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J Biol Chem, Vol. 273, Issue 20, 12203-12209, May 15, 1998
From the MyD88 has a modular organization, an N-terminal
death domain (DD) related to the cytoplasmic signaling domains found in
many members of the tumor necrosis factor receptor (TNF-R) superfamily, and a C-terminal Toll domain similar to that found in the expanding family of Toll/interleukin-1-like receptors (IL-1R). This dual domain
structure, together with the following observations, supports a role
for MyD88 as an adapter in IL-1 signal transduction; MyD88 forms
homodimers in vivo through DD-DD and Toll-Toll
interactions. Overexpression of MyD88 induces activation of the c-Jun
N-terminal kinase (JNK) and the transcription factor NF- The myeloid differentiation protein (MyD88) has no known
biological function (1). Sequence analysis, however, suggests that it
may have signaling capabilities; MyD88 is predicted to have a modular
organization consisting of an N-terminal death domain
(DD)1 separated by a short
linker from a C-terminal Toll domain (2-7).
The N-terminal DD is related to a motif of approximately 90 amino acids
that was initially defined as the region of similarity between the
cytoplasmic tails of the FAS/Apo1/CD95 and TNF receptors required for
their induction of cytotoxic signaling (8, 9). The DD, which has in
recent years been found in many additional proteins, is now known to
mediate protein-protein interactions with other DD sequences forming
either homo- or heterodimers (10). This property is utilized by many
members of the TNF superfamily (i.e. FAS, TNF-R1,
DR3/Apo3/WSL-1/TRAMP, and TRAIL-Rs 1 and 2), in response to ligand
activation, to establish interactions that form the foundation for
building signaling complexes that can induce responses such as
cytotoxicity, activation of the c-Jun N-terminal kinase
(JNK)/stress-activated protein kinases, and/or activation of the
transcription factor nuclear factor MyD88's C-terminal Toll domain is comprised of approximately 130 amino
acids (5). This domain was originally described based on the homology
between the cytoplasmic signaling regions of the Drosophila
melanogaster transmembrane protein Toll and the IL-1RI, but is now
found in an expanding family of proteins, most of which are cell
surface receptors (5, 12-14). MyD88 is the only reported mammalian
protein with a Toll domain that is not predicted to be a transmembrane.
The Toll domain lacks an intrinsic signaling capacity and thereby
transduces signals by recruiting associated proteins. It is not known
whether Toll domains function in an analogous manner to DDs by
mediating Toll-Toll interactions. However, the discovery that the
Toll-containing IL-1 receptor accessory protein (IL-1RAcP) acts as a
co-receptor for IL-1RI and is an indispensable molecule in the IL-1RI
signal transduction complex suggests that interactions between like
domains may have a role in the formation of signaling complexes
(15-17).
In recent years some of the proteins involved in the proximal signaling
events associated with IL-1RI-induced activation of NF- Cell Culture--
The 293T human embryonic kidney cell line or
293 cells (ATCC CRL 1573) were cultured in Dulbecco's modified
Eagle's medium supplemented with 10% fetal calf serum and
penicillin/streptomycin (100 µg/ml of each) and grown in 5%
CO2 at 37 °C.
Northern Blot Analysis--
Isolation of total RNA from various
mouse tissues was carried out as described elsewhere (23, 24). A MyD88
antisense RNA probe was synthesized by in vitro
transcription in the presence of 12.5 µM
Expression Vectors--
Mouse MyD88 was first identified as a
transcript encoding a protein of 243 residues (1). However, since then
several lines of evidence suggest that the transcript for MyD88 is 53 amino acids longer (predicted molecular mass of ~33 kDa) and starts at Met minus 53 (4, 25, 26). To obtain full-length mMyD88 cDNA,
total RNA isolated from murine bone marrow was reverse transcribed using a cDNA cycle kit from Promega, amplified by PCR (JT478 5'-gtt ctc cat acc ctt ggt-3' and JT318 5'-cgc atc agt ctc atc ttc-3') and
subcloned into PCRII TA-cloning vector (InvitroGen). A modified pCRIII
(InvitroGen) mammalian expression vector was constructed by cloning a
Kozak consensus sequence (GCCACC) and the Flag epitope (MDYKDDDK)
between the BamHI and EcoRI sites of PCR-III to
yield pMet-Flag-V63. MyD88 was subcloned as an EcoRI
fragment into pMet-Flag-V63 to give pFlag-MyD88 or into pMet-Myc (27)
to give pMyc-MyD88. MyD88-F56N (referred to as MyD88-lpr) and MyD88
lacking the DD (MyD88-
MyD88, an Adapter Protein Involved in Interleukin-1
Signaling*
§,,
,,,, and§§
Institute of Biochemistry,
¶ Ludwig Institute of Cancer Research, Lausanne Branch,
University of Lausanne, Switzerland, ** Swiss Institute for Experimental
Cancer Research (ISREC), Chemin des Boveresses 155, CH-1066 Epalinges,
Switzerland, Center of Tumor Biology, Breisacher Strasse 117, 79106 Freiburg, Germany, and Department of
Dermatology, University of Geneva Medical School, CH-1211
Geneva 4, Switzerland
ABSTRACT
Top
Abstract
Introduction
Procedures
Results
Discussion
References
B through
its DD. A point mutation in MyD88, MyD88-lpr (F56N), which prevents
dimerization of the DD, also blocks induction of these activities.
MyD88-induced NF-B activation is inhibited by the dominant negative
versions of TRAF6 and IRAK, which also inhibit IL-1-induced NF-B
activation. Overexpression of MyD88-lpr or MyD88-Toll (expressing only
the Toll domain) acted to inhibit IL-1-induced NF-B and JNK
activation in a 293 cell line overexpressing the IL-1RI. MyD88
coimmunoprecipitates with the IL-1R signaling complex in an
IL-1-dependent manner.
INTRODUCTION
Top
Abstract
Introduction
Procedures
Results
Discussion
References
B (NF-B) (11).
B have been
identified. This has revealed the striking similarity between the
IL-1RI and Drosophila Toll signaling pathways. Toll induces
Dorsal activation (a homolog of NF-B) which like NF-B is normally
held in an inactive state in the cytoplasm by the IB-like inhibitory
protein, Cactus. Following stimulation, these inhibitory proteins
become phosphorylated, ubiquinated, and degraded via
proteasome-mediated pathways, which frees NF-B/Dorsal to translocate
into the nucleus and begin transcription. The Drosophila Ser/Thr kinase Pelle is believed to be involved in the phosphorylation of Cactus (18). In the IL-1 pathway, a Ser/Thr kinase that is rapidly
recruited to the IL-1RI complex, within seconds of IL-1 binding, has
recently been identified (19). This kinase, the IL-1 receptor
associated kinase (IRAK), is highly homologous to Pelle but not to
other mammalian Ser/Thr kinases. Interestingly, both Pelle and IRAK
have N-terminal DDs (19). In the Toll pathway a second protein exists
with a DD, Tube, which regulates the activity of Pelle through DD-DD
interactions (20-22). Additional DD-containing adapter molecules may,
therefore, also exist in the IL-1 pathway. With its dual domain
organization MyD88 has ideal properties to function as an adapter
linking Toll and death modules. Here, we examine this intriguing
possibility by analyzing the functional role(s) of the MyD88
domains.
EXPERIMENTAL PROCEDURES
Top
Abstract
Introduction
Procedures
Results
Discussion
References
-[32P]UTP (400 Ci/mmol; Amersham International,
Amersham, UK). Following extensive washing of the Northern blot, the
membrane was exposed to x-ray films (XAR; Eastman Kodak Co.) for 4 days.
DD) were generated by PCR using the following
primers: MyD88-lpr, JT317 5'-gga gat ggg caa cga gta ct-3' and JT318;
MyD88-DD, JT386 5'-cga gga gga ctg cca gaa-3' and JT318 and then
cloned as EcoRI fragments into pMet-Flag-V63. MyD88 encoding
the Toll domain (amino acids 161-296) and deletions within this
region, Toll-N (amino acids 161-296), Toll-C (amino acids 230-296),
and Toll-282-296 (amino acids 161-281) were amplified by PCR with the following primers: Toll, JT749 5'-ttc gat gcc ttt atc tgc-3' and
JT318; Toll-N, JT749 and JT752 5'-cta gct ctg tag ata atc-3'; Toll-C,
JT751 5'-agc aag gaa tgt gac ttc-3' and JT318 and Toll-282-296, with primers JT749 and JT750 5'-cta ggt gca agg gtt ggt-3'. MyD88-N was
made by removing the EcoRV fragment from pFlag-MyD88. All constructs were confirmed by sequencing. Yeast expression vectors were
prepared by cloning DNA for MyD88 and the deletion mutants (indicated
above) as EcoRI fragment into the LexA DNA-binding domain
vector, pBTM116 (28), GAL4 DNA-binding domain vector, pGBT9
(CLONTECH), and into the GAL4 activation domain
vector, pGAD10 (CLONTECH).
B luc (Victor Jongeneel, Lausanne, CH); Myc-IL-1RI, IRAK and
IL-1RAcP (Keith Ray and Filippo Volpe, Glaxo Welcome, UK); Flag-JNK
(Christian Widman, Denver, CO); TRAF6 (287-522) and TRAF2 (87-501)
(Harold Wajant, Stuttgard, Germany). IRAK encoding the DD (amino acids
1-217) was amplified by PCR with the following primers: JT651 5'-gaa
ttc atg gcc ggg ggg ccg-3' and JT902 5'-tca ctt gag ctc ctc cga gaa
gtt-3'.
Yeast Two-Hybrid Interaction Analysis-- Protein/protein interactions were analyzed by cotransforming plasmids encoding the LexA-DNA binding (LexA-db) fusion proteins or GAL4-DNA binding (GAL4-db) fusion proteins with plasmids encoding the various GAL4-activation domain (GAL4-ab) fusion proteins (2.5 µg of each plasmid) into Saccharomyces cerevisiae strain CTY10-5d (used with LexA-db constructs) or Y190 (used with GAL4-db constructs) following the Two-Hybrid System protocol (CLONTECH). Filter lift assays for colony color development were done as described previously (29).
Generation of Glutathione S-Transferase (GST)-MyD88 and in
Vitro Binding Assays--
MyD88 was cloned as an EcoRI fragment
into pGEX-4T-1 (Pharmacia Biotech Inc.). GST fusion proteins were
induced with isopropyl-thiogalactoside and purified on
glutathione-agarose beads as described elsewhere (30).
35S-Labeled MyD88 and mutant versions were generated with
the TNT T7 coupled reticulocyte lysate system (Promega) according to
the manufacturer's instructions. Following translation
35S-labeled reticulocyte lysates (2 µl) were incubated
with 20 µl of GST-MyD88 (~3 µg) bound to the GST beads in 1 ml of
binding buffer (50 mM HEPES, pH 7.6, 250 mM
NaCl, 0.1% Nonidet P-40, 5 mM EDTA) and incubated for
1 h at 4 °C as described previously (31). After incubation the
GST beads were pelleted for 2 min at low speed and then washed six
times with binding buffer. The washed beads were boiled in SDS sample
buffer and loaded onto 12% SDS-polyacrylamide gels which were enhanced
by incubation in En3HanceTM (Du Pont) prior to
fluorography at 
80 °C.
Antibodies/Western Blot Analysis-- Monoclonal antibodies used for immunoprecipitations and Western blotting include anti-Flag M2 antibody (Kodak Biosciences) used at a concentration of 5 µg/ml, antibody against the Myc epitope (9E10, Sigma) used at a concentration of 1 µg/ml, anti-VSV antibody (Sigma) used at a dilution of 1:20,000, anti-JNK2 antibody (Santa Cruz Biotechnology) used at a dilution of 1:1000, and antibodies against the active phosphorylated form of JNK, Anti-ACTIVETM (Promega) used at a dilution of 1:5000. Antiserum against MyD88 (AL126) was generated using a peptide spanning amino acids 54-77 (MGFEYLEIRELETRPDPTRSLLDA), which was synthesized using the multiple antigen technology (31). The antiserum was affinity-purified on the MyD88 peptide coupled to CNBr-Sepharose 4B (Pharmacia) and used at a dilution of 1:500. For Western analysis protein extracts were separated by SDS-PAGE and transferred to Hybond ECL nitrocellulose membrane (Amersham Life Science). Blots were incubated with the antibodies in blocking buffer (PBS, 0.5% Tween 20, 5% skim milk) followed by horseradish peroxidase-conjugated goat anti-mouse IgG or anti-rabbit IgG (Jackson ImmunoResearch Labs Inc.) diluted 1:2000 in blocking buffer. Bound antibody was detected using the enhanced chemiluminescence kit (Amersham International) according to the protocol of the manufacturer.
Gel Permeation Chromatography-- 293T cells (1 × 107) were transiently transfected with Flag-MyD88 (12 µg). 24 h after transfection the cells were harvested and lysed in PBS (300 µl) containing CompleteTM protease inhibitor mixture by mild sonication (four times for 5 s each). The soluble cellular extract (150 µl) was mixed with the internal standards catalase and ovalbumin, then loaded onto a Superdex-200 HR10/30 column, and the proteins were eluted in PBS at 0.5 ml/min. Every second fraction (250 µl) was precipitated with trichloroacetic acid and then analyzed by Western blotting with anti-Flag antibody. The column was calibrated with the following standard proteins: thyroglobulin (669 kDa), ferritin (440 kDa), catalase (232 kDa), aldolase (158 kDa), bovine serum albumin (67 kDa), ovalbumin (43 kDa), chymotrypsinogen A (25 kDa), and ribonuclease A (13.7 kDa).
Tissue Extracts, and Coimmunoprecipitation--
Tissue extracts
were prepared from BalbC mice by homogenization in PBS containing 1%
Nonidet P-40 and CompleteTM protease inhibitor mixture
(Boehringer Mannheim). The extracts were spun at 13,000 rpm for 20 min
at 4 °C, and the supernatants were collected for Western blotting
analysis. Cellular extracts were obtained from 293T cells harvested
26 h after transfection and lysed as described previously (27).
For coimmunoprecipitation of MyD88 and its deletion mutants,
transfected 293T cells (1 × 106), were lysed in 200 µl of lysis buffer (50 mM Tris, pH 7.8, 150 mM NaCl, 0.1% Nonidet P-40, 5 mM EDTA). The
lysates were incubated with 3 µg of anti-Flag agarose at 4 °C
overnight. The agarose beads were washed five times with lysis buffer,
and the precipitated proteins were then fractionated on 12% SDS-PAGE
and analyzed by Western blotting. To detect MyD88 associated with the
IL-1RI complex, 3 × 106 transfected 293T cells were
first treated with IL-1
(200 ng/ml) for 3 min, the complex was then
precipitated by the addition of 3 µg of anti-Flag M2 antibody to the
cellular lysates (500 µl) for 3 h and then 10 µl of protein
G-agarose for an additional hour, and MyD88 was detected by Western
analysis. Cells were treated with IL-1 and lyzed as described
elsewhere (19). Protein content of tissue and cell extracts was
determined using the BCA protein determination kit (Pierce).
NF-B Activation Assays--
Electrophoretic mobility shift
assays were carried out as described previously (32). In brief, total
cellular extracts were prepared from transfected 293 cells (2 × 106) using a high salt detergent buffer (Totex) (20 mM Hepes, pH 7.9, 350 mM NaCl, 20% (w/v)
glycerol, 1% (w/v) Nonidet P-40, 1 mM MgCl2,
0.5 mM EDTA, 0.1 mM EGTA, 0.5 mM
DTT, 0.1% phenylmethylsulfonyl fluoride, 1% aprotinin). The cells
were harvested by centrifugation, washed once in ice-cold PBS (Sigma),
and resuspended in four cell volumes of Totex buffer. After 30 min on
ice, the lysates were centrifuged for 5 min at 13,000 × g at 4 °C. The protein content of the supernatant was
determined, and equal amounts of protein (10-20 µg) were added to a
reaction mixture containing 20 µg of bovine serum albumin (Sigma), 2 µg of poly(dI-dC) (Boehringer Mannheim), 2 µl of buffer D+ (20 mM Hepes, pH 7.9, 20% glycerin, 100 mM KCl,
0.5 mM EDTA, 0.25% Nonidet P-40, 2 mM DTT,
0.1% phenylmethylsulfonyl fluoride), 4 µl of buffer F (20% Ficoll
400, 100 mM Hepes, 300 mM KCl, 10 mM DTT, 0.1% phenylmethylsulfonyl fluoride), and 100,000 cpm (Cerenkov) of a 32P-labeled oligonucleotide in a final
volume of 20 µl. For the supershift assays, 1.0 µl of antibody was
added to the reaction simultaneously with the probe and incubated as
described. Anti-p65 antibodies were purchased from Santa Cruz
Biotechnology. The NF-B oligonucleotides (Promega) was labeled using
-[32P]ATP (3000 Ci/mmol; Amersham) and T4
polynucleotide kinase (Promega).
B reporter assays, 2 × 105 293T or 293 Myc-IL-1RI cells were transfected by the calcium phosphate method. A
stable cell line expressing the Myc-tagged IL-1RI cells was obtained by
transfection of 293 with a Myc-IL-1RI expression plasmid and selection
with G418 (600 µg/ml) (Life Technologies, Inc.). Drug-resistant clones were tested for expression of Myc-IL-1RI by Western analysis with Myc antibody. The cells were harvested 24-42 h after transfection and lysed with 400 µl of lysis buffer (1% Triton X-100, 25 mM glycylglycine, pH 7.8, 14 mM
MgSO4, 4 mM EGTA, 1 mM DTT). Where indicated IL-1 (Boehringer Mannheim) (10 ng/ml) was added to the
medium 36 h after transfection for 6 h before the cells were harvested. Aliquots of cell lysates (1-5 µl) were mixed with 100 µl of luciferase assay reagent (Promega), and the luciferase activity was determined using a biocounter M2500 luminometer (Inotech, Zurich).
-Galactosidase activity was determined in a mixture containing 50 µl of cell extract and 50 µl of a buffer containing the substrate
o-nitrophenyl--D-galactopyranoside (Sigma).
Samples were incubated at 37 °C until a yellow color developed, and
then the absorbance was determined at 405 nm. These values were used to
normalize transfection efficiency.
Detection of JNK Activity--
293T cells transfected with the
Flag-JNK vector and the indicated expression plasmids were harvested
24 h after transfection and lysed in 0.1% Nonidet P-40 lysis
buffer. 38 h after transfection of 293 Myc-IL-1RI, 20 ng/ml
IL-1 was added for an additional 7 h before the cells were
harvested and lysed as above. Equivalent amounts of protein were
separated by 12% SDS-PAGE and subjected to Western analysis with
anti-JNK2 antibody or with Anti-ACTIVETM antibody
(Promega). Kinase assays were performed on transfected cells (1 × 10 6) serum-starved for 16 h. JNK was immunoprecipated
from cell extracts with 5 µg of anti-Flag antibody for 2 h at
4 °C. The washed Sepharose beads were incubated with 1 µg of
GST-JNK (Santa Cruz) in 40 µl of kinase buffer containing 20 mM HEPES (pH 7.5), 20 mM -glycerophosphate, 10 mM p-nitrophenyl phosphate, 10 mM
MgCl2, 1 mM DTT, and 50 mM Na3VO4) at 30 °C for 20 min. The reactions
were separated by SDS-PAGE and transferred to nitrocellulose. To ensure
that comparable levels of JNK were present the membrane was probed with
anti-Flag antibodies, following autoradiography.
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RESULTS |
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Top
Abstract
Introduction
Procedures
Results
Discussion
References
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Expression of MyD88-- The murine MyD88 transcript was originally reported to be expressed in myeloid precursor enriched murine bone marrow cells and not in nonmyeloid tissues (1). Since then, MyD88 mRNA has been detected in a number of nonmyeloid cell lines (4, 26). Here we extend this analysis to show that the murine MyD88 transcript (approximately 2.2 kilobase pairs) is present in many tissues, in fact in all tissues tested except for the brain (Fig. 1A). In order to examine the expression pattern of the MyD88 protein, we generated antibodies against a synthetic peptide (corresponding to residues 54-77) of murine MyD88, which specifically recognized the 30-kDa Flag-MyD88 protein expressed in 293T cells (Fig. 1B). MyD88 was detected in many tissues with highest levels found in the ovary, adrenal gland, prostate, and thymus (Fig. 1C). However, in certain tissues (kidney, liver, and spleen), which have MyD88 transcript the protein was not detected, possibly as a result of post-transcriptional regulation in these tissues.
|
MyD88 Forms Homodimers--
Many adapter proteins involved in
signal transduction form homo- and heterotypic interactions through
like domains. As the death domain is a region that frequently promotes
such interactions, MyD88 was analyzed for this capacity. Two-hybrid
analysis, in vitro binding studies, and mammalian cell
coimmunoprecipations revealed that MyD88 forms homodimers (Figs.
2 and 3,
A-C). To assess whether the
DD mediates self-association, various point and deletion mutants of
MyD88 were generated. Phe56 was chosen for mutagenesis
based on sequence alignment of the MyD88 DD with the DD of Fas (3). A
mutation at this position corresponds to the lprcp mutation
(33) known to abolish cytotoxic signaling of Fas, probably by
disrupting the conformation of the DD as revealed by recent NMR
experiments (34). Mutation of Phe56 to Asn inhibited
association of full-length MyD88 with a truncated form containing the
DD (MyD88-DD), indicating that dimerization is mediated through the DD
of MyD88-DD. Surprisingly, MyD88-lpr was still capable of interacting
with MyD88 (Figs. 2 and 3A), suggesting the presence of a
second domain involved in self-association. Two constructs encoding the
Toll domain of MyD88 (MyD88-Toll and MyD88-DD) were therefore tested
for their ability to bind to MyD88 (Figs. 2 and 3, A and
B). MyD88-Toll bound to full-length MyD88 and also to itself
but not to MyD88-DD. However, MyD88-Toll did not dimerize with either
Toll-N (containing the first half of the domain), Toll-C (containing
the second half of the domain), or Toll-282-296 (missing 15 amino
acids at the C terminus), suggesting that the entire domain is required
for dimerization. The peptide deleted in Toll-282-296 is homologous
to a peptide in the Toll domain of the IL-1RI within which are residues
that have been shown to be critical for IL-1 signaling (35).
|
|
Signaling Activities of MyD88; Activation of JNK-- To learn more about the physiological activity(ies), we first tested whether overexpression of MyD88 could induce cytotoxicity like many of the DD-containing proteins. Surprisingly overexpression of MyD88 and MyD88-DD, but not MyD-lpr or MyD-Toll induced apoptosis in 293T. The observed cytotoxicity was apparent only after extended periods (36-50 h) following transfection, therefore delayed by comparison with the cytotoxic effects induced by the death receptors in similar experiments. The cytotoxic effects of MyD88 were not apparent in other cell types tested (COS, McF7), suggesting that MyD88-induced cytotoxicity in 293T cells may be a secondary effect due to high levels of MyD88 in these cells.
Many signaling pathways which implicate DD-containing adapter proteins lead to activation of the JNK/stress-activated protein kinase pathway, which prototypically involves the sequential activation of MEKK1, SEK1, JNK, and c-Jun (37, 38). To test the possibility that MyD88 might activate this kinase cascade, 293T cells were cotransfected with MyD88 and Flag-JNK. Flag-JNK was immunoprecipated from cell lysates and tested for its activity using GST c-Jun as a substrate. MyD88, but not MyD88-lpr induced JNK activation (Fig. 4A). Activation of JNK was also detected by Western analysis using an antibody that specifically recognizes the active, phosphorylated form of the kinase. MyD88 and MyD88N significantly induced activation of JNK (Fig. 4B). That neither MyD88-lpr nor MyD88-Toll activated JNK suggests that DD of MyD88 is critical for this activity.
|
Activation of the Transcription Factor NF-B--
Both the death
and Toll domains represent motifs that are often involved in NF-B
activation. To test whether MyD88 could activate NF-B
electrophoretic mobility shift assays were carried out on cellular
extracts from transfected 293 cells. Overexpression of MyD88 or
MyD88-DD led to significant activation of NF-B in the absence of
exogenous stimuli (such as TNF- or IL-1) (Fig. 5A), whereas in cells
transfected with empty expression vector, MyD88-lpr or MyD88-DD
specific NF-B complexes were not detected, suggesting that the DD of
MyD88 is responsible for this activation. Supershift experiments with
p65 antibody demonstrated that p65 is a component of the activated
NF-B complex (Fig. 5A, right panel).
|
B-dependent reporter plasmid (pNF-BLuc) by
cotransfecting 293T cells with pNF-BLuc and the various MyD88
constructs (Fig. 5B). In agreement with the electrophoretic
mobility shift assays, MyD88 and MyD88-DD strongly induced NF-B
activation in 293 cells, and the mutants MyD88-lpr and MyD88-DD were
inactive. MyD88 induced the activity of pNF-BLuc in a
dose-dependent manner (Fig. 5C) and failed to
activate pHIV-84, a luciferase reporter plasmid containing a mutation
in the NF-B elements of the HIV promoter, confirming the specificity
of this activation (Fig. 5D). NF-B activation following
transient transfection with the MyD88 expression vector was also
observed in HeLa and McF7 cells (data not shown).
MyD88 Is an Adaptor Protein in the IL-1-signaling Pathway--
The
observations that MyD88 efficiently induced NF-B and JNK activation
together with its dual domain structure hinted at a role for MyD88 in
IL-1 signaling. TRAF6 is required for IL-1-induced NF-B activation,
whereas TRAF2 has been implicated in NF-B activation signaled
through TNF (39-41). Dominant negative versions of these TRAFs are
known to block IL-1- and TNF-induced NF-B activation, respectively.
TRAF6 (287-522) but not TRAF2 (87-501) significantly inhibited
MyD88-induced NF-B activation in 293T, suggesting that MyD88 is most
likely involved in IL-1 signaling and that TRAF6 functions downstream
of MyD88 (Fig. 6A). Dominant
negative IRAK (1-217) also inhibited MyD88-induced NF-B activation,
suggesting that MyD88 functions upstream of IRAK (Fig.
6A).
|
), TRAF2 (87-501) (
), or IRAK (1-217) (
), and 1 µg of
pNF-B and JNK
activity. As the DD of MyD88 is essential for these activities, we
tested whether MyD88-lpr could act to block IL-1-induced NF-B and
JNK activation. When a cell line (293 Myc-IL-1RI), which overexpressses the IL-1RI and responses to IL-1 treatment by activating the
NF-B-dependent reporter plasmid, approximately 20-fold
was transfected with MyD88-lpr; IL-1-dependent NF-B
activation was inhibited in a dose-dependent manner (Fig.
6B). Overexpression of MyD88-lpr did not affect NF-B activation signaled by TNF or induced by coexpression of TRAMP, demonstrating that the dominant-negative effect of the MyD88 mutant to
IL-1 signaling was specific (Fig. 6B). MyD88-Toll
overexpression also blocked IL-1-mediated NF-B activation (Fig.
6B). IL-1-induced JNK activation was similarly inhibited in
293 IL-1RI cells by overexpression of MyD88-lpr or -Toll (Fig.
6C).
The ability of MyD88-Toll to block these IL-1-induced signals suggested
the possibility that MyD88 may directly associate with the IL-1RI
and/or IL-1RAcP. We tested this possibility using the yeast two-hybrid
system, but did not detect an association of MyD88 with either of the
receptor chains. Also an association between MyD88 and one of the
receptor chains alone was also not detected in coimmunoprecipitation
experiments using 293T cells transfected with MyD88 and IL-1RI or
IL-1RAcP (data not shown). However, in similar experiments using 293T
cells transfected with MyD88 and both of the receptor chains, MyD88 was
detected in the IL-1RI complex in an IL-1-dependent manner
(Fig. 6D).
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DISCUSSION |
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Top
Abstract
Introduction
Procedures
Results
Discussion
References
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IL-1 is a potent cytokine that elicits multiple diverse effects on
immunological and inflammatory processes. It exerts its various
biological activities mainly through activation of the transcription
factors NF-B and activating protein 1, which regulate the expression
of numerous genes involved in these processes. Signaling cascades
leading to the activation of these transcription factors are initiated
by IL-1-induced complex formation of the IL-1RI and the IL-1RAcP
(15-17). This in turn leads to IRAK recruitment to the receptor
complex where IRAK becomes highly phosphorylated (19). Phosphorylated
IRAK is then believed to dissociate from the receptor complex and
interact with TRAF6, and it becomes rapidly degraded via a
proteasome-dependent pathway (39, 42). The results
described above show that overexpression of MyD88 activates both
NF-B (in a pathway upstream of IRAK and TRAF6) and JNK (activating protein 1) and therefore mimics these two IL-1-induced cellular responses. Moreover, MyD88 associates with the IL-1RI complex in an
IL-1-dependent manner and, dominant-negative forms of MyD88 (MyD88-lpr and MyD88-Toll) block IL-1 signaling. Our findings therefore
demonstrate that MyD88 has an important role in mediating the cellular
responses to this cytokine.
How can our findings be incorporated into the current model of IL-1 signaling? Experiments with the dominant negative mutants of MyD88 (MyD88-lpr and MyD88-Toll) indicate the MyD88-Toll domain links MyD88 with upstream components of the IL-1 pathway. Indeed, the Toll domain of MyD88 has recently been demonstrated to link MyD88 with the IL-1R complex (36). Despite the ability of MyD88-Toll to mediate homophilic interactions between MyD88 molecules, we and others (36) did not detect an interaction of MyD88 with either of the two receptor chains alone. MyD88, however, associates with the receptor complex after IL-1 stimulation and thus aggregation of receptor chains (36). This suggests the possibility that IL-1-induced heterocomplex formation induces association of the IL-1RI and IL-1RAcP via their respective Toll domains creating a novel interaction surface, in an analogous manner to those formed through DD-DD interactions in Fas- or TNF-R1-signaling complexes, that allows for the recruitment of MyD88 through homophilic interactions. We have shown that MyD88 forms homodimers through DD-DD and Toll-Toll interactions and therefore is probably recruited as a dimer to the IL-1RI complex.
The MyD88-DD is critical for MyD88-induced activation of NF-B and
JNK. This suggests that the DD engages downstream proteins involved in
these pathways. Recently it was demonstrated that a kinase-defective
form of IRAK (IRAK K239S) and a novel IRAK-like molecule termed IRAK-2,
also involved in IL-1-induced NF-B activation, interact with MyD88
(36, 43). MyD88 associates with both of these proteins through its
N-terminal domain and in the case of IRAK also via interactions
mediated through its Toll domain (36, 43). MyD88 therefore utilizes its
dual domain organization to function as an adapter linking Toll- and
death-containing protein modules in IL-1-signaling cascades.
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ACKNOWLEDGEMENTS |
|---|
We thank Moira Cockell, Eric Meldrum, and Catherine Torgler for advice with yeast two-hybrid interaction assays and Verena Rubio and Sylvie Hertig for technical assistance. We also thank Filippo Volpe and Kostis Alevizopoulos for helpful discussions and reagents.
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FOOTNOTES |
|---|
* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
§ Supported by the Human Frontier Science Program.
§§ To whom correspondence should be addressed: Institute of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland. Tel.: 41 21 692 5738; Fax: 41 21 692 5705; E-mail: jurg.tschopp{at}ib.unil.ch.
1
The abbreviations used are: DD, death domain;
JNK, Jun N-terminal kinase; IL, interleukin; IL-1R, interleukin 1 receptor; AcP, accessory protein; IRAK, IL-1 receptor-associated
kinase; NF, nuclear factor; GST, glutathione S-transferase;
TNF, tumor necrosis factor; DTT, dithiothreitol; PBS,
phosphate-buffered saline; PAGE, polyacrylamide gel electrophroresis;
PCR, polymerase chain reaction; HIV, human immunodeficiency virus; Luc,
luciferase; -gal, -galactosidase; db, DNA binding.
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REFERENCES |
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Top
Abstract
Introduction
Procedures
Results
Discussion
References
|
|---|
- Lord, K. A., Hoffman-Liebermann, B., and Liebermann, D. A. (1990) Oncogene 5, 1095-1097[Medline] [Order article via Infotrieve]
- Feinstein, E., Kimchi, A., Wallach, D., Boldin, M., and Varfolomeev, E. (1995) Trends Biochem. Sci. 20, 342-344[CrossRef][Medline] [Order article via Infotrieve]
- Hofmann, K., and Tschopp, J. (1995) FEBS Lett. 371, 321-323[CrossRef][Medline] [Order article via Infotrieve]
- Hardiman, G., Rock, F. L., Balasubramanian, S., Kastelein, R. A., and Bazan, J. F. (1996) Oncogene 13, 2467-2475[Medline] [Order article via Infotrieve]
-
Mitcham, J. L.,
Parnet, P.,
Bonnert, T. P.,
Garka, K. E.,
Gerhart, M. J.,
Slack, J. L.,
Gayle, M. A.,
Dower, S. K.,
and Sims, J. E.
(1996)
J. Biol. Chem.
271,
5777-5783
[Abstract/Free Full Text] - Hultmark, D. (1994) Biochem. Biophys. Res. Commun. 199, 144-146[CrossRef][Medline] [Order article via Infotrieve]
- Yamagata, M., Merlie, J. P., and Sanes, J. R. (1994) Gene (Amst.) 139, 223-228[CrossRef][Medline] [Order article via Infotrieve]
-
Itoh, N.,
and Nagata, S.
(1993)
J. Biol. Chem.
268,
10932-10937
[Abstract/Free Full Text] - Tartaglia, L. A., Ayres, T. M., Wong, G. H., and Goeddel, D. V. (1993) Cell 74, 845-853[CrossRef][Medline] [Order article via Infotrieve]
-
Boldin, M. P.,
Mett, I. L.,
Varfolomeev, E. E.,
Chumakov, I.,
Shemer-Avni, Y.,
Camonis, J. H.,
and Wallach, D.
(1995)
J. Biol. Chem.
270,
387-391
[Abstract/Free Full Text] - Nagata, S. (1997) Cell 88, 355-365[CrossRef][Medline] [Order article via Infotrieve]
- Hashimoto, C., Hudson, K. L., and Anderson, K. V. (1988) Cell 52, 269-279[CrossRef][Medline] [Order article via Infotrieve]
- Medzhitov, R., Preston-Hurlburt, P., and Janeway, C. A., Jr. (1997) Nature 388, 394-397[CrossRef][Medline] [Order article via Infotrieve]
-
Parnet, P.,
Garka, K. E.,
Bonnert, T. P.,
Dower, S. K.,
and Sims, J. E.
(1996)
J. Biol. Chem.
271,
3967-3970
[Abstract/Free Full Text] -
Greenfeder, S. A.,
Nunes, P.,
Kwee, L.,
Labow, M.,
Chizzonite, R. A.,
and Ju, G.
(1995)
J. Biol. Chem.
270,
13757-13765
[Abstract/Free Full Text] -
Wesche, H.,
Korherr, C.,
Kracht, M.,
Falk, W.,
Resch, K.,
and Martin, M. U.
(1997)
J. Biol. Chem.
272,
7727-7731
[Abstract/Free Full Text] -
Huang, J.,
Gao, X.,
Li, S.,
and Cao, Z.
(1997)
Proc. Natl. Acad. Sci. U. S. A.
94,
12829-12832
[Abstract/Free Full Text] - Shelton, C. A., and Wasserman, S. A. (1993) Cell 72, 515-525[CrossRef][Medline] [Order article via Infotrieve]
- Cao, Z., Henzel, W. J., and Gao, X. (1996) Science 271, 1128-1131[Abstract]
- Galindo, R. L., Edwards, D. N., Gillespie, S. K., and Wasserman, S. A. (1995) Development 121, 2209-2218[Abstract]
- Grosshans, J., Bergmann, A., Haffter, P., and Nusslein-Volhard, C. (1994) Nature 372, 563-566[CrossRef][Medline] [Order article via Infotrieve]
- Letsou, A., Alexander, S., and Wasserman, S. A. (1993) EMBO J. 12, 3449-3458[Medline] [Order article via Infotrieve]
- Sappino, A. P., Huarte, J., Vassali, J. D., and Belin, D. (1991) J. Clin. Invest. 87, 962-971
-
French, L. E.,
Chonn, A.,
Ducrest, D.,
Baumann, B.,
Belin, D.,
Wohlwend, A.,
Kiss, J. Z.,
Sappino, A. P.,
Tschopp, J.,
and Schifferli, J. A.
(1993)
J. Cell Biol.
122,
1119-1130
[Abstract/Free Full Text] -
Harroch, S.,
Gothelf, Y.,
Revel, M.,
and Chebath, J.
(1995)
Nucleic Acids Res.
23,
3539-3546
[Abstract/Free Full Text] - Bonnert, T. P., Garka, K. E., Parnet, P., Sonoda, G., Testa, J. R., and Sims, J. E. (1997) FEBS Lett. 402, 81-84[CrossRef][Medline] [Order article via Infotrieve]
- Bodmer, J. L., Burns, K., Schneider, P., Hofmann, K., Steiner, V., Thome, M., Bornand, T., Hahne, M., Schroter, M., Becker, K., Wilson, A., French, L. E., Browning, J. L., MacDonald, H. R., and Tschopp, J. (1997) Immunity 6, 79-88[CrossRef][Medline] [Order article via Infotrieve]
-
Chien, C. T.,
Bartel, P. L.,
Sternglanz, R.,
and Fields, S.
(1991)
Proc. Natl. Acad. Sci. U. S. A.
88,
9578-9582
[Abstract/Free Full Text] -
Breeden, L.,
and Nasmyth, K.
(1985)
Cold Spring Harbor Symp. Quant. Biol.
50,
643-650
[Abstract/Free Full Text] - Smith, D. B., and Johnson, K. S. (1988) Gene (Amst.) 67, 31-40[CrossRef][Medline] [Order article via Infotrieve]
- Hsu, H., Xiong, J., and Goeddel, D. V. (1995) Cell 81, 495-504[CrossRef][Medline] [Order article via Infotrieve]
-
Pahl, H. L.,
Sester, M.,
Burgert, H. G.,
and Baeuerle, P. A.
(1996)
J. Cell Biol.
132,
511-522
[Abstract/Free Full Text] - Nagata, S. (1994) Semin. Immunol. 6, 3-8[CrossRef][Medline] [Order article via Infotrieve]
- Huang, B., Eberstadt, M., Olejniczak, E. T., Meadows, R. P., and Fesik, S. W. (1996) Nature 384, 638-641[CrossRef][Medline] [Order article via Infotrieve]
-
Heguy, A.,
Baldari, C. T.,
Macchia, G.,
Telford, J. L.,
and Melli, M.
(1992)
J. Biol. Chem.
267,
2605-2609
[Abstract/Free Full Text] - Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S., and Cao, Z. (1997) Immunity 7, 837-847[CrossRef][Medline] [Order article via Infotrieve]
- Kyriakis, J. M., and Avruch, J. (1996) Bioessays 18, 567-577[CrossRef][Medline] [Order article via Infotrieve]
-
Kyriakis, J. M.,
and Avruch, J.
(1996)
J. Biol. Chem.
271,
24313-24316
[Free Full Text] - Cao, Z., Xiong, J., Takeuchi, M., Kurama, T., and Goeddel, D. V. (1996) Nature 383, 443-446[CrossRef][Medline] [Order article via Infotrieve]
- Hsu, H., Shu, H. B., Pan, M. G., and Goeddel, D. V. (1996) Cell 84, 299-308[CrossRef][Medline] [Order article via Infotrieve]
-
Rothe, M.,
Sarma, V.,
Dixit, V. M.,
and Goeddel, D. V.
(1995)
Science
269,
1424-1427
[Abstract/Free Full Text] -
Yamin, T.-T.,
and Miller, D. K.
(1997)
J. Biol. Chem.
272,
21540-21547
[Abstract/Free Full Text] -
Muzio, M.,
Ni, J.,
Feng, P.,
and Dixit, V. M.
(1997)
Science
278,
1612-1615
[Abstract/Free Full Text]
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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|
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|
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|
|
|
|
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A. E. Medvedev, K. Thomas, A. Awomoyi, D. B. Kuhns, J. I. Gallin, X. Li, and S. N. Vogel Cutting Edge: Expression of IL-1 Receptor-Associated Kinase-4 (IRAK-4) Proteins with Mutations Identified in a Patient with Recurrent Bacterial Infections Alters Normal IRAK-4 Interaction with Components of the IL-1 Receptor Complex J. Immunol., June 1, 2005; 174(11): 6587 - 6591. [Abstract] [Full Text] [PDF]
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D. Y. Jung, H. Lee, B.-Y. Jung, J. Ock, M.-S. Lee, W.-H. Lee, and K. Suk TLR4, but Not TLR2, Signals Autoregulatory Apoptosis of Cultured Microglia: A Critical Role of IFN-{beta} as a Decision Maker J. Immunol., May 15, 2005; 174(10): 6467 - 6476. [Abstract] [Full Text] [PDF]
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M. Loiarro, C. Sette, G. Gallo, A. Ciacci, N. Fanto, D. Mastroianni, P. Carminati, and V. Ruggiero Peptide-mediated Interference of TIR Domain Dimerization in MyD88 Inhibits Interleukin-1-dependent Activation of NF-{kappa}B J. Biol. Chem., April 22, 2005; 280(16): 15809 - 15814. [Abstract] [Full Text] [PDF]
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J. Stack, I. R. Haga, M. Schroder, N. W. Bartlett, G. Maloney, P. C. Reading, K. A. Fitzgerald, G. L. Smith, and A. G. Bowie Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence J. Exp. Med., March 21, 2005; 201(6): 1007 - 1018. [Abstract] [Full Text] [PDF]
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S. M. Sacre, E. Andreakos, M. Feldmann, and B. M. Foxwell Endotoxin signaling in human macrophages: signaling via an alternate mechanism Innate Immunity, December 1, 2004; 10(6): 445 - 452. [Abstract] [PDF]
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N. Nozaki, T. Shishido, Y. Takeishi, and I. Kubota Modulation of Doxorubicin-Induced Cardiac Dysfunction in Toll-Like Receptor-2-Knockout Mice Circulation, November 2, 2004; 110(18): 2869 - 2874. [Abstract] [Full Text] [PDF]
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V. M. Abrahams, P. Bole-Aldo, Y. M. Kim, S. L. Straszewski-Chavez, T. Chaiworapongsa, R. Romero, and G. Mor Divergent Trophoblast Responses to Bacterial Products Mediated by TLRs J. Immunol., October 1, 2004; 173(7): 4286 - 4296. [Abstract] [Full Text] [PDF]
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 K. A. Barsness, J. Arcaroli, A. H. Harken, E. Abraham, A. Banerjee, L. Reznikov, and R. C. McIntyre Hemorrhage-induced acute lung injury is TLR-4 dependent Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R592 - R599. [Abstract] [Full Text] [PDF]
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 K. W. Boehme and T. Compton Innate Sensing of Viruses by Toll-Like Receptors J. Virol., August 1, 2004; 78(15): 7867 - 7873. [Full Text] [PDF]
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D. D. Bolz, R. S. Sundsbak, Y. Ma, S. Akira, C. J. Kirschning, J. F. Zachary, J. H. Weis, and J. J. Weis MyD88 Plays a Unique Role in Host Defense but Not Arthritis Development in Lyme Disease J. Immunol., August 1, 2004; 173(3): 2003 - 2010. [Abstract] [Full Text] [PDF]
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 D. S. Wheeler, J. D. Catravas, K. Odoms, A. Denenberg, V. Malhotra, and H. R. Wong Epigallocatechin-3-gallate, a Green Tea-Derived Polyphenol, Inhibits IL-1{beta}-Dependent Proinflammatory Signal Transduction in Cultured Respiratory Epithelial Cells J. Nutr., May 1, 2004; 134(5): 1039 - 1044. [Abstract] [Full Text] [PDF]
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K.-J. Han, X. Su, L.-G. Xu, L.-H. Bin, J. Zhang, and H.-B. Shu Mechanisms of the TRIF-induced Interferon-stimulated Response Element and NF-{kappa}B Activation and Apoptosis Pathways J. Biol. Chem., April 9, 2004; 279(15): 15652 - 15661. [Abstract] [Full Text] [PDF]
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E. Andreakos, S. M. Sacre, C. Smith, A. Lundberg, S. Kiriakidis, T. Stonehouse, C. Monaco, M. Feldmann, and B. M. Foxwell Distinct pathways of LPS-induced NF-{kappa}B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP Blood, March 15, 2004; 103(6): 2229 - 2237. [Abstract] [Full Text] [PDF]
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H.-K. Lee, S. Dunzendorfer, and P. S. Tobias Cytoplasmic Domain-mediated Dimerizations of Toll-like Receptor 4 Observed by {beta}-Lactamase Enzyme Fragment Complementation J. Biol. Chem., March 12, 2004; 279(11): 10564 - 10574. [Abstract] [Full Text] [PDF]
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K. S. Kobayashi and R. A. Flavell Shielding the double-edged sword: negative regulation of the innate immune system J. Leukoc. Biol., March 1, 2004; 75(3): 428 - 433. [Abstract] [Full Text] [PDF]
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C. Kollewe, A.-C. Mackensen, D. Neumann, J. Knop, P. Cao, S. Li, H. Wesche, and M. U. Martin Sequential Autophosphorylation Steps in the Interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling J. Biol. Chem., February 13, 2004; 279(7): 5227 - 5236. [Abstract] [Full Text] [PDF]
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T. Shishido, N. Nozaki, S. Yamaguchi, Y. Shibata, J. Nitobe, T. Miyamoto, H. Takahashi, T. Arimoto, K. Maeda, M. Yamakawa, et al. Toll-Like Receptor-2 Modulates Ventricular Remodeling After Myocardial Infarction Circulation, December 9, 2003; 108(23): 2905 - 2910. [Abstract] [Full Text] [PDF]
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J. Radons, S. Dove, D. Neumann, R. Altmann, A. Botzki, M. U. Martin, and W. Falk The Interleukin 1 (IL-1) Receptor Accessory Protein Toll/IL-1 Receptor Domain: ANALYSIS OF PUTATIVE INTERACTION SITES BY IN VITRO MUTAGENESIS AND MOLECULAR MODELING J. Biol. Chem., December 5, 2003; 278(49): 49145 - 49153. [Abstract] [Full Text] [PDF]
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L. A. B. Joosten, M. I. Koenders, R. L. Smeets, M. Heuvelmans-Jacobs, M. M. A. Helsen, K. Takeda, S. Akira, E. Lubberts, F. A. J. van de Loo, and W. B. van den Berg Toll-Like Receptor 2 Pathway Drives Streptococcal Cell Wall-Induced Joint Inflammation: Critical Role of Myeloid Differentiation Factor 88 J. Immunol., December 1, 2003; 171(11): 6145 - 6153. [Abstract] [Full Text] [PDF]
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S.-J. Yeo, J.-G. Yoon, and A.-K. Yi Myeloid Differentiation Factor 88-dependent Post-transcriptional Regulation of Cyclooxygenase-2 Expression by CpG DNA: TUMOR NECROSIS FACTOR-{alpha} RECEPTOR-ASSOCIATED FACTOR 6, A DIVERGING POINT IN THE Toll-LIKE RECEPTOR 9-SIGNALING J. Biol. Chem., October 17, 2003; 278(42): 40590 - 40600. [Abstract] [Full Text] [PDF]
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J. Y. Lee, J. Ye, Z. Gao, H. S. Youn, W. H. Lee, L. Zhao, N. Sizemore, and D. H. Hwang Reciprocal Modulation of Toll-like Receptor-4 Signaling Pathways Involving MyD88 and Phosphatidylinositol 3-Kinase/AKT by Saturated and Polyunsaturated Fatty Acids J. Biol. Chem., September 26, 2003; 278(39): 37041 - 37051. [Abstract] [Full Text] [PDF]
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 F. Sandor, E. Latz, F. Re, L. Mandell, G. Repik, D. T. Golenbock, T. Espevik, E. A. Kurt-Jones, and R. W. Finberg Importance of extra- and intracellular domains of TLR1 and TLR2 in NF{kappa}B signaling J. Cell Biol., September 15, 2003; 162(6): 1099 - 1110. [Abstract] [Full Text] [PDF]
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 H.-S. Mun, F. Aosai, K. Norose, M. Chen, L.-X. Piao, O. Takeuchi, S. Akira, H. Ishikura, and A. Yano TLR2 as an essential molecule for protective immunity against Toxoplasma gondii infection Int. Immunol., September 1, 2003; 15(9): 1081 - 1087. [Abstract] [Full Text] [PDF]
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S. Okugawa, Y. Ota, T. Kitazawa, K. Nakayama, S. Yanagimoto, K. Tsukada, M. Kawada, and S. Kimura Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages Am J Physiol Cell Physiol, August 1, 2003; 285(2): C399 - C408. [Abstract] [Full Text] [PDF]
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M. MacGillivray, M. T. Herrera-Abreu, C.-W. Chow, C. Shek, Q. Wang, E. Vachon, G.-S. Feng, K. A. Siminovitch, C. A. G. McCulloch, and G. P. Downey The Protein Tyrosine Phosphatase SHP-2 Regulates Interleukin-1-induced ERK Activation in Fibroblasts J. Biol. Chem., July 11, 2003; 278(29): 27190 - 27198. [Abstract] [Full Text] [PDF]
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L.-H. Bin, L.-G. Xu, and H.-B. Shu TIRP, a Novel Toll/Interleukin-1 receptor (TIR) Domain-containing Adapter Protein Involved in TIR Signaling J. Biol. Chem., June 27, 2003; 278(27): 24526 - 24532. [Abstract] [Full Text] [PDF]
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T. Bartfai, M. M. Behrens, S. Gaidarova, J. Pemberton, A. Shivanyuk, and J. Rebek Jr A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses PNAS, June 24, 2003; 100(13): 7971 - 7976. [Abstract] [Full Text] [PDF]
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 N. Bahi, G. Friocourt, A. Carrie, M. E. Graham, J. L. Weiss, P. Chafey, F. Fauchereau, R. D. Burgoyne, and J. Chelly IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis Hum. Mol. Genet., June 15, 2003; 12(12): 1415 - 1425. [Abstract] [Full Text] [PDF]
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S. H. Rhee, B. W. Jones, V. Toshchakov, S. N. Vogel, and M. J. Fenton Toll-like Receptors 2 and 4 Activate STAT1 Serine Phosphorylation by Distinct Mechanisms in Macrophages J. Biol. Chem., June 13, 2003; 278(25): 22506 - 22512. [Abstract] [Full Text] [PDF]
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S.-J. Yeo, D. Gravis, J.-G. Yoon, and A.-K. Yi Myeloid Differentiation Factor 88-dependent Transcriptional Regulation of Cyclooxygenase-2 Expression by CpG DNA: ROLE OF NF-{kappa}B AND p38 J. Biol. Chem., June 13, 2003; 278(25): 22563 - 22573. [Abstract] [Full Text] [PDF]
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L. A.J. O'Neill, A. Dunne, M. Edjeback, P. Gray, C. Jefferies, and C. Wietek Mal and MyD88: adapter proteins involved in signal transduction by Toll-like receptors Innate Immunity, February 1, 2003; 9(1): 55 - 59. [Abstract] [PDF]
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K. Burns, S. Janssens, B. Brissoni, N. Olivos, R. Beyaert, and J. Tschopp Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4 J. Exp. Med., January 20, 2003; 197(2): 263 - 268. [Abstract] [Full Text] [PDF]
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H. Sun, B. N. Bristow, G. Qu, and S. A. Wasserman A heterotrimeric death domain complex in Toll signaling PNAS, October 1, 2002; 99(20): 12871 - 12876. [Abstract] [Full Text] [PDF]
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K. Ross, L. Yang, S. Dower, F. Volpe, and F. Guesdon Identification of Threonine 66 as a Functionally Critical Residue of the Interleukin-1 Receptor-associated Kinase J. Biol. Chem., September 27, 2002; 277(40): 37414 - 37421. [Abstract] [Full Text] [PDF]
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N. Tsuboi, Y. Yoshikai, S. Matsuo, T. Kikuchi, K.-I. Iwami, Y. Nagai, O. Takeuchi, S. Akira, and T. Matsuguchi Roles of Toll-Like Receptors in C-C Chemokine Production by Renal Tubular Epithelial Cells J. Immunol., August 15, 2002; 169(4): 2026 - 2033. [Abstract] [Full Text] [PDF]
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J. A. Thomas, M. F. Tsen, D. J. White, and J. W. Horton IRAK contributes to burn-triggered myocardial contractile dysfunction Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H829 - H836. [Abstract] [Full Text] [PDF]
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V. Mamidipudi, X. Li, and M. W. Wooten Identification of Interleukin 1 Receptor-associated Kinase as a Conserved Component in the p75-Neurotrophin Receptor Activation of Nuclear Factor-kappa B J. Biol. Chem., July 26, 2002; 277(31): 28010 - 28018. [Abstract] [Full Text] [PDF]
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J. Radons, S. Gabler, H. Wesche, C. Korherr, R. Hofmeister, and W. Falk Identification of Essential Regions in the Cytoplasmic Tail of Interleukin-1 Receptor Accessory Protein Critical for Interleukin-1 Signaling J. Biol. Chem., May 3, 2002; 277(19): 16456 - 16463. [Abstract] [Full Text] [PDF]
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 T. Vasselon and P. A. Detmers Toll Receptors: a Central Element in Innate Immune Responses Infect. Immun., March 1, 2002; 70(3): 1033 - 1041. [Full Text] [PDF]
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 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]
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A. Sesto, M. Navarro, F. Burslem, and J. L. Jorcano Analysis of the ultraviolet B response in primary human keratinocytes using oligonucleotide microarrays PNAS, February 20, 2002; (2002) 52678999. [Abstract] [Full Text] [PDF]
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J. Mizukami, G. Takaesu, H. Akatsuka, H. Sakurai, J. Ninomiya-Tsuji, K. Matsumoto, and N. Sakurai Receptor Activator of NF-{kappa}B Ligand (RANKL) Activates TAK1 Mitogen-Activated Protein Kinase Kinase Kinase through a Signaling Complex Containing RANK, TAB2, and TRAF6 Mol. Cell. Biol., February 15, 2002; 22(4): 992 - 1000. [Abstract] [Full Text] [PDF]
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J. D. McCurdy, T.-J. Lin, and J. S. Marshall Toll-like receptor 4-mediated activation of murine mast cells J. Leukoc. Biol., December 1, 2001; 70(6): 977 - 984. [Abstract] [Full Text] [PDF]
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D. HWANG Modulation of the expression of cyclooxygenase-2 by fatty acids mediated through Toll-like receptor 4-derived signaling pathways FASEB J, December 1, 2001; 15(14): 2556 - 2564. [Abstract] [Full Text] [PDF]
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S. Prebeck, C. Kirschning, S. Durr, C. da Costa, B. Donath, K. Brand, V. Redecke, H. Wagner, and T. Miethke Predominant Role of Toll-Like Receptor 2 Versus 4 in Chlamydia pneumoniae-Induced Activation of Dendritic Cells J. Immunol., September 15, 2001; 167(6): 3316 - 3323. [Abstract] [Full Text] [PDF]
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C. Jefferies, A. Bowie, G. Brady, E.-L. Cooke, X. Li, and L. A. J. O'Neill Transactivation by the p65 Subunit of NF-{kappa}B in Response to Interleukin-1 (IL-1) Involves MyD88, IL-1 Receptor-Associated Kinase 1, TRAF-6, and Rac1 Mol. Cell. Biol., July 15, 2001; 21(14): 4544 - 4552. [Abstract] [Full Text] [PDF]
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T. Kaisho, O. Takeuchi, T. Kawai, K. Hoshino, and S. Akira Endotoxin-Induced Maturation of MyD88-Deficient Dendritic Cells J. Immunol., May 1, 2001; 166(9): 5688 - 5694. [Abstract] [Full Text] [PDF]
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G. Takaesu, J. Ninomiya-Tsuji, S. Kishida, X. Li, G. R. Stark, and K. Matsumoto Interleukin-1 (IL-1) Receptor-Associated Kinase Leads to Activation of TAK1 by Inducing TAB2 Translocation in the IL-1 Signaling Pathway Mol. Cell. Biol., April 1, 2001; 21(7): 2475 - 2484. [Abstract] [Full Text]
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X. Li, M. Commane, Z. Jiang, and G. R. Stark IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK) PNAS, March 29, 2001; (2001) 71054198. [Abstract] [Full Text]
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 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]
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 C. Bonny, A. Oberson, S. Negri, C. Sauser, and D. F. Schorderet Cell-Permeable Peptide Inhibitors of JNK: Novel Blockers of {beta}-Cell Death Diabetes, January 1, 2001; 50(1): 77 - 82. [Abstract] [Full Text]
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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]
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H. Hacker, R. M. Vabulas, O. Takeuchi, K. Hoshino, S. Akira, and H. Wagner Immune Cell Activation by Bacterial CpG-DNA through Myeloid Differentiation Marker 88 and Tumor Necrosis Factor Receptor-Associated Factor (TRAF)6 J. Exp. Med., August 21, 2000; 192(4): 595 - 600. [Abstract] [Full Text] [PDF]
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T. Sareneva, I. Julkunen, and S. Matikainen IFN-{alpha} and IL-12 Induce IL-18 Receptor Gene Expression in Human NK and T Cells J. Immunol., August 15, 2000; 165(4): 1933 - 1938. [Abstract] [Full Text] [PDF]
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 L. A. J. O'Neill The Interleukin-1 Receptor/Toll-like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense Sci. Signal., August 8, 2000; 2000(44): re1 - re1. [Abstract] [Full Text] [PDF]
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A. Bowie, E. Kiss-Toth, J. A. Symons, G. L. Smith, S. K. Dower, and L. A. J. O'Neill A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling PNAS, July 30, 2000; (2000) 160027697. [Abstract] [Full Text]
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U. Bocker, A. Schottelius, J. M. Watson, L. Holt, L. L. Licato, D. A. Brenner, R. B. Sartor, and C. Jobin Cellular Differentiation Causes a Selective Down-regulation of Interleukin (IL)-1beta -mediated NF-kappa B Activation and IL-8 Gene Expression in Intestinal Epithelial Cells J. Biol. Chem., April 14, 2000; 275(16): 12207 - 12213. [Abstract] [Full Text] [PDF]
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C. Jobin and R. B. Sartor The Ikappa B/NF-kappa B system: a key determinant of mucosal inflammation and protection Am J Physiol Cell Physiol, March 1, 2000; 278(3): C451 - C462. [Abstract] [Full Text] [PDF]
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J. Hawiger, R. A. Veach, X.-Y. Liu, S. Timmons, and D. W. Ballard Ikappa B Kinase Complex Is an Intracellular Target for Endotoxic Lipopolysaccharide in Human Monocytic Cells Blood, September 1, 1999; 94(5): 1711 - 1716. [Abstract] [Full Text] [PDF]
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