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Departments of
*
Pediatrics and
Molecular Biology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75235; and
Tularik, Inc., South San Francisco, CA 94080
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B, which directs expression of innate and adaptive immune
response genes. To study IRAK function in cytokine
signaling, we generated cells and mice lacking the IRAK protein.
IRAK-deficient fibroblasts show diminished activation of NF-B when
stimulated with IL-1. Immune effector cells without IRAK exhibit a
defective IFN-
response to costimulation with IL-18. Furthermore,
mice lacking the Irak gene demonstrate an attenuated
response to injected IL-1. Deletion of Irak, however,
does not affect the ability of mice to develop delayed-type
hypersensitivity or clear infection with the intracellular
parasite, Listeria monocytogenes. These results
demonstrate that although IRAK participates in IL-1 and IL-18 signal
transduction, residual cytokine responsiveness operates through an
IRAK-independent pathway. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1 initiates the innate
host immune response, including induction of fever and synthesis of
hepatic acute phase proteins (reviewed in Ref. 1). It
stimulates neutrophil release into the peripheral circulation
(2) and activates vascular endothelium to increase vessel
wall adhesiveness to circulating effector cells in the general area of
injury (3, 4). IL-1 also directs the secretion of other
cytokines, such as TNF-, IL-6, and IFN-.
The IL-1 family of cytokines includes the agonists IL-1ß, IL-1,
and the IL-1R antagonist (5). Both IL-1 agonists signal
through the IL-1R type 1
(IL-1R1)4 (6, 7) and initiate a number of downstream events, including nuclear
translocation of NF-B, a rel-related transcription factor
that activates expression of many inflammatory and immune response
genes (7, 8, 9).
IL-1 binding to the IL-1R1 induces the formation of a receptor complex
that includes the IL-1R accessory protein (10, 11, 12). An
intracellular adapter molecule, MyD88, is then recruited to the complex
(13), providing a platform for the IL-1R-associated kinase
(IRAK) (14). IRAK subsequently undergoes phosphorylation
and interacts with the TNFR-associated factor-6, a downstream
transducer required for NF-B activation induced by IL-1
(14, 15, 16).
IRAK is also involved in IL-18 signal transduction. Though its amino
acid sequence and chromosomal localization differ from those of
IL-1, IL-1ß, and the IL-1Ra, IL-18 shares structural features with
these IL-1 family members (17, 18). In conjunction with
IL-12, IL-18 supports Th1 lymphocyte development and proliferation
(17, 19), enhances NK cell proliferation and activity
(20, 21), and induces IFN- production in both types of
cells (17, 19, 21, 22, 23). The ligand binding subunit of the
IL-18R is the IL-1R-related protein (24), and IL-18
stimulation of cells also leads to IRAK activation and NF-B nuclear
translocation (19, 25, 26).
Although the role of IRAK in NF-B activation mediated by either IL-1
or IL-18 has not been defined, two lines of evidence suggest that it
may be required. First, IRAK is a vertebrate homologue of the
Drosophila protein kinase Pelle. Pelle is required in a
signaling cascade that specifies body axis formation; genetic
inactivation of pelle completely blocks nuclear localization
of Dorsal, the Drosophila rel protein that establishes
dorsoventral polarity in the embryo (27, 28). Second,
experiments involving mutant forms of the IL-1R1 have demonstrated a
close association between IRAK activity and NF-B activation.
Mutations in the cytoplasmic tail of the receptor that block NF-B
activation also cannot recruit IRAK to the receptor complex
(29).
In this report we describe the generation and initial characterization
of IRAK-deficient cells and mice. We show that cells lacking IRAK fail
to activate NF-B in response to IL-1 stimulation. We also show that
IL-18 signaling is compromised in IRAK-deficient cells. We further
demonstrate that IRAK-deficient animals exhibit an impaired response to
IL-1 stimulation. Finally, Irak-null mice retain a normal
response to Listeria monocytogenes infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Genomic DNA from five mouse YACs spanning the telocentric murine X chromosome from positions 29.4 to 30.5 (C39D5, D7413C, H864F2, C176B11, and B7S6, provided by A. Chatterjee, Houston, TX) (30) were screened using PCR. The upstream primer corresponded to intron 5 and had the sequence TTAAGAAGCTCTGTTT. The downstream primer was from exon 6 and had the sequence CCTTCCATAGATTTGG. These primers amplified a 137-bp fragment. PCR products were resolved on a 1.5% agarose gel stained with ethidium bromide.
Generation of IRAK-deficient mice
Two overlapping clones spanning the murine Irak locus were isolated from a 129 Sv genomic library using the human IRAK cDNA as a probe. A targeting vector was constructed which replaced 7 kb of the Irak gene, including 3.5 kb of the 5' regulatory region, exons 1–8, and most of exon 9 with a neomycin resistance gene and included the HSV-tk gene in the vector sequence.
E1.1C ES cells (from K. Graves, Dallas, TX) were cultured on mitotically inactivated STO cells (from J. Herz, Dallas, TX) in DMEM supplemented with 15% FCS, penicillin-streptomycin, L-glutamine, nonessential amino acids, and 2-ME. ES cells were electroporated in medium with linearized targeting vector (50 µg/ml). Transformants were selected in G418 and ganciclovir, and doubly resistant clones were screened by Southern blot hybridization of NdeI-digested DNA and a random-primed 3'-flanking probe and were confirmed using both a 5'-flanking probe and neomycin resistance gene probe.
Chimeric mice were produced from embryos injected with targeted ES cells. Male chimeras were bred with C57BL/6 females. Germline transmission of injected ES cells was determined by agouti coat color and the presence of the targeted locus determined by Southern blotting of tail genomic DNA. Heterozygous females were then crossed back to chimeric founders to yield homozygous and hemizygous null mice. Subsequent generations were produced by sibling-sibling intercrosses.
Generation of IRAK-deficient fibroblasts
IRAK-deficient murine embryonic fibroblasts (MEFs) were obtained from 11.5 day postconception embryos and selected and transformed as described previously (31). Neomycin-resistant MEFs derived from the same ES cell subclone (provided by J. Herz) and prepared using the same methods served as controls for all experiments.
Generation of activated splenocytes and in vitro response to IL-18
Spleens were harvested from IRAK-deficient mice and heterozygous
littermates and transferred to medium (RPMI 1640 supplemented with 10%
fetal bovine serum, 50 µM 2-ME, 2 mM L-glutamine, 0.1 mM
nonessential amino acids, 50 U/ml penicillin, and 50 µg/ml
streptomycin). Spleen cells were dispersed by grinding the spleens
between two frosted glass slides. After filtration of the ground spleen
through a cell strainer, RBC were removed by hypotonic lysis. Spleen
cells (4 x 106 cells/ml) were washed with
medium and stimulated with immobilized -CD3 mAb (1 µg/ml) for 3
days. Cells were washed with medium, transferred to a 24-well plate
(1 x 106 cells/well), and incubated with
varying concentrations of murine IL-18 in the absence or the presence
of 10 ng/ml murine IL-12 for 24 h. Culture supernatants were
collected and assayed for IFN- production by ELISA.
Immunoprecipitation and Western blot hybridization
MEFs grown to confluence in 100-mm plates were collected and incubated in 1 ml of lysis buffer on ice with occasional rocking for 30 min. The suspension was centrifuged at 2000 x g for 10 min. Immunoprecipitation and immunoblotting of murine IRAK protein using rabbit polyclonal antisera raised against human IRAK were performed essentially as described for human IRAK (12).
In vitro response to IL-1ß and EMSA
IRAK-deficient and control MEFs were grown to confluence in
100-mm plates. Recombinant human IL-1ß (10 ng/ml), TNF- (10
ng/ml), or no cytokine was added to the medium. Nuclear extracts were
prepared 30 min after incubation with the cytokine as previously
described (32) and were tested for the ability to shift
the electrophoretic mobility of a
32-P-radiolabeled oligonucleotide containing an
NF-B binding site derived from the human Ig -chain promoter.
Delayed-type hypersensitivity response
Mice were sensitized to 2,4-dinitrofluorobenzene (DNFB) and challenged later, essentially as previously described (33). For sensitization, shaved abdomens of mice were treated with 25 µl of 0.5% DNFB in acetone/olive oil (4/1). Seven days later, baseline ear thickness was measured, and one ear from each mouse was challenged with 0.2% DNFB (10 µl/side of ear pinna). Twenty-four hours later, ear thickness was measured three times, and the average change from baseline was recorded.
In vivo response to IL-1ß injection
Before cytokine injection, 20 µl of whole blood was obtained
from each animal for complete blood counts (CBC) and differential
leukocyte count. Animals were then injected with recombinant murine
IL-1ß i.p. (R&D Systems, Minneapolis, MN). One and a half hours after
cytokine injection, serum was obtained from half the animals for
subsequent cytokine analysis. Three hours postinjection, serum was
obtained from the remaining half of the injected animals. Six hours
after injection, an additional 20 µl of whole blood was drawn from
each animal for CBC and differential count determinations. Twenty-four
hours after injection, animals were euthanized, and serum was
collected. Hybrid (C57BL/6 x 129 Sv/J) wild-type (WT) and
knockout (KO) mice from F3 and
F4 generations were used in these experiments.
Serum IL-6 and TNF- concentrations were measured using ELISA (R & D
Systems).
CBC was measured using an automated cell counter (Coulter Electronics, Hialeah, FL). Differential counts were determined manually, and absolute numbers of polymorphonuclear leukocytes were calculated by multiplying the total white blood cell count by the fraction of neutrophils plus the fraction of band forms.
L. monocytogenes infection
Virulent L. monocytogenes isolated from homogenized mouse liver (provided by C. Lu, Dallas, TX) was grown in brain-heart infusion broth and frozen at -70°C in 200-µl aliquots in 25% glycerol at a density of 3 x 109 CFU/ml.
Mice were injected i.p. with live Listeria organisms. For determination of lethal dose, six groups of five WT mice each were injected with 3 x 103, 3 x 104, 3 x 105, 3 x 106, and 3 x 107 CFU/25 g and monitored daily for survival. The WT and KO mice were then injected with 2 x 104, 2 x 105, 1.2 x 106, and 1.2 x 107 CFU/25 g and were monitored daily for survival. For determination of chronic infection, mice surviving infection with 2.5–5.0 x 106 CFU/25 g were sacrificed 45–60 days after infection, and bacterial organ content was determined. After sacrifice, livers and spleens were removed, weighed, and homogenized in PBS. Lysates were plated as serial 10-fold dilutions on trypticase soy agar plates, and bacterial colonies were counted to determine organ bacterial load (CFU per 100 mg of tissue). For sterilizing immunity experiments, mice surviving and initial infection of 2 x 105 CFU/25 g were rechallenged with a lethal dose (3 x 107 CFU/25 g), and survival was monitored for 2 wk.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous mapping of a panel of hamster-human radiation-induced hybrids (J. L. Allen, unpublished observations) as well as sequencing of four overlapping cosmids covering the human MeCP2 locus by others (GenBank accession no. AF030876) localized Irak to Xq28. This region is syntenic to positions 29.5–29.7 on the murine X chromosome (34).
As a first step in making an IRAK-deficient mouse, we wished to learn
whether murine Irak also mapped to the X chromosome. Using
DNA from five contiguous YACs spanning Xq29.4 to Xq30.5
(30), we assigned murine Irak to a 50-kb region
of overlap between the telomeric end of YAC D741C3 and the centromeric
end of B7S6, between the genes for the type 2 vasopressin receptor
(Avp2r; Xq29.52) and red-sensitive visual pigment (Rsvp; Xq29.7; Fig. 1
). The amplified region contains
sequence from the N-terminal region of the kinase domain and an
adjacent intron. This location falls within the broader map position
for Irak recently defined using interspecific backcross
analysis (35). Examination of known X-linked human and
mouse diseases and syndromes in this region failed to identify any
phenotypes expected for a mutation affecting a cytokine signaling
molecule.
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A). The targeting
plasmid was transfected into E1.1C ES cells, which were then cultured
in the presence of G418 and ganciclovir. A single clone bearing the
targeted allele was identified among 1100 doubly resistant
transformants screened by Southern blot hybridization with the
downstream flanking probe (Fig. 2B, lane 16).
Targeted Irak gene disruption was confirmed with Southern
hybridization using the upstream flanking probe and a probe to the
neor gene (data not shown). The mutant ES
clone was expanded and injected into C57BL/6 blastocysts.
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B
Because most ES cells, including the ones we used, have an XY
karyotype, mutating a gene on the X chromosome leaves these cells and
their descendents without a WT copy. To determine the effect of
deleting Irak on IL-1 signaling, we isolated MEFs from
chimeric embryos, using G418 to select for Irak-null MEFs.
For control cells, we used MEFs derived from E1.1C ES cells bearing a
neor gene flanked by two loxP
sites adjacent to an unrelated autosomal locus (36). MEFs
obtained from chimeric embryos and surviving G418 selection contained
the targeted allele, whereas control cells exhibited a WT restriction
pattern (Fig. 3A).
Furthermore, KO MEFs do not express the IRAK protein, while control
cells do (Fig. 3B).
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on
NF-B activity using EMSA (Fig. 3
C). Control WT cells have
little or no detectable NF-B activity in the resting state.
Stimulation with either IL-1ß or TNF- leads to NF-B activation
in these cells. IRAK-deficient MEFs, like control cells, show little
baseline NF-B activity. When stimulated with IL-1ß, however, the
IRAK-deficient cells showed no increase in NF-B activity.
Furthermore, KO fibroblasts retain the ability to respond to TNF
stimulation with NF-B activation, although the intensity of the
response was attenuated compared with that in control cells. These
results suggest that the IRAK protein transmits the IL-1 signal to
NF-B at the doses assayed. IRAK-deficient mice are viable and fertile
Injection of mutant ES cells into host blastocysts yielded seven
high percentage chimeric mice, as determined by agouti coat color. Two
male chimeras transmitted the allele through the germline.
F1 females bearing the targeted allele were
backcrossed to the male chimeras to produce homozygous and hemizygous
null mice. Fig. 2C shows a typical Southern blot identifying
WT, heterozygous, and KO genotypes.
Mice lacking a wild-type Irak gene appear healthy when housed in clean conditions (filter-top cages, autoclaved bedding and water, and irradiated food). They are indistinguishable from WT and heterozygous littermates and grow normally. To date, KO animals have reached 24 mo of age without apparent ill effects. Their organs appear normal in size, morphology, and relation. Histologic examination of lymphoid organs from immunologically naive animals as well as heart, liver, and kidney uncovered no differences between WT and IRAK-deficient animals. Flow cytometric analysis of major leukocyte subpopulations from bone marrow, lymph nodes, Peyer’s patches, thymus, spleen, and peripheral blood showed normal numbers of lymphocytes, macrophages, and granulocytes in both WT and KO mice. IRAK-deficient animals breed well and have normal-sized litters.
Irak-deficient mice exhibit an attenuated response to IL-1
In humans and other mammals IL-1 causes fever, cytokine secretion
(including IL-6 and TNF-), and reactive neutrophilia among other
responses (5). Inhibition of IL-1 signaling by passive
immunization against IL-1, IL-1R1 antagonism (37, 38), or
genetic deletion of the cytokine or the type I receptor
(39, 40, 41) decreases or abolishes these responses. To
determine whether IRAK mediates these IL-1 responses, we challenged WT
and IRAK-deficient mice with IL-1ß and measured serum cytokine
concentrations and neutrophils in peripheral blood.
We injected animals with three i.p. doses of murine IL-1ß (1, 10, and
20 µg/kg) and assayed serum IL-6 and TNF- concentrations at 1.5
and 3 h after injection. Before injection of IL-1, we performed
baseline CBCs in animals receiving the highest IL-1 dose. We avoided
sampling more than 200 µl of whole blood (10% of the estimated blood
volume of a 25-g mouse) during the 6-h test period to prevent
introducing a stress response associated with hypovolemic or
hemorrhagic shock. Neither WT nor KO mice had detectable circulating
IL-6 or TNF- before IL-1 stimulation (data not shown). One and a
half hours after IL-1 injection, WT mice showed a marked increase in
the serum IL-6 response (Fig. 4A). IRAK-deficient mice also
exhibited an IL-6 response to IL-1 administration, but this response
was significantly attenuated compared with that of WT animals at the
three doses tested (Fig. 4A). By three hours after
injection, IL-6 concentrations in WT animals had declined and no longer
differed from those in KO animals (data not shown).
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concentrations, whereas
KO animals showed a diminished TNF response at both doses (Fig. 4B). In fact, TNF was undetectable in one of six animals
tested with the 10µg/kg dose and barely exceeded the ELISA detection
threshold (>23.4 pg/ml) for four of the remaining five animals (Fig. 4B). We did not assay TNF- concentrations in the mice
treated with the lowest IL-1 dose. Therefore, IRAK also appears to
mediate a modest, but definite, increase in serum TNF-
concentrations following systemic IL-1ß administration. Together,
these data demonstrate that IRAK-deficient mice display impaired early
cytokine responsiveness to parenterally administered IL-1ß.
IL-1 mediates the translocation of neutrophils from the bone marrow to
the peripheral circulation in response to infection or injury. We
therefore examined reactive neutrophilia, the acute elevation of
neutrophils in circulating blood, in response to IL-1 stimulation to
determine whether deletion of Irak affected this process.
Six hours after IL-1 injection, we determined the CBC and calculated
the percent change in neutrophils from baseline. The WT animals
responded to 20 µg/kg of IL-1ß with an average 10-fold increase in
circulating neutrophils, whereas KO animals exhibited a significantly
smaller increase, approximately one-third that of WT animals (Fig. 4C). The attenuation of IL-1-induced neutrophilia in KO
animals further supports the hypothesis that deletion of
Irak impairs IL-1 signaling in vivo and suggests that
IRAK-deficient mice may have impaired defenses against a variety of
environmental insults.
IRAK-deficient immune effector cells exhibit reduced responsiveness to IL-18
To determine the function of IRAK in IL-18 signaling, we isolated
WT and KO splenocytes and measured their ability to produce IFN- in
response to stimulation with IL-12 and IL-18. The WT and KO splenocytes
produced no detectable IFN- when treated with IL-18 alone (Fig. 5). Treatment with IL-12 alone resulted
in the production of equal amounts of IFN- by both WT and KO cells.
When stimulated with both IL-12 and increasing doses of IL-18, however,
WT splenocytes produced increasing amounts of IFN-. Splenocytes from
KO mice also secreted increasing amounts of IFN- in response to
IL-12 and IL-18 costimulation, but only approximately half that
produced by WT cells at each dose assayed (Fig. 5). These findings
assign IRAK a role in the response of immune effector cells to
IL-18.
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We have also begun to investigate the role played by IRAK in the immune response. We first examined the development of delayed-type hypersensitivity, using contact hypersensitivity as an experimental model. Development of a measurable reaction to a contact immunogen depends on several distinct steps, including Ag processing and presentation, T lymphocyte presence and activation in the lymph node draining the sensitized skin, T cell movement to skin where rechallenge occurs, and the movement of other effector cells to the site of rechallenge (33). IRAK-deficient mice exhibit a brisk contact hypersensitivity response to DNFB, indistinguishable from that of WT controls (data not shown). IRAK is thus not essential in the aforementioned processes involving identification of this Ag and response to repeated exposures.
IRAK-deficient mice have a normal response to Listeria infection
Because both IL-1 and IL-18 have been implicated in the host
response to infection with intracellular parasites
(41, 42, 43, 44, 45), we examined the responses of IRAK-deficient mice
to Listeria infection. L. monocytogenes is a
facultative, Gram-positive intracellular bacterium. When administered a
sublethal inoculum of Listeria, WT mice clear the infection
and develop the ability to eliminate a second infection much more
quickly (sterilizing immunity). We injected WT and KO animals with
sublethal (1.2 x 106 CFU/25 g) and lethal
(1.2 x 107 CFU/25 g) doses and recorded
mortality. No difference in mortality, either in time to death or total
numbers of animals per group, were found between WT and IRAK-deficient
mice (Table I). Furthermore, we observed
no difference in numbers of live Listeria recovered from the
livers and spleens from either WT or IRAK-deficient mice 3 days after
infection (Table II).
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). Thus,
IRAK neither mediates mortality to overwhelming Listeria
infection nor is it required for the development of sterilizing
immunity to Listeria in mice. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-6 secretion when administered IL-1. Mutant
animals are also less capable of mobilizing neutrophils in response to
injected IL-1 than their WT counterparts. Furthermore, in acute
experiments, IL-18-treated splenocytes from IRAK-deficient mice produce
approximately half the IFN- of those produced by their WT
counterparts. We generated IRAK-deficient mice from a single mutant ES cell clone, raising the possibility that the impaired cytokine responsiveness could be due to other mutations introduced into ES cells during transfection and selection and not to specific inactivation of the Irak gene. Two circumstances argue against this eventuality. First, another independent research group has targeted the Irak locus and described essentially identical findings. They report impaired IL-1 responsiveness in fibroblasts isolated from IRAK-deficient embryos and postnatal mice (46) and diminished biochemical and biological responses to IL-18 in mice, Th1 lymphocytes, and NK cells lacking IRAK (47). Furthermore, defective cytokine responses persist in our mice at the F6 generation, suggesting, although not confirming, that only the mutant Irak locus is responsible for the phenotype seen in our animals.
The defective cytokine and neutrophil responses in IRAK-deficient
animals and the impaired IFN- production by splenocytes isolated
from mice lacking IRAK may be due partly or entirely to lack of optimal
NF-B activation induced by IL-1 and IL-18. We have shown that
fibroblasts lacking IRAK do not activate NF-B in response to IL-1,
but retain the ability to do so with TNF treatment. Kanakaraj et al.
(46) also demonstrate attenuation of IL-1-induced NF-B
activation in IRAK-deficient fibroblasts, but report overriding this
diminished responsiveness with increasing doses of IL-1. At 10 ng/ml
(the maximum dose used by Kanakaraj et al.), we still see marked
down-regulation of signal-induced NF-B activation, although we have
also observed partial restoration of NF-B responsiveness to IL-1 in
cells that have undergone prolonged passage in culture (data not
shown).
Deletion of IRAK, therefore, attenuates, but does not eliminate, the cytokine responsiveness of mutant mice and cells. These results contrast with those seen in mice lacking MyD88, the adapter protein that provides a platform for IRAK recruitment to the activated receptor complex. MyD88-deficient animals produce no IL-6 or TNF when given IL-1, and cells from these mice fail to respond to IL-18 (48). These results suggest that while MyD88 mediates the known biological functions of IL-1 and IL-18, IRAK is not strictly required for these same functions. The presence of IRAK results in optimal signaling through both receptors, but its absence does not abolish signal transduction. Therefore, signal initiated at the IL-1R1, IL-18R, and human Toll-like receptor-4 (49) must pass through MyD88. In IRAK-deficient mice, the signal proceeds through an IRAK-independent pathway but loses strength. The signaling mechanism operative in mice lacking IRAK may represent a compensatory response to IRAK deletion or may reflect a bifurcation of the signal that occurs in the WT downstream of MyD88. Furthermore, this alternate route may be mediated by an IRAK-like molecule, such as IRAK2 (50), or may operate through an unrelated mechanism. Both redundancy and compensation could explain why mice can still produce IL-6 and TNF and mobilize neutrophils in response to IL-1 as well as retain delayed hypersensitivity and clear Listeria infections.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. James A. Thomas, Department of Pediatrics, Room NA5.320A, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9148. E-mail address:
3 Current address: Department of Biology, University of California at San Diego, La Jolla, CA 92093-0634.
4 Abbreviations used in this paper: IL-1R1, IL-1R type 1; IRAK, IL-1R-associated kinase; MEF, murine embryonic fibroblast; DNFB, 2,4-dinitrofluorobenzene; CBC, complete blood count; WT, wild type; KO, knockout; YAC, yeast artificial chromosome; ES cell, embryonic stem cell.
Received for publication December 10, 1998. Accepted for publication May 5, 1999.
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R. Zhande, S. M. Dauphinee, J. A. Thomas, M. Yamamoto, S. Akira, and A. Karsan FADD Negatively Regulates Lipopolysaccharide Signaling by Impairing Interleukin-1 Receptor-Associated Kinase 1-MyD88 Interaction Mol. Cell. Biol., November 1, 2007; 27(21): 7394 - 7404. [Abstract] [Full Text] [PDF]
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M. P. Butler, J. A. Hanly, and P. N. Moynagh Kinase-active Interleukin-1 Receptor-associated Kinases Promote Polyubiquitination and Degradation of the Pellino Family: DIRECT EVIDENCE FOR PELLINO PROTEINS BEING UBIQUITIN-PROTEIN ISOPEPTIDE LIGASES J. Biol. Chem., October 12, 2007; 282(41): 29729 - 29737. [Abstract] [Full Text] [PDF]
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 C. Brikos, R. Wait, S. Begum, L. A. J. O'Neill, and J. Saklatvala Mass Spectrometric Analysis of the Endogenous Type I Interleukin-1 (IL-1) Receptor Signaling Complex Formed after IL-1 Binding Identifies IL-1RAcP, MyD88, and IRAK-4 as the Stable Components Mol. Cell. Proteomics, September 1, 2007; 6(9): 1551 - 1559. [Abstract] [Full Text] [PDF]
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T. Kawagoe, S. Sato, A. Jung, M. Yamamoto, K. Matsui, H. Kato, S. Uematsu, O. Takeuchi, and S. Akira Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling J. Exp. Med., May 14, 2007; 204(5): 1013 - 1024. [Abstract] [Full Text] [PDF]
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Y. Luo, H.-J. Kwon, S. Montano, M. Georgiadis, M. G. Goebl, and M. A. Harrington Phosphorylation of SIMPL modulates RelA-associated NF-{kappa}B-dependent transcription Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1013 - C1023. [Abstract] [Full Text] [PDF]
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 E. L. Lowe, T. M. Doherty, H. Karahashi, and M. Arditi Review: Ubiquitination and de-ubiquitination: role in regulation of signaling by Toll-like receptors Innate Immunity, December 1, 2006; 12(6): 337 - 345. [Abstract] [PDF]
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 H. Hacker and M. Karin Regulation and Function of IKK and IKK-Related Kinases Sci. Signal., October 17, 2006; 2006(357): re13 - re13. [Abstract] [Full Text] [PDF]
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 J. Arcaroli, E. Silva, J. P. Maloney, Q. He, D. Svetkauskaite, J. R. Murphy, and E. Abraham Variant IRAK-1 Haplotype Is Associated with Increased Nuclear Factor-{kappa}B Activation and Worse Outcomes in Sepsis Am. J. Respir. Crit. Care Med., June 15, 2006; 173(12): 1335 - 1341. [Abstract] [Full Text] [PDF]
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M. Lotz, D. Gutle, S. Walther, S. Menard, C. Bogdan, and M. W. Hornef Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells J. Exp. Med., April 17, 2006; 203(4): 973 - 984. [Abstract] [Full Text] [PDF]
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 J. Sun, F. Wiklund, F.-C. Hsu, K. Balter, S. L. Zheng, J.-E. Johansson, B. Chang, W. Liu, T. Li, A. R. Turner, et al. Interactions of sequence variants in interleukin-1 receptor-associated kinase4 and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk. Cancer Epidemiol. Biomarkers Prev., March 1, 2006; 15(3): 480 - 485. [Abstract] [Full Text] [PDF]
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 Y. Fu, C. Xie, J. Chen, J. Zhu, H. Zhou, J. Thomas, X. J. Zhou, and C. Mohan Innate Stimuli Accentuate End-Organ Damage by Nephrotoxic Antibodies via Fc Receptor and TLR Stimulation and IL-1/TNF-{alpha} Production J. Immunol., January 1, 2006; 176(1): 632 - 639. [Abstract] [Full Text] [PDF]
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A. Dunne and L. O'Neill New insights into the post-translational modification of Toll-like receptor signaling molecules Innate Immunity, December 1, 2005; 11(6): 325 - 332. [Abstract] [PDF]
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T. P. Carroll, C. M. Greene, C. C. Taggart, A. G. Bowie, S. J. O'Neill, and N. G. McElvaney Viral Inhibition of IL-1- and Neutrophil Elastase-Induced Inflammatory Responses in Bronchial Epithelial Cells J. Immunol., December 1, 2005; 175(11): 7594 - 7601. [Abstract] [Full Text] [PDF]
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K. Ohnuma, T. Yamochi, M. Uchiyama, K. Nishibashi, S. Iwata, O. Hosono, H. Kawasaki, H. Tanaka, N. H. Dang, and C. Morimoto CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells Mol. Cell. Biol., September 1, 2005; 25(17): 7743 - 7757. [Abstract] [Full Text] [PDF]
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J.-a Kim, D. C. Yeh, M. Ver, Y. Li, A. Carranza, T. P. Conrads, T. D. Veenstra, M. A. Harrington, and M. J. Quon Phosphorylation of Ser24 in the Pleckstrin Homology Domain of Insulin Receptor Substrate-1 by Mouse Pelle-like Kinase/Interleukin-1 Receptor-associated Kinase: CROSS-TALK BETWEEN INFLAMMATORY SIGNALING AND INSULIN SIGNALING THAT MAY CONTRIBUTE TO INSULIN RESISTANCE J. Biol. Chem., June 17, 2005; 280(24): 23173 - 23183. [Abstract] [Full Text] [PDF]
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H. Cheung, N.-J. Chen, Z. Cao, N. Ono, P. S. Ohashi, and W.-C. Yeh Accessory Protein-Like Is Essential for IL-18-Mediated Signaling J. Immunol., May 1, 2005; 174(9): 5351 - 5357. [Abstract] [Full Text] [PDF]
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S. Uematsu, S. Sato, M. Yamamoto, T. Hirotani, H. Kato, F. Takeshita, M. Matsuda, C. Coban, K. J. Ishii, T. Kawai, et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction J. Exp. Med., March 21, 2005; 201(6): 915 - 923. [Abstract] [Full Text] [PDF]
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D. De Nardo, P. Masendycz, S. Ho, M. Cross, A. J. Fleetwood, E. C. Reynolds, J. A. Hamilton, and G. M. Scholz A Central Role for the Hsp90{middle dot}Cdc37 Molecular Chaperone Module in Interleukin-1 Receptor-associated-kinase-dependent Signaling by Toll-like Receptors J. Biol. Chem., March 18, 2005; 280(11): 9813 - 9822. [Abstract] [Full Text] [PDF]
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F. Hatao, M. Muroi, N. Hiki, T. Ogawa, Y. Mimura, M. Kaminishi, and K.-i. Tanamoto Prolonged Toll-like receptor stimulation leads to down-regulation of IRAK-4 protein J. Leukoc. Biol., October 1, 2004; 76(4): 904 - 908. [Abstract] [Full Text] [PDF]
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E. Lye, C. Mirtsos, N. Suzuki, S. Suzuki, and W.-C. Yeh The Role of Interleukin 1 Receptor-associated Kinase-4 (IRAK-4) Kinase Activity in IRAK-4-mediated Signaling J. Biol. Chem., September 24, 2004; 279(39): 40653 - 40658. [Abstract] [Full Text] [PDF]
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M. Siedlar, M. Frankenberger, E. Benkhart, T. Espevik, M. Quirling, K. Brand, M. Zembala, and L. Ziegler-Heitbrock Tolerance Induced by the Lipopeptide Pam3Cys Is Due to Ablation of IL-1R-Associated Kinase-1 J. Immunol., August 15, 2004; 173(4): 2736 - 2745. [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. 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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J.-L. Imler and L. Zheng Biology of Toll receptors: lessons from insects and mammals J. Leukoc. Biol., January 1, 2004; 75(1): 18 - 26. [Abstract] [Full Text] [PDF]
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N. Suzuki, S. Suzuki, U. Eriksson, H. Hara, C. Mirtosis, N.-J. Chen, T. Wada, D. Bouchard, I. Hwang, K. Takeda, et al. IL-1R-Associated Kinase 4 Is Required for Lipopolysaccharide- Induced Activation of APC J. Immunol., December 1, 2003; 171(11): 6065 - 6071. [Abstract] [Full Text] [PDF]
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S. Akira Toll-like Receptor Signaling J. Biol. Chem., October 3, 2003; 278(40): 38105 - 38108. [Full Text] [PDF]
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A. E. Medvedev, A. Lentschat, D. B. Kuhns, J. C.G. Blanco, C. Salkowski, S. Zhang, M. Arditi, J. I. Gallin, and S. N. Vogel Distinct Mutations in IRAK-4 Confer Hyporesponsiveness to Lipopolysaccharide and Interleukin-1 in a Patient with Recurrent Bacterial Infections J. Exp. Med., August 18, 2003; 198(4): 521 - 531. [Abstract] [Full Text] [PDF]
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C. Ropert, M. Closel, A. C. L. Chaves, and R. T. Gazzinelli Inhibition of a p38/Stress-Activated Protein Kinase-2-Dependent Phosphatase Restores Function of IL-1 Receptor-Associated Kinase-1 and Reverses Toll-Like Receptor 2- and 4-Dependent Tolerance of Macrophages J. Immunol., August 1, 2003; 171(3): 1456 - 1465. [Abstract] [Full Text] [PDF]
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 J. A. Thomas, S. B. Haudek, T. Koroglu, M. F. Tsen, D. D. Bryant, D. J. White, D. F. Kusewitt, J. W. Horton, and B. P. Giroir IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction Am J Physiol Heart Circ Physiol, August 1, 2003; 285(2): H597 - H606. [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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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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R. M. Hobbs and F. M. Watt Regulation of Interleukin-1{alpha} Expression by Integrins and Epidermal Growth Factor Receptor in Keratinocytes from a Mouse Model of Inflammatory Skin Disease J. Biol. Chem., May 23, 2003; 278(22): 19798 - 19807. [Abstract] [Full Text] [PDF]
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N. Suzuki, N.-J. Chen, D. G. Millar, S. Suzuki, T. Horacek, H. Hara, D. Bouchard, K. Nakanishi, J. M. Penninger, P. S. Ohashi, et al. IL-1 Receptor-Associated Kinase 4 Is Essential for IL-18-Mediated NK and Th1 Cell Responses J. Immunol., April 15, 2003; 170(8): 4031 - 4035. [Abstract] [Full Text] [PDF]
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C. Deng, C. Radu, A. Diab, M. F. Tsen, R. Hussain, J. S. Cowdery, M. K. Racke, and J. A. Thomas IL-1 Receptor-Associated Kinase 1 Regulates Susceptibility to Organ-Specific Autoimmunity J. Immunol., March 15, 2003; 170(6): 2833 - 2842. [Abstract] [Full Text] [PDF]
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 B. Shen and J. L. Manley Pelle kinase is activated by autophosphorylation during Toll signaling in Drosophila Development, March 6, 2003; 129(8): 1925 - 1933. [Abstract] [Full Text] [PDF]
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A. Dunne and L. A. J. O'Neill The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense Sci. Signal., February 25, 2003; 2003(171): re3 - re3. [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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S.-J. Yeo, J.-G. Yoon, S.-C. Hong, and A.-K. Yi CpG DNA Induces Self and Cross-Hyporesponsiveness of RAW264.7 Cells in Response to CpG DNA and Lipopolysaccharide: Alterations in IL-1 Receptor-Associated Kinase Expression J. Immunol., January 15, 2003; 170(2): 1052 - 1061. [Abstract] [Full Text] [PDF]
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S. Bozinovski, J. E. Jones, R. Vlahos, J. A. Hamilton, and G. P. Anderson Granulocyte/Macrophage-Colony-stimulating Factor (GM-CSF) Regulates Lung Innate Immunity to Lipopolysaccharide through Akt/Erk Activation of NFkappa B and AP-1 in Vivo J. Biol. Chem., November 1, 2002; 277(45): 42808 - 42814. [Abstract] [Full Text] [PDF]
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K.-Y. Yu, H.-J. Kwon, D. A. M. Norman, E. Vig, M. G. Goebl, and M. A. Harrington Cutting Edge: Mouse Pellino-2 Modulates IL-1 and Lipopolysaccharide Signaling J. Immunol., October 15, 2002; 169(8): 4075 - 4078. [Abstract] [Full Text] [PDF]
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J. A. Thomas, M. F. Tsen, D. J. White, and J. W. Horton TLR4 inactivation and rBPI21 block burn-induced myocardial contractile dysfunction Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1645 - H1655. [Abstract] [Full Text] [PDF]
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J. C. M. Morel, C. C. Park, K. Zhu, P. Kumar, J. H. Ruth, and A. E. Koch Signal Transduction Pathways Involved in Rheumatoid Arthritis Synovial Fibroblast Interleukin-18-induced Vascular Cell Adhesion Molecule-1 Expression J. Biol. Chem., September 13, 2002; 277(38): 34679 - 34691. [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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S. Li, A. Strelow, E. J. Fontana, and H. Wesche IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase PNAS, April 16, 2002; 99(8): 5567 - 5572. [Abstract] [Full Text] [PDF]
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E. P. McDermott and L. A. J. O'Neill Ras Participates in the Activation of p38 MAPK by Interleukin-1 by Associating with IRAK, IRAK2, TRAF6, and TAK-1 J. Biol. Chem., March 1, 2002; 277(10): 7808 - 7815. [Abstract] [Full Text] [PDF]
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A. Castrillo, D. J. Pennington, F. Otto, P. J. Parker, M. J. Owen, and L. Bosca Protein Kinase C{epsilon} Is Required for Macrophage Activation and Defense Against Bacterial Infection J. Exp. Med., October 29, 2001; 194(9): 1231 - 1242. [Abstract] [Full Text] [PDF]
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 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]
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B. Wang, C. Feliciani, I. Freed, Q. Cai, and D. N. Sauder Insights into molecular mechanisms of contact hypersensitivity gained from gene knockout studies J. Leukoc. Biol., August 1, 2001; 70(2): 185 - 191. [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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 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]
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M. T. Diaz-Meco and J. Moscat MEK5, a New Target of the Atypical Protein Kinase C Isoforms in Mitogenic Signaling Mol. Cell. Biol., February 15, 2001; 21(4): 1218 - 1227. [Abstract] [Full Text]
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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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U. Kalina, D. Kauschat, N. Koyama, H. Nuernberger, K. Ballas, S. Koschmieder, G. Bug, W.-K. Hofmann, D. Hoelzer, and O. G. Ottmann IL-18 Activates STAT3 in the Natural Killer Cell Line 92, Augments Cytotoxic Activity, and Mediates IFN-{gamma} Production by the Stress Kinase p38 and by the Extracellular Regulated Kinases p44erk-1 and p42erk-21 J. Immunol., August 1, 2000; 165(3): 1307 - 1313. [Abstract] [Full Text] [PDF]
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J. L. Swantek, M. F. Tsen, M. H. Cobb, and J. A. Thomas IL-1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin J. Immunol., April 15, 2000; 164(8): 4301 - 4306. [Abstract] [Full Text] [PDF]
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 Z. CAO, M. TANAKA, C. REGNIER, M. ROTHE, A. YAMIT-HEZI, J.D. WORONICZ, M.E. FUENTES, M.H. DURNIN, S.A. DALRYMPLE, and D.V. GOEDDEL NF-{kappa}B Activation by Tumor Necrosis Factor and Interleukin-1 Cold Spring Harb Symp Quant Biol, January 1, 1999; 64(0): 473 - 484. [Abstract] [PDF]
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L. Li, S. Cousart, J. Hu, and C. E. McCall Characterization of Interleukin-1 Receptor-associated Kinase in Normal and Endotoxin-tolerant Cells J. Biol. Chem., July 21, 2000; 275(30): 23340 - 23345. [Abstract] [Full Text] [PDF]
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M. K. MacGillivray, T. F. Cruz, and C. A. G. McCulloch The Recruitment of the Interleukin-1 (IL-1) Receptor-associated Kinase (IRAK) into Focal Adhesion Complexes Is Required for IL-1beta -induced ERK Activation J. Biol. Chem., July 28, 2000; 275(31): 23509 - 23515. [Abstract] [Full Text] [PDF]
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T. L. Born, D. E. Smith, K. E. Garka, B. R. Renshaw, J. S. Bertles, and J. E. Sims Identification and Characterization of Two Members of a Novel Class of the Interleukin-1 Receptor (IL-1R) Family. DELINEATION OF A NEW CLASS OF IL-1R-RELATED PROTEINS BASED ON SIGNALING J. Biol. Chem., September 22, 2000; 275(39): 29946 - 29954. [Abstract] [Full Text] [PDF]
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E. Vig, M. Green, Y. Liu, K.-Y. Yu, H.-J. Kwon, J. Tian, M. G. Goebl, and M. A. Harrington SIMPL Is a Tumor Necrosis Factor-specific Regulator of Nuclear Factor-kappa B Activity J. Biol. Chem., March 9, 2001; 276(11): 7859 - 7866. [Abstract] [Full Text] [PDF]
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J. C. M. Morel, C. C. Park, J. M. Woods, and A. E. Koch A Novel Role for Interleukin-18 in Adhesion Molecule Induction through NFkappa B and Phosphatidylinositol (PI) 3-Kinase-dependent Signal Transduction Pathways J. Biol. Chem., September 28, 2001; 276(40): 37069 - 37075. [Abstract] [Full Text] [PDF]
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L. Ling and D. V. Goeddel T6BP, a TRAF6-interacting protein involved in IL-1 signaling PNAS, August 15, 2000; 97(17): 9567 - 9572. [Abstract] [Full Text] [PDF]
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