive cells (12, 13). The LPS response mediated by TLR2 requires the plasma protein LBP and is greatly enhanced by the presence of cell surface CD14 (membrane CD14 (mCD14)). Moreover, LPS treatment of TLR2-expressing cells results in the activation of NF-B and in a subsequent induction of genes that initiate adaptive immunity, such as IL-8. Therefore, TLR2 appears to be a signaling molecule for LPS (12). However, the proximal signaling events leading to the activation of NF-B by TLR2 remain to be elucidated.

Here we provide evidence that TLR2 can interact with mCD14 to form the LPS receptor complex. LPS treatment leads to receptor oligomerization and to subsequent recruitment of IL-1R-associated kinase (IRAK). In addition, our results implicate myeloid differentiation protein (MyD88), TNF receptor-associated factor 6 (TRAF6), and NF-B-inducing kinase (NIK) in the TLR2-mediated activation of NF-B. We demonstrate that C-terminal deletion variants act as dominant-negative (DN) receptors in that they can form complexes with wild-type (WT) TLR2 but fail to recruit IRAK in response to LPS.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Antisera

The entire TLR2 ECD fused with human IgG Fc was used as immunogen to raise anti-TLR2 polyclonal Ab. Anti-Flag M2 monoclonal and anti-IRAK antiserum were purchased from Eastman Kodak (New Haven, CT) and Transduction Laboratories (Lexington, KY), respectively.

FACS analysis

Human PBLs were isolated by Ficoll-diatrizoate density gradient centrifugation from normal volunteer donors. PBLs (1 x 10⁶) were suspended in PBS/2% BSA in a volume of 0.25 ml containing PE-conjugated CD14 mAb (Dako, 1:250 dilution) for 30 min on ice. A total of 1 µg of purified anti-TLR2 IgG and FITC-conjugated goat anti-rabbit secondary Ab (1/100 dilution; Caltag, Burlingame, CA) were added sequentially; each were incubated for 40 min on ice. FACS analyses were performed with a FACScan (Becton Dickinson, Mountain View, CA).

Construction of expression plasmids

The amino terminal epitope tag version of mCD14 (gD.mCD14) was constructed by adding an XhoI restriction site immediately upstream of threonine at position 21 (the first amino acid of the predicted mature form of mCD14) and linking this to amino acids 1–53 of HSV type 1 glycoprotein D (gD) as described previously (14). Mammalian expression vectors encoding DN forms of MyD88-DN 152–296(152–296), TRAF2-DN 87–501(87–501), TRAF6-DN 289–522(289–522), IRAK-DN 1–96(1–96), IRAK2-DN 1–96(1–96), receptor interacting protein (RIP)-DN 559–671(559–671), and NIK-DN (KK429–430AA) have been described elsewhere (15, 16, 17, 18, 19, 20). The Flag epitope (DYKDDDDK) was positioned at amino acid 1 of the mature form of TLR2 by oligonucleotide-directed mutagenesis.

Cell culture and transfection

Human embryonic kidney 293 cells were maintained in low glucose DMEM/HAM’s F12 (50:50) medium supplemented with 10% FBS, 2 mM glutamine, 100 µg/ml penicillin, and 100 µg/ml streptomycin. The 293 stable cell line expressing an epitope-tagged version of TLR2, as well as transfection conditions, have been described previously (12). The total amount of DNA was kept constant in all transfections by supplementing pRK5 vector DNA.

Luciferase reporter assay

Cells were transfected with the indicated expression plasmids together with 0.5 µg of the luciferase reporter plasmid pGL3-ELAM.tk and 0.05 µg of the Renilla luciferase reporter vector as an internal control (12). After 20 h, cells were treated with Escherichia coli LCD25 LPS (50 ng/ml; List Biological Labs, Campbell, CA) supplemented with LBP in serum-free medium for 6 h. Luciferase activity was measured by using reagents from Promega (Madison, WI) and was expressed as relative luciferase activity by dividing firefly luciferase activity by that of Renilla luciferase.

Immunoprecipitation and Western blot analysis

Transfected cells were incubated with LPS in the presence of LBP, washed once with PBS (pH 7.5), and lysed for 15 min on ice in 0.5 ml of lysis buffer (25 mM HEPES (pH 7.6), 150 mM NaCl, 0.1% Nonidet P-40, 5 mM EDTA, 10 µg/ml aprotinin, 10 µg/ml leupeptin, and 20% glycerol). Lysates were clarified by centrifugation at 4°C for 15 min at 100,000 x g. Cell lysates were incubated with 1 µg of anti-gD mAb and 20 µl of 50% (v/v) protein A-agarose (Pierce, Rockford, IL) overnight at 4°C with gentle rocking. After three washings with lysis buffer, precipitated complexes were solubilized by boiling in SDS sample buffer, fractionated by 10% SDS-PAGE, and transferred to polyvinylidene difluoride membranes. The membranes were blocked with PBS (pH 7.5) containing 5% nonfat dry milk and 0.05% Tween 20 and were blotted with the indicated Abs. After two washes, the blots were incubated with HRP-conjugated goat anti-mouse IgG (Jackson ImmunoResearch Laboratories, West Grove, PA) for 1 h. After washing the membranes, the reactive bands were visualized with the enhanced chemiluminescence system (Amersham, Arlington Heights, IL).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Coexpression of mCD14 and TLR2 in a subset of leukocytes

We have shown previously that TLR2 serves as a signal transducer to mediate transmembrane LPS signaling (12). In addition, mCD14, when coexpressed with TLR2, can dramatically increase LPS responsiveness in 293 cells. To examine the biological significance of this observation, we determined whether mCD14 and TLR2 are coexpressed on the cell surface of leukocytes by using FACS analysis. Freshly isolated human PBLs were incubated sequentially with a PE-conjugated anti-CD14 mAb and an unconjugated TLR2 Ab followed by FITC-conjugated goat anti-rabbit IgG secondary Ab and were subsequently analyzed by flow cytometry. mCD14 is a marker for monocytes, and we observed that nearly all mCD14⁺ cells also expressed TLR2. In addition, a population of cells was detected that expressed TLR2 but not mCD14 (Fig. 1). We have not yet characterized these cells. However, the identification of two subsets of leukocytes, either expressing TLR2 alone or coexpressing mCD14 and TLR2, is consistent with the CD14-independent and CD14-dependent signaling pathways of LPS activation observed in vivo as well as in vitro (21, 22). Alternatively, LPS-responsive cells may use soluble CD14 for signaling.

View larger version (31K): [in this window] [in a new window]   FIGURE 1. Expression of mCD14 and TLR2 on PBLs. Human PBLs were prepared and stained with anti-CD14 and TLR2 Abs as described in Materials and Methods. Data are presented as double color fluorescence histograms with a log scale of fluorescence intensity. The percentage of two subsets of PBLs is indicated; one expressed only TLR2, and the other contained both mCD14 and TLR2 on the cell surface. Experiments were performed twice with similar results.

We subsequently examined whether TLR2 and mCD14 could form a complex on the cell surface. 293 cells were transiently transfected with a version of CD14 containing the gD epitope tag alone (gD.mCD14) or with Flag-tagged versions of either TLR2 (Flag.TLR2) or, as a control, IL-1R and IL-1R accessory proteins (Flag.IL-1Rs). Lysates of these cells were immunoprecipitated with Abs specific for the gD epitope tag, and coprecipitating Flag-tagged receptors were detected on blots with an anti-Flag mAb. Under these conditions, we observed that mCD14 does indeed associate with TLR2 in the absence of LPS, and this interaction was also observed after LPS stimulation (Fig. 2A). We did not observe an association between mCD14 and IL-1Rs, suggesting specificity of the interaction between mCD14 and TLR2 (Fig. 2A).

View larger version (28K): [in this window] [in a new window]   FIGURE 2. TLR2 and mCD14 form a receptor complex, and LPS treatment induces TLR2 oligomerization and recruitment of IRAK. A, gD.mCD14, Flag.TLR2, or Flag.IL-1Rs expression plasmids were transfected in 293 cells as indicated. At 20 h posttransfection, cells were treated for 2 min with LPS (100 ng/ml) in the presence of LBP or left unstimulated. Detergent (60 mM octylglucoside plus 1% Triton X-100) lysates of each transfection were immunoprecipitated with anti-gD mAb and subsequently immunoblotted with anti-Flag M2 Ab to determine the associated proteins (top). B, 293-gD.TLR2 cells transiently expressing Flag.TLR2 were stimulated with LPS (100 ng/ml) for the indicated length of time. TLR2 complexes from cell lysates were immunoprecipitated with anti-gD Ab and immunoblotted with antiserum against Flag epitope (top) or IRAK (middle), respectively. In addition, anti-gD immunoblotting was used to verify that equal amounts of gD.mCD14 or gD.TLR2 were immunoprecipitated (bottom of A or B, respectively). Data shown are representative of two separate experiments. IP, immunoprecipitation; WB, Western blot.

The Ser/Thr kinase IRAK has been implicated in the induction of NF-B by IL-1 and by a constitutively active TLR4 (28, 29). We examined whether IRAK was recruited to the TLR2 complex. IRAK coprecipitated with TLR2 in 293 cells stimulated with LPS, and this complex reached a peak at 5 min after LPS stimulation (Fig. 2B). The kinetics of association of TLR2 with IRAK recruitment closely followed the time course of TLR2 oligomerization (Fig. 2B). These results show that TLR2 recruits IRAK, and suggest that LPS-induced TLR2 oligomerization is a critical step for TLR2 signal transduction. However, it remains possible that LPS may induce other molecular events, such as the recruitment of additional receptor subunits, which in turn create docking sites for more signaling proteins.

TLR2 C-terminal deletion variants form complexes with TLR2 and fail to recruit IRAK

We have reported previously that TLR2 variants with C-terminal deletions of either 13 or 141 aa (TLR2-1 and TLR2-2, respectively) and a variant in which the entire ECD of TLR2 is replaced with a portion of the ECD of CD4 (CD4.TLR2) are defective for the induction of an NF-B responsive endothelial leukocyte adhesion molecule reporter gene (12). We used these variants to characterize the domains of TLR2 that are necessary for TLR2 oligomerization. gD-tagged TLR2-1, TLR2-2, or CD4.TLR2 were transiently coexpressed with full-length Flag-tagged TLR2 in 293 cells. Immunoprecipitation of WT gD.TLR2, gD.TLR2-1, or gD.TLR-2 resulted in the coprecipitation of Flag-tagged TLR2 (Fig. 3). Likewise, the reciprocal immunoprecipitation of Flag.TLR2 results in the coprecipitation of WTgD.TLR2, gD.TLR2-1 or gD.TLR2-2 (data not shown). CD4.TLR2 failed to associate with WT Flag.TLR2, suggesting that the ECD is required for receptor complex formation. We subsequently determined whether the C-terminal truncation variants of TLR2 were defective in the recruitment of IRAK. The full-length TLR2 (WT) or two deletion constructs were transiently expressed in 293 cells, and receptor complexes were immunoprecipitated and immunoblotted with anti-IRAK antiserum. Whereas the WT TLR2 showed LPS-inducible IRAK recruitment, TLR2-1 or TLR2-2 failed to associate with IRAK (Fig. 4). The C-terminal region of 13 aa that is deleted in TLR2-1 is homologous to a region of the IL-1R that is required for association with IRAK. Likewise, this carboxyl-terminal tail of TLR2 appears essential for IRAK recruitment and subsequent signal transduction.

View larger version (44K): [in this window] [in a new window]   FIGURE 3. Domain requirements for receptor interactions. Flag.TLR2 was expressed together with gD.TLR2, gD.TLR2-1, gD.TLR2-2, or CD4.TLR2 by transient transfection. Immunoprecipitation and immunoblotting were performed using antisera as indicated. Experiments were performed three times with similar results.

View larger version (29K): [in this window] [in a new window]   FIGURE 4. Carboxyl-terminal tail of TLR2 is required for recruitment of IRAK upon LPS stimulation. gD-tagged full-length TLR2-WT, TLR2-1, or TLR2-2 was expressed in 293 cells by transient transfection (1 µg DNA of each construct) and immunoprecipitated with anti-gD Ab. Immunocomplexes were blotted with antiserum to IRAK or the gD epitope, respectively. Data are representative of two independent experiments.

TLR2-1 and TLR2-2 abrogate WT TLR2-induced NF-B activity in 293 cells

The ability of 1 or 2 to form heteromers with WT TLR2 (Fig. 3) coupled with their failure to recruit IRAK suggests that these variants might act as DN proteins. To test this possibility, we cotransfected 1 or 2 with WT TLR2 and examined their effects on LPS-induced NF-B activity. Whereas expression of WT TLR2 resulted in LPS responsiveness, coexpression of 1 or 2 results in a significant blocking of TLR2-mediated NF-B activity (Fig. 5). These results demonstrated that these intracellular deletion variants can serve as DN receptors and are in agreement with the observation that TLR2 is capable of forming oligomers in the overexpressing 293 cells (Fig. 3). In addition, the expression of WT TLR2, as determined by immunoblots, remained unchanged in the presence of 2 mutant (Fig. 5). The residual NF-B-dependent reporter gene activity seen during the coexpression of WT and the deletion variants of TLR2 is probably mediated by a portion of homomeric WT TLR2.

View larger version (45K): [in this window] [in a new window]   FIGURE 5. DN effect of intracellular deletion mutants (TLR2-1 or TLR2-2) on WT receptor signaling. Left, LPS-induced NF-B activation is mediated by TLR2-WT. Right, TLR2 deletion mutants (TLR2-1 or TLR2-2) function in a DN fashion when coexpressed with TLR2-WT. 293 cells were transfected with a luciferase reporter gene driven by the LPS-responsive enhancer of the IL-8 gene along with 0.1 µg of empty vector (pRK5) or TLR2 expression plasmids (left). In addition to 0.1 µg of TLR2-WT, 0.1, 0.5, or 1.0 µg of TLR2-WT, TLR2-1, or TLR2-2 expression plasmids were cotransfected in 293 cells together with the reporter plasmids. At 20 h posttransfection, cells were incubated with LPS (50 ng/ml) in the presence of LBP for 6 h and subsequently lysed for the measurement of luciferase activity. Expression of each protein was monitored by immunoprecipitation with anti-gD Ab followed by Western blotting using anti-gD Ab. Data are representative of three independent experiments. TLR2-WT and TLR2-1 migrated at the same apparent m.w.

MyD88, IRAK, TRAF6, and NIK participate in TLR2-mediated NF-B induction

Recent studies have revealed the proximal signaling events leading to IL-1-induced NF-B activation (30, 31), in which the receptor-associated adapter protein, MyD88, recruits IRAK and IRAK2 to the receptor complexes. IRAK and IRAK2 then interact with another cytoplasmic adapter protein named TRAF6, which in turn relays a signal through the NIK to I-B kinases 1 and 2, leading to NF-B activation. Similar results have been reported for the activation of NF-B by a constitutively active version of TLR4 (28, 29).

Due to the conservation of the cytoplasmic domains of TLR2 and the IL-1R family, we examined whether TLR2-mediated NF-B activation requires the signaling components that are known to be used in the IL-1 pathway. We observed that DN versions of MyD88, IRAK, TRAF6, or NIK attenuated TLR2-mediated NF-B activation (Fig. 6). Activation was not blocked by DN versions of IRAK2, TRAF2, or RIP. TRAF2 and RIP are signaling molecules involved in the activation of NF-B by TNF, whereas IRAK2 binds to IL-1R1. These results implicate MyD88, IRAK, TRAF6, and NIK in signaling the activation of NF-B by TLR2. Similarly, a recent report showed that DN versions of MyD88, IRAK, TRAF6, and NIK but not TRAF2 inhibited LPS-induced NF-B activity in human dermal microvessel endothelial and monocytic leukemia cells (32). We reproducibly observed that NIK-DN was a more potent inhibitor of TLR2 activity than IRAK-DN or TRAF6-DN. One interpretation of these results that is currently being investigated is that there are IRAK- and TRAF6-independent pathways that lead to the activation of NIK; thus, DN versions of IRAK or TRAF6 only partially block NF-B activation.

View larger version (26K): [in this window] [in a new window]   FIGURE 6. Effects of various DN signaling proteins on LPS-induced NF-B activity. Luciferase activity was determined in 293 cells transfected with the indicated amounts of expression plasmids together with the luciferase reporter plasmids for 20 h, followed by a 6-h treatment of LPS at 50 ng/ml in the presence of LBP in serum-free medium. Vector control showed the basal level of relative luciferase activity at 0.06. The results shown are representative of three duplicate experiments.

	Footnotes

 
¹ Address correspondence and reprint requests to Dr. Paul J. Godowski, Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080-4990. E-mail address:

² Abbreviations used in this paper: TLR, Toll-like receptor; MyD88, myeloid differentiation protein; IRAK, IL-1R-associated kinase; TRAF, TNF receptor-associated factor; CNTFR, ciliary neurotrophic factor receptor; WT, wild type; LBP, LPS-binding protein; ECD, extracellular domain; NIK, NF-B-inducing kinase; DN, dominant-negative; mCD14, membrane CD14; RIP, receptor-interacting protein; gD, HSV type 1 glycoprotein D.

Received for publication March 3, 1999. Accepted for publication April 27, 1999.

	References

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1. 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]
2. Morisato, D., K. V. Anderson. 1995. Signaling pathways that establish the dorsal-ventral pattern of the Drosophila embryo. Annu. Rev. Genet. 29:371.[Medline]
3. Lemaitre, B., J. M. Reichhart, J. A. Hoffmann. 1997. Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proc. Natl. Acad. Sci. USA 94:14614.[Abstract/Free Full Text]
4. Lemaitre, B., E. Nicolas, L. Michaut, J. M. Reichhart, J. A. Hoffmann. 1996. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973.[Medline]
5. Bone, R. C.. 1991. Gram-negative sepsis. Chest 100:802.[Abstract/Free Full Text]
6. Rietschel, E. T., H. Brade. 1992. Bacterial endotoxins. Sci. Am. 267:54.[Medline]
7. Wright, S. D., R. A. Ramos, P. S. Tobias, R. J. Ulevitch, J. C. Mathison. 1990. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249:1431.[Abstract/Free Full Text]
8. Schumann, R. R., S. R. Leong, G. W. Flaggs, P. W. Gray, S. D. Wright, J. C. Mathison, P. S. Tobias, R. J. Ulevitch. 1990. Structure and function of lipopolysaccharide binding protein. Science 249:1429.[Abstract/Free Full Text]
9. Ulevitch, R. J., P. S. Tobias. 1995. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol. 13:437.[Medline]
10. 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]
11. Medzhitov, R., Jr C. A. Janeway. 1998. Self-defense: the fruit fly style. Proc. Natl. Acad. Sci. USA 95:429.[Free Full Text]
12. 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]
13. Kirschning, C. J., H. Wesche, T. M. Ayres, M. Rothe. 1998. Human Toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J. Exp. Med. 188:2091.[Abstract/Free Full Text]
14. Mark, M. R., D. T. Scadden, Z. Wang, Q. Gu, A. Goddard, P. J. Godowski. 1994. rse, a novel receptor-type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain. J. Biol. Chem. 269:10720.[Abstract/Free Full Text]
15. Malinin, N. L., M. P. Boldin, A. V. Kovalenko, D. Wallach. 1997. MAP3K-related kinase involved in NF-B induction by TNF, CD95, and IL-1. Nature 385:540.[Medline]
16. Wesche, H., W. I. Henzel, W. Shillinglaw, S. Li, Z. Cao. 1997. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7:837.[Medline]
17. Rothe, M., V. Sarma, V. M. Dixit, D. V. Goeddel. 1995. TRAF2-mediated activation of NF-B by TNF receptor 2 and CD40. Science 269:1424.[Abstract/Free Full Text]
18. Cao, Z., J. Xiong, M. Takeuchi, T. Kurama, D. V. Goeddel. 1996. TRAF6 is a signal transducer for interleukin-1. Nature 383:443.[Medline]
19. Ting, A. T., F. X. Pimentel-Muinos, B. Seed. 1996. RIP mediates tumor necrosis factor receptor 1 activation of NF-B but not Fas/APO-1-initiated apoptosis. EMBO J. 15:6189.[Medline]
20. 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]
21. Haziot, A., E. Ferrero, F. Kontgen, N. Hijiya, S. Yamamoto, J. Silver, C. L. Stewart, S. M. Goyert. 1996. Resistance to endotoxin shock and reduced dissemination of Gram-negative bacteria in CD14-deficient mice. Immunity 4:407.[Medline]
22. Fenton, M. J., D. T. Golenbock. 1998. LPS-binding proteins and receptors. J. Leukocyte Biol. 64:25.[Abstract]
23. Lemmon, M. A., J. Schlessinger. 1994. Regulation of signal transduction and signal diversity by receptor oligomerization. Trends Biochem. Sci. 19:459.[Medline]
24. Murakami, M., M. Hibi, N. Nakagawa, T. Nakagawa, K. Yasukawa, K. Yamanishi, T. Taga, T. Kishimoto. 1993. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science 260:1808.[Abstract/Free Full Text]
25. Davis, S., T. H. Aldrich, N. Stahl, L. Pan, T. Taga, T. Kishimoto, N. Y. Ip, G. D. Yancopoulos. 1993. LIFRß and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science 260:1805.[Abstract/Free Full Text]
26. Klein, R. D., D. Sherman, W. H. Ho, D. Stone, G. L. Bennett, B. Moffat, R. Vandlen, L. Simmons, Q. Gu, J. A. Hongo, et al 1997. A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature 387:717.[Medline]
27. Buj-Bello, A., J. Adu, L. G. Pinon, A. Horton, J. Thompson, A. Rosenthal, M. Chinchetru, V. L. Buchman, A. M. Davies. 1997. Neurturin responsiveness requires a GPI-linked receptor and the Ret receptor tyrosine kinase. Nature 387:721.[Medline]
28. Medzhitov, R., P. Preston-Hurlburt, E. Kopp, A. Stadlen, C. Chen, S. Ghosh, Jr C. A. Janeway. 1998. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2:253.[Medline]
29. Muzio, M., G. Natoli, S. Saccani, M. Levrero, A. Mantovani. 1998. The human Toll signaling pathway: divergence of nuclear factor B and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J. Exp. Med. 187:2097.[Abstract/Free Full Text]
30. 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]
31. Burns, K., F. Martinon, C. Essling, H. Pahl, P. Schneider, J.-L. Bodmer, F. D. Marco, L. French, J. Tschopp. 1998. MyD88, an adaptor protein involved in interleukin-1 signaling. J. Biol. Chem. 273:12203.[Abstract/Free Full Text]
32. Zhang, F. X., C. J. Kirschning, R. Mancinelli, X.-P. Xu, Y. Jin, E. Faure, A. Mantovani, M. Rothe, M. Muzio, M. Arditi. 1999. Bacterial lipopolysaccharide activates nuclear factor-B through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J. Biol. Chem. 274:7611.[Abstract/Free Full Text]
33. Poltorak, A., I. Smirnova, X. He, M.-Y. Liu, C. Van Huffel, D. Birdwell, E. Alejos, M. Silva, X. Du, P. Thompson, et al 1998. Genetic and physical mapping of the Lps locus: identification of the Toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol. Dis. 24:340.[Medline]
34. Poltorak, A., X. He, I. Smirnova, M.-Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, et al 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085.[Abstract/Free Full Text]
35. Qureshi, S. T., L. Lariviere, G. Leveque, S. Clermont, K. J. Moore, P. Gros, D. Malo. 1999. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J. Exp. Med. 189:615.[Abstract/Free Full Text]

This article has been cited by other articles:

				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]

				M. Inada, C. Matsumoto, S. Uematsu, S. Akira, and C. Miyaura Membrane-Bound Prostaglandin E Synthase-1-Mediated Prostaglandin E2 Production by Osteoblast Plays a Critical Role in Lipopolysaccharide-Induced Bone Loss Associated with Inflammation J. Immunol., August 1, 2006; 177(3): 1879 - 1885. [Abstract] [Full Text] [PDF]

				T. A. Richardson, M. Sherman, L. Antonovic, S. S. Kardar, H. W. Strobel, D. Kalman, and E. T. Morgan HEPATIC AND RENAL CYTOCHROME P450 GENE REGULATION DURING CITROBACTER RODENTIUM INFECTION IN WILD-TYPE AND TOLL-LIKE RECEPTOR 4 MUTANT MICE Drug Metab. Dispos., March 1, 2006; 34(3): 354 - 360. [Abstract] [Full Text] [PDF]

				R. W. DePaolo, R. Lathan, B. J. Rollins, and W. J. Karpus The Chemokine CCL2 Is Required for Control of Murine Gastric Salmonella enterica Infection Infect. Immun., October 1, 2005; 73(10): 6514 - 6522. [Abstract] [Full Text] [PDF]

				D.R. Dixon and R.P. Darveau Lipopolysaccharide Heterogeneity: Innate Host Responses to Bacterial Modification of Lipid A Structure Journal of Dental Research, July 1, 2005; 84(7): 584 - 595. [Abstract] [Full Text] [PDF]

				P. Tobias and L. K. Curtiss Thematic review series: The Immune System and Atherogenesis. Paying the price for pathogen protection: toll receptors in atherogenesis J. Lipid Res., March 1, 2005; 46(3): 404 - 411. [Abstract] [Full Text] [PDF]

				N. J. Mason, J. Fiore, T. Kobayashi, K. S. Masek, Y. Choi, and C. A. Hunter TRAF6-Dependent Mitogen-Activated Protein Kinase Activation Differentially Regulates the Production of Interleukin-12 by Macrophages in Response to Toxoplasma gondii Infect. Immun., October 1, 2004; 72(10): 5662 - 5667. [Abstract] [Full Text] [PDF]

				F. Urlichs and C. P. Speer Neutrophil Function in Preterm and Term Infants NeoReviews, October 1, 2004; 5(10): e417 - e430. [Full Text] [PDF]

				M. Triantafilou, M. Manukyan, A. Mackie, S. Morath, T. Hartung, H. Heine, and K. Triantafilou Lipoteichoic Acid and Toll-like Receptor 2 Internalization and Targeting to the Golgi Are Lipid Raft-dependent J. Biol. Chem., September 24, 2004; 279(39): 40882 - 40889. [Abstract] [Full Text] [PDF]

				E. LeBouder, J. E. Rey-Nores, N. K. Rushmere, M. Grigorov, S. D. Lawn, M. Affolter, G. E. Griffin, P. Ferrara, E. J. Schiffrin, B. P. Morgan, et al. Soluble Forms of Toll-Like Receptor (TLR)2 Capable of Modulating TLR2 Signaling Are Present in Human Plasma and Breast Milk J. Immunol., December 15, 2003; 171(12): 6680 - 6689. [Abstract] [Full Text] [PDF]

				C. J. Hertz, Q. Wu, E. M. Porter, Y. J. Zhang, K.-H. Weismuller, P. J. Godowski, T. Ganz, S. H. Randell, and R. L. Modlin Activation of Toll-Like Receptor 2 on Human Tracheobronchial Epithelial Cells Induces the Antimicrobial Peptide Human {beta} Defensin-2 J. Immunol., December 15, 2003; 171(12): 6820 - 6826. [Abstract] [Full Text] [PDF]

				R. Haase, C. J. Kirschning, A. Sing, P. Schrottner, K. Fukase, S. Kusumoto, H. Wagner, J. Heesemann, and K. Ruckdeschel A Dominant Role of Toll-Like Receptor 4 in the Signaling of Apoptosis in Bacteria-Faced Macrophages J. Immunol., October 15, 2003; 171(8): 4294 - 4303. [Abstract] [Full Text] [PDF]

				R. Avitsur, D. A. Padgett, F. S. Dhabhar, J. L. Stark, K. A. Kramer, H. Engler, and J. F. Sheridan Expression of glucocorticoid resistance following social stress requires a second signal J. Leukoc. Biol., October 1, 2003; 74(4): 507 - 513. [Abstract] [Full Text] [PDF]

				L. J. Crossley Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1 J. Leukoc. Biol., October 1, 2003; 74(4): 583 - 592. [Abstract] [Full Text] [PDF]

				C. L. Holmes, J. A. Russell, and K. R. Walley Genetic Polymorphisms in Sepsis and Septic Shock: Role in Prognosis and Potential for Therapy Chest, September 1, 2003; 124(3): 1103 - 1115. [Abstract] [Full Text] [PDF]

				E. S. Van Amersfoort, T. J. C. Van Berkel, and J. Kuiper Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock Clin. Microbiol. Rev., July 1, 2003; 16(3): 379 - 414. [Abstract] [Full Text] [PDF]

				C. S. M. Oude Nijhuis, E. Vellenga, S. M. G. J. Daenen, W. A. Kamps, and E. S. J. M. de Bont Endothelial Cells Are Main Producers of Interleukin 8 through Toll-Like Receptor 2 and 4 Signaling during Bacterial Infection in Leukopenic Cancer Patients Clin. Vaccine Immunol., July 1, 2003; 10(4): 558 - 563. [Abstract] [Full Text] [PDF]

				P. A. Sieling, W. Chung, B. T. Duong, P. J. Godowski, and R. L. Modlin Toll-Like Receptor 2 Ligands as Adjuvants for Human Th1 Responses J. Immunol., January 1, 2003; 170(1): 194 - 200. [Abstract] [Full Text] [PDF]

				D. Caccavo, N. M. Pellegrino, M. Altamura, A. Rigon, L. Amati, A. Amoroso, and E. Jirillo Review: Antimicrobial and immunoregulatory functions of lactoferrin and its potential therapeutic application Innate Immunity, December 1, 2002; 8(6): 403 - 417. [Abstract] [PDF]

				E. E. Putnins, A.-R. Sanaie, Q. Wu, and J. D. Firth Induction of Keratinocyte Growth Factor 1 Expression by Lipopolysaccharide Is Regulated by CD-14 and Toll-Like Receptors 2 and 4 Infect. Immun., December 1, 2002; 70(12): 6541 - 6548. [Abstract] [Full Text] [PDF]

				K. Gee, W. Lim, W. Ma, D. Nandan, F. Diaz-Mitoma, M. Kozlowski, and A. Kumar Differential Regulation of CD44 Expression by Lipopolysaccharide (LPS) and TNF-{alpha} in Human Monocytic Cells: Distinct Involvement of c-Jun N-Terminal Kinase in LPS-Induced CD44 Expression J. Immunol., November 15, 2002; 169(10): 5660 - 5672. [Abstract] [Full Text] [PDF]

				P. Henneke, O. Takeuchi, R. Malley, E. Lien, R. R. Ingalls, M. W. Freeman, T. Mayadas, V. Nizet, S. Akira, D. L. Kasper, et al. Cellular Activation, Phagocytosis, and Bactericidal Activity Against Group B Streptococcus Involve Parallel Myeloid Differentiation Factor 88-Dependent and Independent Signaling Pathways J. Immunol., October 1, 2002; 169(7): 3970 - 3977. [Abstract] [Full Text] [PDF]

				E. A. Kurt-Jones, L. Mandell, C. Whitney, A. Padgett, K. Gosselin, P. E. Newburger, and R. W. Finberg Role of Toll-like receptor 2 (TLR2) in neutrophil activation: GM-CSF enhances TLR2 expression and TLR2-mediated interleukin 8 responses in neutrophils Blood, August 13, 2002; 100(5): 1860 - 1868. [Abstract] [Full Text] [PDF]

				J. Kim, M.-T. Ochoa, S. R. Krutzik, O. Takeuchi, S. Uematsu, A. J. Legaspi, H. D. Brightbill, D. Holland, W. J. Cunliffe, S. Akira, et al. Activation of Toll-Like Receptor 2 in Acne Triggers Inflammatory Cytokine Responses J. Immunol., August 1, 2002; 169(3): 1535 - 1541. [Abstract] [Full Text] [PDF]

				S. B. Mizel and J. A. Snipes Gram-negative Flagellin-induced Self-tolerance Is Associated with a Block in Interleukin-1 Receptor-associated Kinase Release from Toll-like Receptor 5 J. Biol. Chem., June 14, 2002; 277(25): 22414 - 22420. [Abstract] [Full Text] [PDF]

				K. Ruckdeschel, O. Mannel, and P. Schrottner Divergence of Apoptosis-Inducing and Preventing Signals in Bacteria-Faced Macrophages Through Myeloid Differentiation Factor 88 and IL-1 Receptor-Associated Kinase Members J. Immunol., May 1, 2002; 168(9): 4601 - 4611. [Abstract] [Full Text] [PDF]

				B. G. Yipp, G. Andonegui, C. J. Howlett, S. M. Robbins, T. Hartung, M. Ho, and P. Kubes Profound Differences in Leukocyte-Endothelial Cell Responses to Lipopolysaccharide Versus Lipoteichoic Acid J. Immunol., May 1, 2002; 168(9): 4650 - 4658. [Abstract] [Full Text] [PDF]

				J. Hu, R. Jacinto, C. McCall, and L. Li Regulation of IL-1 Receptor-Associated Kinases by Lipopolysaccharide J. Immunol., April 15, 2002; 168(8): 3910 - 3914. [Abstract] [Full Text] [PDF]

				T. Vasselon, W. A Hanlon, S. D Wright, and P. A. Detmers Toll-like receptor 2 (TLR2) mediates activation of stress-activated MAP kinase p38 J. Leukoc. Biol., March 1, 2002; 71(3): 503 - 510. [Abstract] [Full Text] [PDF]

				P.-L. Wang and K. Ohura PORPHYROMONAS GINGIVALIS LIPOPOLYSACCHARIDE SIGNALING IN GINGIVAL FIBROBLASTS-CD14 AND TOLL-LIKE RECEPTORS Critical Reviews in Oral Biology & Medicine, March 1, 2002; 13(2): 132 - 142. [Abstract] [Full Text] [PDF]

				L. D. Hawkins, S. T. Ishizaka, P. McGuinness, H. Zhang, W. Gavin, B. DeCosta, Z. Meng, H. Yang, M. Mullarkey, D. W. Young, et al. A Novel Class of Endotoxin Receptor Agonists with Simplified Structure, Toll-Like Receptor 4-Dependent Immunostimulatory Action, and Adjuvant Activity J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 655 - 661. [Abstract] [Full Text] [PDF]

				J. Ismaili, J. Rennesson, E. Aksoy, J. Vekemans, B. Vincart, Z. Amraoui, F. Van Laethem, M. Goldman, and P. M. Dubois Monophosphoryl Lipid A Activates Both Human Dendritic Cells and T Cells J. Immunol., January 15, 2002; 168(2): 926 - 932. [Abstract] [Full Text] [PDF]

				J. Kollet, C. Witek, J. D. Gentry, X. Liu, S. D. Schwartzbach, and T. M. Petro Deletional Analysis of the Murine IL-12 p35 Promoter Comparing IFN-{gamma} and Lipopolysaccharide Stimulation J. Immunol., November 15, 2001; 167(10): 5653 - 5663. [Abstract] [Full Text] [PDF]

				N. Silverman and T. Maniatis NF-{kappa}B signaling pathways in mammalian and insect innate immunity Genes & Dev., September 15, 2001; 15(18): 2321 - 2342. [Full Text] [PDF]

				P. S. Gilmour, I. Rahman, S. Hayashi, J. C. Hogg, K. Donaldson, and W. MacNee Adenoviral E1A primes alveolar epithelial cells to PM10-induced transcription of interleukin-8 Am J Physiol Lung Cell Mol Physiol, September 1, 2001; 281(3): L598 - L606. [Abstract] [Full Text] [PDF]

				Y. Bulut, E. Faure, L. Thomas, O. Equils, and M. Arditi Cooperation of Toll-Like Receptor 2 and 6 for Cellular Activation by Soluble Tuberculosis Factor and Borrelia burgdorferi Outer Surface Protein A Lipoprotein: Role of Toll-Interacting Protein and IL-1 Receptor Signaling Molecules in Toll-Like Receptor 2 Signaling J. Immunol., July 15, 2001; 167(2): 987 - 994. [Abstract] [Full Text] [PDF]

				M. A. Moors, L. Li, and S. B. Mizel Activation of Interleukin-1 Receptor-Associated Kinase by Gram-Negative Flagellin Infect. Immun., July 1, 2001; 69(7): 4424 - 4429. [Abstract] [Full Text] [PDF]

				L. Rabehi, T. Irinopoulou, B. Cholley, N. Haeffner-Cavaillon, and M.-P. Carreno Gram-Positive and Gram-Negative Bacteria Do Not Trigger Monocytic Cytokine Production through Similar Intracellular Pathways Infect. Immun., July 1, 2001; 69(7): 4590 - 4599. [Abstract] [Full Text] [PDF]

				Y. Liu, Y. Wang, M. Yamakuchi, S. Isowaki, E. Nagata, Y. Kanmura, I. Kitajima, and I. Maruyama Upregulation of Toll-Like Receptor 2 Gene Expression in Macrophage Response to Peptidoglycan and High Concentration of Lipopolysaccharide Is Involved in NF-{kappa}B Activation Infect. Immun., May 1, 2001; 69(5): 2788 - 2796. [Abstract] [Full Text] [PDF]

				S. C. Dreskin, G. W. Thomas, S. N. Dale, and L. E. Heasley Isoforms of Jun Kinase Are Differentially Expressed and Activated in Human Monocyte/Macrophage (THP-1) Cells J. Immunol., May 1, 2001; 166(9): 5646 - 5653. [Abstract] [Full Text] [PDF]

				M. D. Lehner, S. Morath, K. S. Michelsen, R. R. Schumann, and T. Hartung Induction of Cross-Tolerance by Lipopolysaccharide and Highly Purified Lipoteichoic Acid Via Different Toll-Like Receptors Independent of Paracrine Mediators J. Immunol., April 15, 2001; 166(8): 5161 - 5167. [Abstract] [Full Text] [PDF]

				Q. Wang, R. Dziarski, C. J. Kirschning, M. Muzio, and D. Gupta Micrococci and Peptidoglycan Activate TLR2{right-arrow}MyD88{right-arrow}IRAK{right-arrow}TRAF{right-arrow}NIK{right-arrow}IKK{right-arrow}NF-{kappa}B Signal Transduction Pathway That Induces Transcription of Interleukin-8 Infect. Immun., April 1, 2001; 69(4): 2270 - 2276. [Abstract] [Full Text] [PDF]

				J. M. Kyriakis and J. Avruch Mammalian Mitogen-Activated Protein Kinase Signal Transduction Pathways Activated by Stress and Inflammation Physiol Rev, April 1, 2001; 81(2): 807 - 869. [Abstract] [Full Text] [PDF]

				T. Kikuchi, T. Matsuguchi, N. Tsuboi, A. Mitani, S. Tanaka, M. Matsuoka, G. Yamamoto, T. Hishikawa, T. Noguchi, and Y. Yoshikai Gene Expression of Osteoclast Differentiation Factor Is Induced by Lipopolysaccharide in Mouse Osteoblasts Via Toll-Like Receptors J. Immunol., March 1, 2001; 166(5): 3574 - 3579. [Abstract] [Full Text] [PDF]

				C. J. Hertz, S. M. Kiertscher, P. J. Godowski, D. A. Bouis, M. V. Norgard, M. D. Roth, and R. L. Modlin Microbial Lipopeptides Stimulate Dendritic Cell Maturation Via Toll-Like Receptor 2 J. Immunol., February 15, 2001; 166(4): 2444 - 2450. [Abstract] [Full Text] [PDF]

				J.A. Boch, N. Wara-aswapati, and P.E. Auron CONCISE REVIEW Biological: Interleukin 1 Signal Transduction-- Current Concepts and Relevance to Periodontitis Journal of Dental Research, February 1, 2001; 80(2): 400 - 407. [Abstract] [PDF]

				P.-Y. Perera, T. N. Mayadas, O. Takeuchi, S. Akira, M. Zaks-Zilberman, S. M. Goyert, and S. N. Vogel CD11b/CD18 Acts in Concert with CD14 and Toll-Like Receptor (TLR) 4 to Elicit Full Lipopolysaccharide and Taxol-Inducible Gene Expression J. Immunol., January 1, 2001; 166(1): 574 - 581. [Abstract] [Full Text] [PDF]

				D. H. Wyllie, E. Kiss-Toth, A. Visintin, S. C. Smith, S. Boussouf, D. M. Segal, G. W. Duff, and S. K. Dower Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses J. Immunol., December 15, 2000; 165(12): 7125 - 7132. [Abstract] [Full Text] [PDF]

				Hua Yang, J. M. Daun, J. R. Rose, W. J. Christ, F. Gusovsky, and J. C. Chow Examination of chlorpromazine and other amphipathic drugs on the activity of lipopolysaccharide antagonists, E5564 and E5531 Innate Immunity, December 1, 2000; 6(6): 447 - 452. [Abstract] [PDF]

				E. Cario and D. K. Podolsky Differential Alteration in Intestinal Epithelial Cell Expression of Toll-Like Receptor 3 (TLR3) and TLR4 in Inflammatory Bowel Disease Infect. Immun., December 1, 2000; 68(12): 7010 - 7017. [Abstract] [Full Text] [PDF]

				R. I. Tapping, S. Akashi, K. Miyake, P. J. Godowski, and P. S. Tobias Toll-Like Receptor 4, But Not Toll-Like Receptor 2, Is a Signaling Receptor for Escherichia and Salmonella Lipopolysaccharides J. Immunol., November 15, 2000; 165(10): 5780 - 5787. [Abstract] [Full Text] [PDF]

				M. M. Monick, A. B. Carter, D. M. Flaherty, M. W. Peterson, and G. W. Hunninghake Protein Kinase C {zeta} Plays a Central Role in Activation of the p42/44 Mitogen-Activated Protein Kinase by Endotoxin in Alveolar Macrophages J. Immunol., October 15, 2000; 165(8): 4632 - 4639. [Abstract] [Full Text] [PDF]

				S. Thoma-Uszynski, S. M. Kiertscher, M. T. Ochoa, D. A. Bouis, M. V. Norgard, K. Miyake, P. J. Godowski, M. D. Roth, and R. L. Modlin Activation of Toll-Like Receptor 2 on Human Dendritic Cells Triggers Induction of IL-12, But Not IL-10 J. Immunol., October 1, 2000; 165(7): 3804 - 3810. [Abstract] [Full Text] [PDF]

				K. M. Ardeshna, A. R. Pizzey, S. Devereux, and A. Khwaja The PI3 kinase, p38 SAP kinase, and NF-kappa B signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells Blood, August 1, 2000; 96(3): 1039 - 1046. [Abstract] [Full Text] [PDF]

				M. Hirschfeld, Y. Ma, J. H. Weis, S. N. Vogel, and J. J. Weis Cutting Edge: Repurification of Lipopolysaccharide Eliminates Signaling Through Both Human and Murine Toll-Like Receptor 2 J. Immunol., July 15, 2000; 165(2): 618 - 622. [Abstract] [Full Text] [PDF]

				K. Tabeta, K. Yamazaki, S. Akashi, K. Miyake, H. Kumada, T. Umemoto, and H. Yoshie Toll-Like Receptors Confer Responsiveness to Lipopolysaccharide from Porphyromonas gingivalis in Human Gingival Fibroblasts Infect. Immun., June 1, 2000; 68(6): 3731 - 3735. [Abstract] [Full Text] [PDF]

				L. Caradonna, L. Amati, T. Magrone, N.M. Pellegrino, E. Jirillo, and D. Caccavo Invited review: Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance Innate Immunity, June 1, 2000; 6(3): 205 - 214. [Abstract] [PDF]

				A. E. Medvedev, K. M. Kopydlowski, and S. N. Vogel Inhibition of Lipopolysaccharide-Induced Signal Transduction in Endotoxin-Tolerized Mouse Macrophages: Dysregulation of Cytokine, Chemokine, and Toll-Like Receptor 2 and 4 Gene Expression J. Immunol., June 1, 2000; 164(11): 5564 - 5574. [Abstract] [Full Text] [PDF]

				G. Scholz, K. Cartledge, and A. R. Dunn Hck Enhances the Adherence of Lipopolysaccharide-stimulated Macrophages via Cbl and Phosphatidylinositol 3-Kinase J. Biol. Chem., May 5, 2000; 275(19): 14615 - 14623. [Abstract] [Full Text] [PDF]

				J. A. Thomas, R. L. Modlin, H. D. Brightbill, and P. J. Godowski Toll Genes and Responsiveness to Bacterial Endotoxins N. Engl. J. Med., March 2, 2000; 342(9): 664 - 665. [Full Text]

				T. K. Means, E. Lien, A. Yoshimura, S. Wang, D. T. Golenbock, and M. J. Fenton The CD14 Ligands Lipoarabinomannan and Lipopolysaccharide Differ in Their Requirement for Toll-Like Receptors J. Immunol., December 15, 1999; 163(12): 6748 - 6755. [Abstract] [Full Text] [PDF]

				M. N. Becker, G. Diamond, M. W. Verghese, and S. H. Randell CD14-dependent Lipopolysaccharide-induced beta -Defensin-2 Expression in Human Tracheobronchial Epithelium J. Biol. Chem., September 15, 2000; 275(38): 29731 - 29736. [Abstract] [Full Text] [PDF]

				S. H. Rhee and D. Hwang Murine TOLL-like Receptor 4 Confers Lipopolysaccharide Responsiveness as Determined by Activation of NFkappa B and Expression of the Inducible Cyclooxygenase J. Biol. Chem., October 27, 2000; 275(44): 34035 - 34040. [Abstract] [Full Text] [PDF]

				S. Frantz, R. A. Kelly, and T. Bourcier Role of TLR-2 in the Activation of Nuclear Factor kappa B by Oxidative Stress in Cardiac Myocytes J. Biol. Chem., February 9, 2001; 276(7): 5197 - 5203. [Abstract] [Full Text] [PDF]

				A. S. Kristof, J. Marks-Konczalik, and J. Moss Mitogen-activated Protein Kinases Mediate Activator Protein-1-dependent Human Inducible Nitric-oxide Synthase Promoter Activation J. Biol. Chem., March 9, 2001; 276(11): 8445 - 8452. [Abstract] [Full Text] [PDF]

				W. Ma, W. Lim, K. Gee, S. Aucoin, D. Nandan, M. Kozlowski, F. Diaz-Mitoma, and A. Kumar The p38 Mitogen-activated Kinase Pathway Regulates the Human Interleukin-10 Promoter via the Activation of Sp1 Transcription Factor in Lipopolysaccharide-stimulated Human Macrophages J. Biol. Chem., April 20, 2001; 276(17): 13664 - 13674. [Abstract] [Full Text] [PDF]

				S. Tauszig, E. Jouanguy, J. A. Hoffmann, and J.-L. Imler From the Cover: Toll-related receptors and the control of antimicrobial peptide expression in Drosophila PNAS, September 12, 2000; 97(19): 10520 - 10525. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, R.-B. Articles by Godowski, P. J. Search for Related Content PubMed PubMed Citation Articles by Yang, R.-B. Articles by Godowski, P. J.