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1
,§,**
*
First Department of Surgery,
Department of Immunology & Medical Zoology,
Department of Otolaryngology,
§
Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan;
¶
Department of Immunology, National Institute of Animal Health, Tsukuba, Japan;
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Institute for Microbial Diseases, Osaka University, Suita, Japan;
#
Vertex Pharmaceuticals, Cambridge, MA 02139; and
**
Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-12 secretion, respectively. Kupffer cells
deficient in Toll-like receptor (TLR) 4, an LPS-signaling receptor, did
not secrete IL-18, IL-1, and IL-12 upon LPS stimulation. In
contrast, Kupffer cells lacking myeloid differentiation factor 88
(MyD88), an adaptor molecule for TLR-mediated-signaling, secreted IL-18
without IL-1 and IL-12 production in a caspase-1-dependent and de
novo synthesis-independent manner. These results indicate that MyD88 is
essential for IL-12 and IL-1 production from Kupffer cells while
their IL-18 secretion is mediated via activation of endogenous
caspase-1 without de novo protein synthesis in a MyD88-independent
fashion after stimulation with LPS. In addition, infection with
Listeria monocytogenes, products of which have the
capacity to activate TLR, increased serum levels of IL-18 in wild-type
and MyD88-deficient mice but not in caspase-1-deficient mice, whereas
it induced elevation of serum levels of IL-12 in both wild-type and
caspase-1-deficient mice but not in MyD88-deficient mice. Taken
together, these results suggested caspase-1-dependent,
MyD88-independent IL-18 release in bacterial
infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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has
been reported to be processed using the same procedures (7, 8).
Recently, Toll-like receptor (TLR) 4 was identified as a signaling
receptor for LPS (9, 10, 11, 12, 13, 14, 15, 16). TLR4-deficient mice do not
respond to LPS (13, 15). The signal transmission of TLRs
including TLR4 has been identified as using a common signaling pathway
shared with that of IL-1R and IL-18R (11, 16, 17). Thus,
after stimulation with LPS, the Toll/IL-1R (TIR) domain of the
cytoplasmic TLR4, which is highly conserved among TLRs, IL-1R, and
IL-18R, recruits myeloid differentiation factor 88 (MyD88), an adaptor
molecule which also contains TIR domain (16). MyD88 then
evokes a chain reaction starting from phosphorylation of the
IL-1R-associated kinase and IL-1R-associated kinase 2 leading to
nuclear translocation of NF-
B (17, 18). Macrophages or
B cells from MyD88-deficient mice were reported to be unresponsive to
LPS in terms of proinflammatory cytokine production or B cell
proliferation, respectively (19). Furthermore, TLR2
signaling activated by bacterial components other than LPS, such as
lipoproteins, has also been shown to share the same signaling pathway
(15, 20, 21).
Caspase-1, like other caspases, is produced as a biologically inactive
precursor (pro-caspase-1), which becomes enzymatically active after
appropriate cleavage (22, 23). Although LPS has been
demonstrated to activate caspase-1 in human macrophages, the
requirement of TLR4 and/or MyD88 for the activation of caspase-1 is
still to be elucidated (24). Here, we investigated whether
TLR4 and/or MyD88 are prerequisites for caspase-1-dependent IL-18
secretion from macrophages upon stimulation with LPS. As expected,
Kupffer cells, tissue macrophages in the liver, from TLR4-deficient
mice did not secrete IL-18, IL-1, and IL-12 production after
stimulated with LPS. However, MyD88-deficient Kupffer cells secreted
biologically active IL-18 but not IL-1 and IL-12 in response to LPS
in a caspase-1-dependent manner, suggesting that LPS-induced activation
of caspase-1 might be independent of MyD88. Indeed, infection with
Listeria monocytogenes induced equivalently elevated serum
IL-18 levels without IL-12 production in MyD88-deficient mice when
compared with wild-type mice, but not in caspase-1-deficient mice.
Therefore, LPS-induced IL-1 and IL-12 secretion was entirely
dependent on MyD88, whereas in vitro LPS stimulation or in vivo
L. monocytogenes infection induced IL-18 secretion in a
caspase-1-dependent fashion even in the absence of MyD88.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Specific pathogen-free female C57BL/6 mice (6–8 wk old) were purchased from SLC (Shizuoka, Japan). Female caspase-1-deficient mice in C57BL/6 background were used (6, 25). MyD88-deficient mice (26), TLR2-deficient mice (15), and TLR4-deficient mice (13) were backcrossed with C57BL/6, and female F8 (6–8 wk old) were used for this study.
Reagents
LPS derived from Escherichia coli 055:B5 was purchased from Difco (Detroit, MI). Cycloheximide (CHX) was purchased from Wako (Osaka, Japan). LPS from Salmonella minnesota Re-595 and actinomycin D (AcD) were obtained from Sigma (St. Louie, MO). E. coli-type synthetic lipid A (compound 506) was kindly provided by Dr. T. Ogawa at Osaka University (Osaka, Japan) (13). Ab raised against p20 of murine-active caspase-1 was kindly provided by Dr. M. Miura at Osaka University (23). Ac-YVAD-CMK, a caspase-1 inhibitor, was purchased from Peptide Institute (Osaka, Japan). Culture medium generally used in this study was RPMI 1640 supplemented with 10% FCS, 100 U/ml penicillin, 100 µg/ml streptomycin, 50 µM 2-ME, and 2 mM L-glutamine.
Kupffer cell preparation
Kupffer cells were isolated from mice with various genetic backgrounds according to the method described previously (27). Kupffer cells (1 x 106/ml) were incubated with various doses of LPS from various kinds of bacteria or synthetic lipid A for the indicated hours. Supernatants were collected, and the cells (5 x 106) were lysed with 200 µl of the lysis buffer for determining intracellular cytokine concentrations (4, 6). In some experiments, Kupffer cells were preincubated with 1 µg/ml AcD or 10 µg/ml CHX for 1 h and vigorously washed with PBS followed by additional incubation with various doses of E. coli O55:B5 LPS for 24 h. The culture supernatants were collected for measuring cytokine levels. The lysis buffer used was the same as that used for Western blotting (described below).
RT-PCR
Kupffer cells isolated from C57BL/6 mice were incubated with 1
µg/ml E. coli O55:B5 LPS for the indicated hours. Total
RNA was extracted from variously treated Kupffer cells as previously
reported (27). The thermocycle conditions were 95°C for
1 min, 58°C for 1 min, and 72°C for 1 min for the denaturing,
annealing, and extension, respectively. The amplifying cycle is 29 for
caspase-1 and 35 for -actin. Sense and antisense primers for
caspase-1 and those for -actin were described previously (25, 28).
Western blotting
Kupffer cells (1 x 106/ml) from C57BL/6 mice were incubated with 1 µg/ml O55:B5 LPS for 1 h. The cells (5 x 106 cells) were incubated for 15 min in the lysis buffer (150 mM NaCl (pH 7.2) supplemented with 20 mM HEPES, 5 mM N-ethylmaleimide, 1 mM PMSF, 2.5 µg/ml leupeptin, 20 U/ml aprotinin, and 0.1% Triton X-100) at 4°C. The proteins in the cell lysate were separated on SDS-PAGE, transferred onto a nitrocellulose membrane, and blotted with anti-p20 of active caspase-1 (23). The proteins bound to the Abs were visualized using the ECL system (Amersham, Buckinghamshire, U.K.).
Assay for cytokines
IL-18 levels were measured by a commercially available ELISA kit
(MBL, Nagoya, Japan). Concentrations of IL-1 and TNF-
were
determined by ELISA kits (Genzyme, Boston, MA). IL-12 p40 levels were
measured by ELISA kit (BioSource International, Camarillo,
CA).
Infection with L. monocytogenes
Mice with various mutations were i.v. infected with 5 x 105 L. monocytogenes. At day 3, the serum was sampled for determining cytokine concentration.
Statistical analysis
All data are shown as mean ± SD. Significance between the control group and a treated group was examined with the unpaired Student’s t test. A p value of <0.05 was regarded as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As previously reported, murine macrophages, including Kupffer
cells, constitutively express IL-18 mRNA, resulting in constant
production of intracellular proIL-18 (29, 30). We measured
the intracellular and extracellular IL-18 concentrations of Kupffer
cells incubated with LPS and compared them with their IL-1 levels,
because both IL-1 and IL-18 share a common, caspase-1-dependent
secretion machinery in response to LPS (4, 5, 7). Kupffer
cells contained a considerable amount and undetectable amounts of IL-18
and IL-12 p40, respectively (Fig. 1
, A, a and C, a). LPS stimulation of Kupffer cells
induced IL-18 secretion without affecting their cytoplasmic IL-18
levels (Fig. 1A). In contrast, LPS stimulation induced
Kupffer cells to increase both cytoplasmic and secreted IL-12 p40 (Fig. 1C). These results illustrate two extreme cases of cytokine
production, one is precursor protein-derived cytokine production
(IL-18) and the other is newly synthesized protein-derived cytokine
production (IL-12 p40). As shown in Fig. 1B, production of
IL-1 showed an intermediate pattern, because Kupffer cells contained
a substantial amount of IL-1 under normal conditions and markedly
increased levels of IL-1 in both their inside and outside after
stimulation with LPS.
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D, caspase-1 mRNA was constitutively expressed in the
Kupffer cells and became more prominent in its expression after
stimulation with LPS. Next, we tested whether active caspase-1,
composed of p20 and p10, was induced in the Kupffer cells by
stimulation with LPS. As determined by immunoblotting using Ab against
p20, cell lysate from LPS-activated Kupffer cells contained both p20
and pro-caspase-1 of 45 kDa, whereas unstimulated Kupffer cells only
expressed pro-caspase-1 (Fig. 1E). Kupffer cell lysate from
caspase-1-deficient mice did not express either pro-caspase-1 or p20
and failed to produce bioactive IL-18 and IL-1 without showing any
defect in their IL-12 p40 production upon LPS stimulation (data not
shown). Therefore, it is presumed that Kupffer cells constitutively
produced pro-caspase-1 that could be activated by stimulation with
LPS.
Taken together, we propose that LPS-induced secretion of IL-18 and
IL-1 from Kupffer cells may result from at least two separate
biological events. One is LPS-mediated intracellular production of
precursors, such as proIL-18, proIL-1 and pro-caspase-1. A second is
LPS-induced activation of caspase-1, whether depending on new protein
synthesis and/or transcription or not, which converts proIL-18 or
proIL-1 into its corresponding active form. In contrast, IL-12 p40
secretion was shown to be a direct result from the transcription and
translation of the corresponding gene in Kupffer cells after the
stimulation with LPS, and this is entirely independent of
caspase-1.
De novo protein synthesis dispensable for IL-18 secretion
The results obtained (Fig. 1) prompted us to examine the
possibility that secretion of IL-18 and IL-1 might result from the
interaction of intracellularly preformed proteins. To test this
possibility, we investigated whether new protein synthesis is required
for the secretion of IL-18 and/or IL-1. As shown in Fig. 2A, the pretreatment with AcD,
a transcriptional inhibitor, or CHX, a translation inhibitor, did not
suppress secretion of IL-18 from Kupffer cells in response to a low
dose of E. coli LPS. However, moderate inhibitory effects
were observed in the case of the stimulation with a high dose of
E. coli LPS. LPS-induced IL-1 secretion was more
effectively, but not completely, suppressed by the pretreatment with
AcD or CHX (Fig. 2B). The amounts of AcD and CHX used for
this study were sufficient for complete inhibition of IL-12 p40 or
TNF- secretion from the LPS-activated Kupffer cells (Fig. 2, C and D). Taken together, these results indicate
that caspase-1-dependent IL-18 secretion does not necessarily require
de novo protein synthesis, particularly in response to a low amount of
LPS, whereas IL-1 secretion was more dependent on new protein
synthesis than IL-18. TNF- and IL-12 p40 secretion was depending
entirely on new protein synthesis. Based on these results, we propose
that IL-18 is partly secreted in a new protein synthesis-independent,
precursor protein-dependent manner but IL-12 is produced only after de
novo protein synthesis.
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To investigate whether caspase-1 dependent IL-18 secretion from
LPS-activated Kupffer cells requires the activation of the LPS
signaling pathway comprised of TLR4 and MyD88, we examined IL-18
secretion by the Kupffer cells from mutant mice deficient in each
molecule. As shown in Fig. 3A,
Kupffer cells from TLR4-deficient mice secreted a much lower amount of
IL-18 in response to E. coli O55:B5 LPS than those from
wild-type mice, whereas Kupffer cells from MyD88-deficient mice showed
an intermediate IL-18 secretion response. Since TLR4-deficient
peritoneal exudate macrophages can respond to E. coli O55:B5
LPS but are completely unresponsive to E. coli-type
synthetic lipid A (506) or S. minnesota Re-595
LPS (13), we examined whether TLR-4-deficient Kupffer
cells secrete IL-18 in response to synthetic lipid A or S.
minnesota LPS. As shown in Fig. 3, B and C,
TLR4-deficient Kupffer cells did not secrete IL-18 in response to
synthetic lipid A (506) or S. minnesota Re-595
LPS, indicating that TLR4 is required for LPS-induced IL-18 secretion
from Kupffer cells. In contrast, MyD88-deficient Kupffer cells could
secrete an intermediate level of IL-18 in response to synthetic lipid A
or S. minnesota Re-595 LPS, indicating that MyD88 is not
essential for LPS-induced secretion of IL-18. Furthermore, like IL-18
secreted from wild-type Kupffer cells, IL-18 secreted from
MyD88-deficient Kupffer cells showed IFN-
inducing activity (data
not shown), suggesting that LPS-induced activation of caspase-1 might
not require MyD88.
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secretion was dependent on
both TLR4 and MyD88. As shown in Fig. 3, E and F,
neither TLR4-deficient nor MyD88-deficient Kupffer cells secreted
IL-1 in response to synthetic lipid A or S. minnesota
Re-595 LPS. This was also the case for IL-12 p40 secretion (data not
shown).
Next, we investigated whether the MyD88-independent pathway was
caspase-1-dependent and was dominant in LPS-induced, TLR4-dependent
IL-18 secretion. As expected, caspase-1-deficient Kupffer cells did not
secrete IL-18 after stimulation with LPS (Fig. 4A). The secretion of IL-18
from MyD88-deficient Kupffer cells was inhibited by the caspase-1
inhibitor equivalent to that from wild-type Kupffer cells (Fig. 4A). In contrast, caspase-1 inhibitor did not inhibit IL-12
production from wild-type Kupffer cells (Fig. 4A).
Caspase-1-independent IL-12 production was also confirmed by the fact
that LPS stimulation induced IL-12 production in caspase-1-deficient
Kupffer cells (Fig. 4A). Vehicle did not inhibit IL-12 p40
or IL-18 secretion from Kupffer cells from any mutant or wild-type mice
(data not shown). Therefore, IL-18 can be secreted from Kupffer cells
upon stimulation with LPS in a TLR4-dependent, MyD88-independent, and
caspase-1-dependent manner. As described above, IL-18 secreted from
wild-type Kupffer cells upon stimulation with LPS are composed of two
phases in which protein synthesis in one and protein-protein
interaction in the other are involved. We first tested the contribution
of de novo protein synthesis to LPS-induced IL-18 secretion by
comparing MyD88-deficient and wild-type Kupffer cells. As shown in Fig. 4B, AcD pretreatment reduced the amount of IL-18 secretion
from wild-type Kupffer cells to 50%, whereas AcD did not significantly
decrease IL-18 secretion from MyD88-deficient Kupffer cells, indicating
that MyD88-independent IL-18 secretion resulted from the cleavage of
preformed proIL-18 by intrinsic caspase-1 that was activated by LPS in
a MyD88-independent fashion. Alternatively, MyD88 might be only
required for de novo synthesis of proIL-18 and/or pro-caspase-1 in
response to LPS. Second, we compared IL-18 secreted from
MyD88-deficient Kupffer cells to that from wild-type Kupffer cells
under the condition of disrupted new protein synthesis. We found the
amounts of IL-18 secreted from AcD-pretreated LPS-stimulated
MyD88-deficient Kupffer cells were almost equivalent to that from
similarly treated wild-type Kupffer cells, indicating that LPS-induced
caspase-1 activation is almost entirely independent of MyD88 (Fig. 4B). Similar results were obtained by the same experiments
except for using CHX instead of AcD (data not shown). The amounts of
intracellular IL-18 were almost equal between both genotype Kupffer
cells (data not shown). Therefore, it is presumed that caspase-1 may be
activated predominantly in a MyD88-independent manner after stimulation
with LPS and that LPS signaling via MyD88 may induce new protein
synthesis of proIL-18 and pro-caspase-1, presumably resulting in the
accumulation of IL-18 to be secreted.
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To confirm TLR-dependent, MyD88-independent caspase-1 activation
in vivo, we compared IL-18 and IL-12 p40 serum levels among mice with
various genetic backgrounds after infection with L.
monocytogenes, which was recently demonstrated to contain
component(s) activating TLR(s) (21). As shown in Fig. 5A, MyD88-deficient mice
showed higher serum levels of IL-18 than wild-type mice after the
infection, whereas TLR4-deficient and caspase-1-deficient mice
contained fewer increased IL-18 levels than wild-type mice and almost
normal IL-18 levels, respectively, indicating IL-18 secretion was
MyD88-independent and caspase-1-dependent in vivo. In clear contrast,
wild-type mice and caspase-1-deficient mice showed elevated serum
levels of IL-12 p40 after the infection, whereas MyD88-deficient mice
showed normal ranges of IL-12 p40 serum levels, indicating that IL-12
p40 production induced by L. monocytogenes infection depends
on MyD88 and that caspase-1 has no effects on IL-12 p40 production
(Fig. 5B). Taken together, these results suggested
MyD88-independent IL-18 accumulation in naturally occurring
infection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In contrast, IL-18 is
well known to be produced as proIL-18 and require appropriate
processing for its secretion. Indeed, IL-18 is constitutively and
stably stored in Kupffer cells whether stimulated or not (Fig. 1A, a). Furthermore, we showed that Kupffer cells
constitutively expressed caspase-1, a processing enzyme required for
bioactive IL-18 secretion upon LPS stimulation (Fig. 1, D
and E). Our present study demonstrated that IL-18 secretion
from LPS-stimulated Kupffer cells is composed of two phases. One is
MyD88-independent activation of endogenous caspase-1, resulting in the
cleavage of endogenously stored proIL-18 into mature IL-18 to be
secreted, and the other is MyD88-dependent de novo synthesis of
proIL-18 and/or pro-caspase-1 that causes additional processing and
secretion of IL-18.
Although both IL-1 and IL-18 are secreted in a caspase-1- and
TLR4-dependent manner after stimulation with LPS (4, 5, 7, 31) (Fig. 3), MyD88 appears to be essential for IL-1 and
IL-12 secretion but not for IL-18 secretion. IL-1 was not secreted
from MyD88-deficient Kupffer cells upon stimulation with synthetic
lipid A or S. minnesota LPS, although a considerable amount
of intracellular IL-1, presumably proIL-1, was constitutively
detected in Kupffer cells (Figs. 1B, a and 3,
D–F). However, biologically active IL-18 was actually
secreted from MyD88-deficient Kupffer cells upon the same stimulation
(Figs. 1A, a and 3, A–C). Several possibilities
account for these apparently distorted results. First, active caspase-1
has a much higher affinity for proIL-18 than for proIL-1. As
previously reported (4, 5), IL-18 secretion from
proIL-18-transfected COS cells required a much lower amount of
caspase-1 for cotransfection than IL-1 secretion from
proIL-1-transfected COS cells did (4, 5). Therefore,
intrinsically expressed caspase-1 might be enough to process IL-18,
whereas IL-1 processing might require additional caspase-1 that is
newly synthesized upon stimulation with LPS in a MyD88-dependent
manner. Second, proIL-18 might be much more easily encountered by
caspase-1 to be processed than proIL-1. In fact, transgenic mice
overexpressing human caspase-1 in their keratinocytes, which
constitutively produce both proIL-18 and proIL-1, spontaneously
contain high levels of biologically active IL-18 but small amounts of
IL-1 in their sera (32). Third, secretion of IL-1
might require another factor(s) in addition to caspase-1, the action of
which might be regulated by MyD88, whereas IL-18 secretion might be
processed only by activated caspase-1. Consequently, it is predicted
that LPS-induced caspase-1 activation requires TLR4 but not MyD88.
L. monocytogenes, a Gram-positive intracellular bacterium,
has been shown to be expelled by the activated innate immune system at
the early infectious phase. Severe combined immunodeficient mice or
RAG2-deficient mice, both of which lack T cells and B cells, can exert
equivalent resistance against L. monocytogenes at the early
phase compared with wild-type mice (33). Several factors,
particularly IL-12 produced by macrophages and dendritic cells and
IFN- by NK cells, have been reported to be intensively involved in
the early clearance of L. monocytogenes
(33, 34, 35). Although TLR2 was recently demonstrated to be
essential for signal activation by heat-killed L.
monocytogenes by using TLR2-transfected Chinese hamster ovary
cells (21), we do not conclude that only TLR2 is involved
in the elevation of serum levels of IL-12 p40 and IL-18 after the
infection (Fig. 5). Interestingly, MyD88-deficient mice which lack
signaling through TLRs (20) showed no elevation of IL-12
p40 serum levels (Fig. 5B), suggesting that either
combination of both TLR2 and TLR4 or TLR(s) other than TLR2 and TLR4
might be critical for IL-12 p40 accumulation. By contrast, serum levels
of IL-18 were equivalently elevated in L.
monocytogenes-infected MyD88-deficient mice when compared with
wild-type mice (Fig. 5A), and IL-18 secretion was
caspase-1-dependent, which was shown to be intact in MyD88-deficient
mice (Figs. 3 and 4), demonstrating that L. monocytogenes
infection is an example of MyD88-independent activation of caspase-1 in
naturally occurring infection.
Upon ligation by Fas ligand, Fas recruits an adaptor molecule, Fas-associated death domain protein, which binds to and activates caspase-8 (36, 37, 38). The activated caspase-8 then activates downstream caspases, including caspase-3, -6, and -7 (39, 40, 41, 42). Recently, it has been reported that MyD88 recruited by the cytoplasmic domain of TLR2 can associate with Fas-associated death domain protein via the interaction between corresponding death domains, presumably resulting in TLR2-mediated apoptotic cell death (43). However, the mechanism underlying the activation of caspase-1 upon stimulation of TLR4 with LPS is still unclear. Our present study may allow us to propose that an unknown adaptor molecule other than MyD88 is recruited by the TIR domain located in TLR4 to activate precursor caspase-11, a possible upstream caspase for caspase-1 (23), or directly pro-caspase-1 (22), consequently leading to the activation of caspase-1.
This is the first report to demonstrate that IL-18 is secreted from
LPS-activated Kupffer cells via two distinctly regulated pathways. One
is the delayed pathway requiring de novo protein synthesis of proIL-18
and pro-caspase-1 in a MyD88-dependent manner (Figs. 3, A-C,
and 4B). The other is the prompt pathway (Fig. 4B). Upon stimulation with LPS, intrinsic pro-caspase-1 is
activated through TLR4-mediated but MyD88-independent signaling. The
activated caspase-1 then cleaves endogenously stored proIL-18, leading
to secretion of biologically active mature IL-18 (
Figs. 2–4). This
rapid secretion machinery characterized by the selective IL-18
secretion without IL-1 and IL-12 induction in Kupffer cells may
contribute to prompt clearance of microbes by activation of the innate
immune system.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kenji Nakanishi, Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, 663-8501 Japan.
3 Abbreviations used in this paper: pro, precursor; TLR, Toll-like receptor; TIR, Toll/IL-1R; MyD88, myeloid differentiation factor 88; CHX, cycloheximide; AcD, actinomycin D.
Received for publication September 5, 2000. Accepted for publication November 15, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 H. Bjorkbacka, K. A. Fitzgerald, F. Huet, X. Li, J. A. Gregory, M. A. Lee, C. M. Ordija, N. E. Dowley, D. T. Golenbock, and M. W. Freeman The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades Physiol Genomics, February 7, 2005; 19(3): 319 - 330. [Abstract] [Full Text] [PDF]
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 M. Yamamoto, K. Yaginuma, H. Tsutsui, J. Sagara, X. Guan, E. Seki, K. Yasuda, M. Yamamoto, S. Akira, K. Nakanishi, et al. ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules Genes Cells, November 1, 2004; 9(11): 1055 - 1067. [Abstract] [Full Text] [PDF]
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 L. A. Rosenthal, L. D. Mikus, A. Tuffaha, A. G. Mosser, R. L. Sorkness, and R. F. Lemanske Jr. Attenuated Innate Mechanisms of Interferon-{gamma} Production in Rats Susceptible to Postviral Airway Dysfunction Am. J. Respir. Cell Mol. Biol., May 1, 2004; 30(5): 702 - 709. [Abstract] [Full Text] [PDF]
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 J. Y. Lee, L. Zhao, H. S. Youn, A. R. Weatherill, R. Tapping, L. Feng, W. H. Lee, K. A. Fitzgerald, and D. H. Hwang Saturated Fatty Acid Activates but Polyunsaturated Fatty Acid Inhibits Toll-like Receptor 2 Dimerized with Toll-like Receptor 6 or 1 J. Biol. Chem., April 23, 2004; 279(17): 16971 - 16979. [Abstract] [Full Text] [PDF]
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 N. M. Tsuji, H. Tsutsui, E. Seki, K. Kuida, H. Okamura, K. Nakanishi, and R. A. Flavell Roles of caspase-1 in Listeria infection in mice Int. Immunol., February 1, 2004; 16(2): 335 - 343. [Abstract] [Full Text] [PDF]
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 W. H. Schott, B. D. Haskell, H. M. Tse, M. J. Milton, J. D. Piganelli, C. M. Choisy-Rossi, P. C. Reifsnyder, A. V. Chervonsky, and E. H. Leiter Caspase-1 Is Not Required for Type 1 Diabetes in the NOD Mouse Diabetes, January 1, 2004; 53(1): 99 - 104. [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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S. S. Way, T. R. Kollmann, A. M. Hajjar, and C. B. Wilson Cutting Edge: Protective Cell-Mediated Immunity to Listeria monocytogenes in the Absence of Myeloid Differentiation Factor 88 J. Immunol., July 15, 2003; 171(2): 533 - 537. [Abstract] [Full Text] [PDF]
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 E. S. Van Amersfoort, T. J. C. Van Berkel, and J. Kuiper Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock Clin. Microbiol. Rev., July 1, 2003; 16(3): 379 - 414. [Abstract] [Full Text] [PDF]
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 J. A. Gracie, S. E. Robertson, and I. B. McInnes Interleukin-18 J. Leukoc. Biol., February 1, 2003; 73(2): 213 - 224. [Abstract] [Full Text] [PDF]
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E. Seki, H. Tsutsui, N. M. Tsuji, N. Hayashi, K. Adachi, H. Nakano, S. Futatsugi-Yumikura, O. Takeuchi, K. Hoshino, S. Akira, et al. Critical Roles of Myeloid Differentiation Factor 88-Dependent Proinflammatory Cytokine Release in Early Phase Clearance of Listeria monocytogenes in Mice J. Immunol., October 1, 2002; 169(7): 3863 - 3868. [Abstract] [Full Text] [PDF]
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B. T. Edelson and E. R. Unanue MyD88-Dependent but Toll-Like Receptor 2-Independent Innate Immunity to Listeria: No Role for Either in Macrophage Listericidal Activity J. Immunol., October 1, 2002; 169(7): 3869 - 3875. [Abstract] [Full Text] [PDF]
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S. E. Applequist, R. P. A. Wallin, and H.-G. Ljunggren Variable expression of Toll-like receptor in murine innate and adaptive immune cell lines Int. Immunol., September 1, 2002; 14(9): 1065 - 1074. [Abstract] [Full Text] [PDF]
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 H. Konishi, H. Tsutsui, T. Murakami, S. Yumikura-Futatsugi, K.-i. Yamanaka, M. Tanaka, Y. Iwakura, N. Suzuki, K. Takeda, S. Akira, et al. IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions PNAS, August 20, 2002; 99(17): 11340 - 11345. [Abstract] [Full Text] [PDF]
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 A. UEHARA, S. SUGAWARA, and H. TAKADA Priming of human oral epithelial cells by interferon-{gamma} to secrete cytokines in response to lipopolysaccharides, lipoteichoic acids and peptidoglycans J. Med. Microbiol., August 1, 2002; 51(8): 626 - 634. [Abstract] [Full Text] [PDF]
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 C. D. Raeburn, C. A. Dinarello, M. A. Zimmerman, C. M. Calkins, B. J. Pomerantz, R. C. McIntyre Jr., A. H. Harken, and X. Meng Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H650 - H657. [Abstract] [Full Text] [PDF]
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S. T. Ahmed, A. Mayer, J.-D. Ji, and L. B. Ivashkiv Inhibition of IL-6 signaling by a p38-dependent pathway occurs in the absence of new protein synthesis J. Leukoc. Biol., July 1, 2002; 72(1): 154 - 162. [Abstract] [Full Text] [PDF]
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T. Kaisho, K. Hoshino, T. Iwabe, O. Takeuchi, T. Yasui, and S. Akira Endotoxin can induce MyD88-deficient dendritic cells to support Th2 cell differentiation Int. Immunol., July 1, 2002; 14(7): 695 - 700. [Abstract] [Full Text] [PDF]
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C. A. Scanga, J. Aliberti, D. Jankovic, F. Tilloy, S. Bennouna, E. Y. Denkers, R. Medzhitov, and A. Sher Cutting Edge: MyD88 Is Required for Resistance to Toxoplasma gondii Infection and Regulates Parasite-Induced IL-12 Production by Dendritic Cells J. Immunol., June 15, 2002; 168(12): 5997 - 6001. [Abstract] [Full Text] [PDF]
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 T. Nomura, I. Kawamura, K. Tsuchiya, C. Kohda, H. Baba, Y. Ito, T. Kimoto, I. Watanabe, and M. Mitsuyama Essential Role of Interleukin-12 (IL-12) and IL-18 for Gamma Interferon Production Induced by Listeriolysin O in Mouse Spleen Cells Infect. Immun., March 1, 2002; 70(3): 1049 - 1055. [Abstract] [Full Text] [PDF]
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K. Adachi, H. Tsutsui, S.-I. Kashiwamura, E. Seki, H. Nakano, O. Takeuchi, K. Takeda, K. Okumura, L. Van Kaer, H. Okamura, et al. Plasmodiumberghei Infection in Mice Induces Liver Injury by an IL-12- and Toll-Like Receptor/Myeloid Differentiation Factor 88-Dependent Mechanism J. Immunol., November 15, 2001; 167(10): 5928 - 5934. [Abstract] [Full Text] [PDF]
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 H. Itoi, Y. Fujimori, H. Tsutsui, K. Matsui, S. Futatsugi, H. Okamura, H. Hara, T. Hada, E. Kakishita, and K. Nakanishi Fas ligand-induced caspase-1-dependent accumulation of interleukin-18 in mice with acute graft-versus-host disease Blood, July 1, 2001; 98(1): 235 - 237. [Abstract] [Full Text] [PDF]
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