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* First Department of Surgery and
Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Japan;
Laboratory of Molecular Immunology, Department of Molecular Biology and Immunology, National Institute for Agrobiological Sciences, Tsukuba, Japan;
Department of Host Defenses, Research Institute for Microbial Diseases, Osaka University, Suita, Japan; and
¶ Core Research for Evolutional Science and Technology, Japan Science and Technology Corp., Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, leading to normal LM
clearance in the host. IFN- knockout (KO) mice were highly
susceptible to LM infection. IL-12/IL-18 double knockout mice were also
highly susceptible. Their susceptibility was less than that of IFN-
KO mice, but more than that of single IL-12 or IL-18 KO mice. Mice
deficient in myeloid differentiation factor 88 (MyD88), an essential
adaptor molecule used by signal transduction pathways of all members of
the Toll-like receptor (TLR) family, showed an inability to produce
IL-12 and IFN- following LM infection and were most susceptible to
LM. Furthermore, MyD88-deficient, but not IFN--deficient, Kupffer
cells could not produce TNF-
in response to LM in vitro, indicating
the importance of MyD88-dependent TNF- production for host defense.
As TLR2 KO, but not TLR4 KO, mice showed partial impairment in their
capacity to produce IL-12, IFN-, and TNF-, TLR2 activation partly
contributed to the induction of IL-12-mediated IFN- production.
These results indicated a critical role for TLRs/MyD88-dependent
IL-12/TNF- production and for IL-12- and IL-18-mediated IFN-
production in early phase clearance of LM. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(4, 5, 6, 7, 8, 9, 10), which subsequently activates
macrophages and neutrophils to kill LM via production of listericidal
molecules, such as NO (2, 11). Therefore, IL-12 and IL-18
seem to play an essential role in early phase clearance of LM by
induction of IFN-. Toll-like receptors (TLRs) have been identified as signaling receptors of the innate immune system and recognize corresponding pathogen-associated molecular patterns (12). TLR2 recognizes Gram-positive bacterial components, including peptide glycan and lipoproteins (12, 13). Studies using TLR2-transfected Chinese hamster ovary cells revealed TLR2 as a signaling receptor for LM products (14). TLR4 is reported to act as a signaling receptor of LPS, Gram-negative bacterial component (13, 15, 16, 17).
Myeloid differentiation factor 88 (MyD88) is an adaptor molecule
essential for signaling through TLR (12, 18, 19).
Pathogen-associated molecular patterns induce recruitment of MyD88 to
the cytoplasmic domain of TLR, resulting in a relay of signal and
activation of NF-
B that causes transcription of IL-12, TNF-, and
other inflammatory cytokines. Furthermore, MyD88 plays a critical role
in IL-18R-mediated IL-18 signaling that induces IFN- production from
IL-12-stimulated innate or acquired immune cells (20).
These results suggest the importance of MyD88 in host defense against
various pathogens. Indeed, MyD88 knockout (KO) mice are highly
susceptible to Staphylococcus aureus infection and show the
disability to produce proinflammatory cytokines
(13). However, our recent study demonstrated the
presence of MyD88-independent IL-18 release in LM-infected mice
(9). Therefore, it is important to understand the
protective role of TLR/MyD88 in LM infection.
In this study we have investigated molecular mechanisms of clearance of
LM in mice. IL-12- or IL-18-deficient (KO) mice lacked the capacity to
produce detectable levels of IFN- in their sera. These mice showed
marked and moderate susceptibility to LM, respectively. IFN- KO mice
entirely lacking the ability to produce IFN-; IL-12/IL-18 double KO
(DKO) mice, lacking upstream cytokines for IFN- induction, showed
much higher susceptibility to LM. However, we found that MyD88 KO mice
that cannot produce IFN-, IL-12, and TNF- are the most
susceptible to LM. These results suggested that both IFN- and
TNF- are essential for host defense against LM.
We conclude that MyD88 is a critical adaptor molecule essentially required for full activation of innate immune system.
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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 Clea Japan (Osaka, Japan). IL-12 KO mice were
provided by Dr. J. Magram (Roche Institute of Molecular Biology,
Nutley, NJ) (21) and were backcrossed with C57BL/6 mice,
and female F8 mice (6–9 wk old) were used for
this study. IL-18 KO mice (22) and IFN- KO mice
(23) were backcrossed with C57BL/6 mice, and female
F8 mice (6–9 wk old) were used. To obtain
C57BL/6-background IL-12/IL-18 DKO mice (6–8 wk old),
F8 mice from C57BL/6-backcrossed IL-18 KO mice
were crossed with F8 mice of C57BL/6-backcrossed
IL-12 KO mice. IL-18R KO mice (24) were backcrossed
with C57BL/6 mice, and female F10 mice (6–9 wk
old) were used. TLR2 KO mice (13), TLR4 KO mice
(15), and MyD88 KO mice (20) were backcrossed
with C57BL/6 mice, and F2 female mice (6–9 wk
old) were used. To obtain TLR2/TLR4 DKO mice (6–9 wk old),
F2 mice from C57BL/6-backcrossed TLR2 KO
mice were crossed with F2 mice from
C57BL/6-backcrossed TLR4 KO mice.
Assay for cytokines
Concentrations of IFN-, IL-12p40, and TNF- were determined
by ELISA kits (Genzyme, Boston, MA).
Infection with LM
LM 43251 (American Type Culture Collection, Manassas, VA) was cultured in Trypsicase Soy Broth (BD Biosciences, Cockeysville, MD). Mice with various genotypes were i.v. inoculated with 5 x 105 LM. At the indicated time points serum was sampled for measurements of various cytokines. On day 3 livers from mice with various genotypes were homogenized, and the LM titer in each homogenate was determined according to the method described previously (4). The survival of various genotype mice inoculated with 5 x 105, 5 x 104, or 5 x 103 LM was judged every 12 h until day 14 after infection.
Kupffer cell preparation
Kupffer cells were prepared as previously shown (9). Culture medium was RPMI 1640 supplemented with 10% FCS, 50 µM 2-ME, and 2 mM L-glutamine. The cells (1 x 106/ml) were cultured with live LM (1 x 106 or 1 x 107/ml). After 1 h in culture, penicillin and streptomycin were added to the culture medium at final concentrations of 100 U/ml and 100 µg/ml, respectively, to limit the growth of LM, the cells were incubated for an additional 24 h (5), and cytokine levels in each supernatant were determined by ELISA.
Histology
Mice were inoculated with 5 x 105 LM and were killed 72 h after infection. Their liver specimens were sampled and fixed in 10% buffered formalin, and the slides were stained with H&E.
Statistics
All data are shown as the mean ± SD of triplicate determinations. Significance between control and experimental groups was examined with unpaired Student’s t test. A value of p < 0.05 was regarded as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production at the early infectious phase of LM
It is well known that IFN- is critical for early phase
clearance of LM (1, 2, 3, 4, 25). We wanted to clarify whether
IL-12 and/or IL-18 play an essential role in early induction of IFN-
production following LM infection. We measured IFN- levels in the
sera of mice with various genotypes after LM infection (Fig. 1
). In wild-type (WT) mice the serum
IFN- level increased and peaked at 24 h postinfection, while
IFN- was undetectable in the sera of IL-12/IL-18 DKO mice. IL-12 or
IL-18 single-KO mice also showed undetectable levels of IFN- in
their sera. These results strongly indicated the requirement for both
IL-12 and IL-18 for IFN- production in LM-infected mice. LM-infected
MyD88 KO mice also displayed an undetectable level of IFN- in their
sera, further substantiating our previous reports that MyD88 is
required for IL-18-mediated IFN- induction (9, 20).
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As both IL-12 and IL-18 contribute to IFN- accumulation (Fig. 1
), we investigated whether both IL-12 and IL-18 are also responsible
for early phase LM clearance in the liver. IL-18 KO mice and IL-12 KO
mice showed partial and severe impairment in LM eradication,
respectively, compared with WT mice (Fig. 2A). As expected, IL-12/IL-18
DKO and IFN- KO mice showed striking impairment in LM eradication.
IFN- KO mice had the largest CFU counts in their livers (Fig. 2A), indicating that IFN- plays an essential role in LM
eradication from the liver.
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A). Furthermore, the absence of expression of IL-18
or IL-18R did not affect IL-12 production in LM-infected mice (Fig. 2C and data not shown). In contrast, MyD88 KO mice did not
produce IL-12 (Fig. 2C), although they could produce IL-18
(9), suggesting a contribution of MyD88 to IL-12
production.
Because MyD88 is an essential adaptor molecule for IL-18R-mediated
signaling (20), we compared CFU counts in the livers of
IL-18R KO mice with those in MyD88 KO mice. Like IL-18 KO mice (Fig. 2A), IL-18R KO mice showed much better LM clearance than
MyD88 KO mice, indicating only moderate contribution of IL-18 signaling
to LM clearance (Fig. 2B).
MyD88-dependent TNF- production is required for LM eradication
We next investigated whether defects in LM clearance in MyD88 KO
mice are solely due to their disability to produce IFN-. For this
purpose we compared listerial burden in the liver between IFN- KO
and MyD88 KO mice. As shown in Fig. 2B, bacterial burden in
the liver of MyD88 KO mice was significantly heavier than that in
IFN- KO mice (p < 0.05).
Listerial burden in the liver of MyD88 KO mice was larger than that in
IFN- KO mice (Fig. 2B), indicating the importance of an
additional factor(s) that was produced in a MyD88-dependent manner. As
TNF- is well known as another important factor for LM clearance
(26, 27, 28), we simultaneously investigated the capacity of
MyD88 KO mice to produce TNF- upon LM infection. TNF- was
undetectable in the sera of LM-infected WT mice. Therefore, we examined
the capacity of macrophages to produce TNF- in response to LM in
vitro. As shown in Fig. 2D, WT Kupffer cells produced
TNF- when stimulated with LM. IL-12- or IL-18-dificient or
IL-12/IL-18 doubly deficient Kupffer cells produced TNF- comparably
to WT Kupffer cells (Fig. 2D), indicating that IL-12 and
IL-18 are dispensable for TNF- production. IFN--deficient cells
secreted slightly less TNF- (Fig. 2D), indicating a minor
role of IFN- in TNF- production. In contrast, MyD88-deficient
Kupffer cells did not produce TNF-, suggesting the involvement of
TNF- in LM clearance.
TLR/MyD88 is required for IL-12 release upon LM infection
MyD88 is essential for IL-12 and TNF- production upon LM
infection (Fig. 2, C and D) (9).
Next, we investigated what types of TLRs are involved in the induction
of IL-12 and TNF-. As shown in Fig. 3A, TLR2 KO mice, but not TLR4
KO mice, showed reduced IL-12p40 production following LM infection.
Similarly, TLR2/TLR4 DKO mice showed a reduction in their capacity to
produce IL-12, indicating that TLR2 partly contributes to IL-12
production independently of TLR4. Consistent with our previous report
(9), MyD88 KO mice failed to produce IL-12 (Fig. 3A), although they secreted IL-18 (data not shown). TLR2 KO
mice and TLR2/TLR4 DKO mice, but not TLR4 KO mice, displayed less
IFN- in their sera than did WT mice post-LM infection (Fig. 3B). As expected from the results with IL-12 (Fig. 3A), MyD88 KO mice were incapable of producing IFN- in
their sera (Fig. 3B). Serum levels of IFN- appeared to
correlate well with those of IL-12 in various mutant mice, suggesting
that IL-12 is principally responsible for determining the IFN-
level. These results suggested the importance of TLR2 and possibly
other TLRs, except for TLR4, in IL-12-dependent IFN- production
after LM challenge.
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production
in response to LM. After being stimulated with a small number of the
bacteria, TLR2-deficient Kupffer cells, unlike TLR4-deficient cells,
produced much less TNF-, as in MyD88-deficient cells (Fig. 3C). However, upon challenge with a large number of LM,
TLR2-deficient cells produced more TNF- than MyD88-deficient Kupffer
cells (Fig. 3D). Collectively, LM infection induces both
IFN- and TNF- production, dependent in part on TLR2 and perhaps
other TLRs. MyD88 is critical for neutrophil recruitment into the liver
As both IFN- and TNF- are involved in the recruitment
of neutrophils, potent effector cells (29, 30, 31, 32), we
investigated inflammatory responses in the liver of the
various mutant mice postinfection. LM-infected WT mice had large
inflammatory foci consisting of numerous neutrophils in the liver (Fig. 4, A and B). In
livers of IL-18 KO or IL-12KO mice we could not find significant
differences in the levels of inflammatory responses compared with WT
mice (data not shown). The inflammatory foci in livers of IFN- KO
mice contained fewer neutrophils in their population (Fig. 4, C and D), indicating the importance of IFN- in
the recruitment of neutrophils. Somewhat surprisingly, IL-12/IL-18 DKO
mice showed a dense infiltration of neutrophils (data not shown), while
IFN- KO mice did not, suggesting the failure of IL-12 and IL-18 to
completely cover the function of IFN-. MyD88 KO mice had much
smaller foci, composed of few neutrophils, than the other mutant mice,
even including IFN- KO mice (Fig. 4, C–F), suggesting
that MyD88 participates in neutrophil recruitment via induction of both
IFN- and TNF-. There were no remarkable differences in the
pathological changes in livers between WT and TLR4 KO mice, but the
foci in TLR2 KO mice contained fewer neutrophils than those in WT or
TLR4 KO mice (Fig. 4, G–J). This may be explained by the
partial impairment in the production of both IFN- and TNF- in
TLR2 KO mice (Fig. 3, B and C). Collectively,
these results suggest the essential role of both IFN- and TNF- in
the early phase clearance of LM via activation and recruitment of
effector cells in the liver.
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Finally, we investigated the mortality of mice with various
genotypes after inoculation with LM. As shown in Fig. 5, WT mice inoculated with the highest
number of LM survived up to 14 days postinfection, at which time they
were sacrificed. The survival rate of IL-18 KO mice was less than that
of WT mice only when they were infected with the highest number of LM
(5 x 105 bacteria; Fig. 5A). All
IL-12 KO and IL-12/IL-18 DKO mice died by day 5 postinfection with the
largest number of LM (Fig. 5A). However, inoculation with a
lesser number of LM (5 x 104 bacteria)
revealed that IL-12/IL-18 DKO mice were more susceptible than IL-12 KO
mice (Fig. 5B). Moreover, all the IL-12/IL-18 DKO mice
survived, but 80% of IFN- KO mice succumbed upon infection with the
smallest number of LM (5 x 103 bacteria;
Fig. 5C). These results strongly indicated the essential
involvement of IFN- in host defense against LM infection. Consistent
with their disability to produce both IFN- and TNF- (
Figs. 1–3),
MyD88 KO mice were most susceptible to LM (Fig. 5). The mortality well
paralleled the LM titer in the liver (Fig. 2) and the intensity of
neutrophil recruitment (Fig. 4). Collectively, LM-induced
MyD88-mediated IL-12 and TNF- production is essential for protection
of mice from fatal LM infection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production
by innate and adaptive immune cells, including T cells, B cells, NK
cells, macrophages, and dendritic cells (10). Here, we
illustrated the importance of endogenous IL-12 and IL-18 in early phase
clearance of LM (Figs. 2 and 5). Although the relative roles of IL-12
and IL-18, which are essential for IFN- production in vivo (Fig. 1),
are still unclear in innate immunity, our present study clearly showed
that IL-12 is much more important in local LM elimination than IL-18
(Fig. 2). We also revealed that MyD88 is essential for induction of
IL-12 plus IL-18-dependent IFN- production (Figs. 1 and 2), because
it allows signaling through TLR and IL-18R, which are activated by LM
and IL-18, respectively. In studies using IFN- KO and MyD88 KO mice
we showed an additional role of MyD88 as an essential molecule to
induce production of TNF- (Fig. 2D). MyD88-dependent
IFN- in combination with MyD88-dependent TNF- accomplish host
defense against LM with efficient recruitment of neutrophils in the
liver (Figs. 4 and 5). Our present results revealed the importance of
innate immune responses that are definitively triggered by
TLR/MyD88-dependent pathways.
Very recently, Neighbors et al. (33) reported that
treatment of BALB/c mice with mAb against IL-18R
, a signaling
component of IL-18R, renders them highly susceptible to sublethal
numbers of LM compared with neutralizing anti-IL-12p40 mAb. Our
present results using IL-12 KO mice on the C57BL/6 background indicated
that endogenous IL-12p40 is more dominantly involved in LM clearance
than IL-18. There are several possibilities that account for this
discrepancy. First, as noted above, they used LM-susceptible BALB/c
mice, while we used LM-resistant C57BL/6 background mice. Second, they
used anti-IL-18R mAb-treated mice, while we used IL-18 KO and
IL-18R KO mice. Both IL-18 KO and IL-18R KO mice had the same
immune responses after LM infection (Fig. 2, A and
B), demonstrating that IL-18R is necessary and sufficient
for IL-18 signaling. Therefore, we suspect that their mAb might inhibit
not only IL-18 signaling but also signaling of an unknown factor(s)
that uses IL-18R -chain. Third, the discrepancy might be due to the
difference in the target tissues examined. The liver, which we
manipulated, is composed of unique residential lymphocytes, including
NK cells and NKT cells, which are meager in the spleen they
used.
As previously reported, IL-18 has capacity to induce TNF- production
by macrophage upon LM infection (33). However, IL-18
deficiency does not reduce TNF- production in response to LM (Fig. 2D), indicating that endogenous IL-18 does not participate
in TNF- production, at least in macrophage levels. Furthermore, we
showed that the absence of IL-18 does not influence IL-12p40 production
(Fig. 2C). Thus, apparently IL-18 does not play a major role
in the production of TNF- or IL-12 after LM infection.
IL-12 KO mice were more susceptible than IL-18 KO mice (Fig. 5),
although both failed to show a detectable serum level of IFN- (Fig. 1). At present we have no definitive explanation for this difference.
However, IL-12 KO mice may have no capacity to develop Th1 cells, while
IL-18 KO mice have such potentiality to develop Th1 cells following
infection in the target organs (10, 22). We measured serum
levels of IFN-. Measurement of local levels of IFN- and
determination of cells that produce IFN- in the liver might be
important for understanding the difference in the host resistance to LM
infection of IL-18 KO and IL-12 KO mice.
Livers of IFN- KO mice contain more LM titer than those of
IL-12/IL-18 DKO mice (Fig. 2). Other factors, in addition to IL-12 and
IL-18, might contribute to IFN--dependent LM clearance. IL-15 is a
candidate because IL-15 synergizes with IL-18 and/or IL-12 for
induction of IFN- (Ref. 34 and our unpublished
observations) and is synthesized by macrophages upon stimulation with
microbe and microbe products, including LM (34, 35).
Furthermore, we tested the involvement of TLR members in LM infection
to induce proinflammatory cytokine production. Because most bacterial
cell wall components, either from Gram-positive or -negative bacteria,
are recognized by TLR2 or TLR4, respectively, we used TLR2 KO mice and
TLR4 KO mice as host (13). We found that TLR2 KO mice
showed a relatively poor response to LM infection in terms of IL-12,
IFN-, and TNF- production (Fig. 3). Therefore, TLR2 seems to be
partly involved in LM signaling. In contrast, MyD88 KO mice completely
lacked the capacity to produce IL-12 and TNF- upon LM infection and
to respond to IL-12 plus IL-18 by IFN- production (Fig. 3). Thus,
TLR2 might form heterodimer by association with another TLR member(s)
to exert its role as a signaling molecule. Further study is required
for identification of other TLRs involved in the response to
LM.
Recruitment of neutrophils in the liver requires both TNF- and
IFN-. WT mice had large inflammatory foci composed of many
neutrophils in their livers, while IFN- KO and MyD88 KO mice showed
intermediate-sized foci with a small number of neutrophils and small
foci containing few neutrophils, respectively (Fig. 4). These results
substantiate further that MyD88-dependent IFN- and TNF-
production plays an essential role in LM clearance in the early
infectious phase via activation and recruitment of effector cells.
In summary, our study showed that both IL-12 and IL-18 contribute to
IFN- production in LM infection. In addition, IL-12 is more
profoundly involved than IL-18 in LM eradication in the liver.
Furthermore, MyD88 plays a pivotal role in early phase clearance of LM
through induction of IFN- and TNF- via TLR signaling. Taken
together, these findings show that MyD88 is essential for determining
host resistance to various microorganisms, including LM, during innate
phase immune response.
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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. E-mail address: nakaken{at}hyo-med.ac.jp
3 Abbreviations used in this paper: LM, Listeria monocytogenes; KO, knockout; DKO, double KO; MyD88, myeloid differentiation factor 88; TLR, Toll-like receptor; WT, wild type.
Received for publication April 9, 2002. Accepted for publication July 24, 2002.
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G. Hajishengallis, M.-A. K. Shakhatreh, M. Wang, and S. Liang Complement Receptor 3 Blockade Promotes IL-12-Mediated Clearance of Porphyromonas gingivalis and Negates Its Virulence In Vivo J. Immunol., August 15, 2007; 179(4): 2359 - 2367. [Abstract] [Full Text] [PDF]
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K. Brandl, G. Plitas, B. Schnabl, R. P. DeMatteo, and E. G. Pamer MyD88-mediated signals induce the bactericidal lectin RegIII{gamma} and protect mice against intestinal Listeria monocytogenes infection J. Exp. Med., August 6, 2007; 204(8): 1891 - 1900. [Abstract] [Full Text] [PDF]
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H. Hara, I. Kawamura, T. Nomura, T. Tominaga, K. Tsuchiya, and M. Mitsuyama Cytolysin-Dependent Escape of the Bacterium from the Phagosome Is Required but Not Sufficient for Induction of the Th1 Immune Response against Listeria monocytogenes Infection: Distinct Role of Listeriolysin O Determined by Cytolysin Gene Replacement Infect. Immun., August 1, 2007; 75(8): 3791 - 3801. [Abstract] [Full Text] [PDF]
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G. Plitas, U. I. Chaudhry, T. P. Kingham, J. R. Raab, and R. P. DeMatteo NK Dendritic Cells Are Innate Immune Responders to Listeria monocytogenes Infection J. Immunol., April 1, 2007; 178(7): 4411 - 4416. [Abstract] [Full Text] [PDF]
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S. S. Way, C. Havenar-Daughton, G. A. Kolumam, N. N. Orgun, and K. Murali-Krishna IL-12 and Type-I IFN Synergize for IFN-{gamma} Production by CD4 T Cells, Whereas Neither Are Required for IFN-{gamma} Production by CD8 T Cells after Listeria monocytogenes Infection J. Immunol., April 1, 2007; 178(7): 4498 - 4505. [Abstract] [Full Text] [PDF]
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 J. Sawaki, H. Tsutsui, N. Hayashi, K. Yasuda, S. Akira, T. Tanizawa, and K. Nakanishi Type 1 cytokine/chemokine production by mouse NK cells following activation of their TLR/MyD88-mediated pathways Int. Immunol., March 1, 2007; 19(3): 311 - 320. [Abstract] [Full Text] [PDF]
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D. D. Bolz, R. S. Sundsbak, Y. Ma, S. Akira, J. H. Weis, T. G. Schwan, and J. J. Weis Dual Role of MyD88 in Rapid Clearance of Relapsing Fever Borrelia spp. Infect. Immun., December 1, 2006; 74(12): 6750 - 6760. [Abstract] [Full Text] [PDF]
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H. Negishi, Y. Fujita, H. Yanai, S. Sakaguchi, X. Ouyang, M. Shinohara, H. Takayanagi, Y. Ohba, T. Taniguchi, and K. Honda Evidence for licensing of IFN-{gamma}-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program PNAS, October 10, 2006; 103(41): 15136 - 15141. [Abstract] [Full Text] [PDF]
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K. A. Archer and C. R. Roy MyD88-Dependent Responses Involving Toll-Like Receptor 2 Are Important for Protection and Clearance of Legionella pneumophila in a Mouse Model of Legionnaires' Disease. Infect. Immun., June 1, 2006; 74(6): 3325 - 3333. [Abstract] [Full Text] [PDF]
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L. Marodi Neonatal Innate Immunity to Infectious Agents Infect. Immun., April 1, 2006; 74(4): 1999 - 2006. [Full Text] [PDF]
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A. M. van der Sar, O. W. Stockhammer, C. van der Laan, H. P. Spaink, W. Bitter, and A. H. Meijer MyD88 Innate Immune Function in a Zebrafish Embryo Infection Model Infect. Immun., April 1, 2006; 74(4): 2436 - 2441. [Abstract] [Full Text] [PDF]
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N. Ozoren, J. Masumoto, L. Franchi, T.-D. Kanneganti, M. Body-Malapel, I. Erturk, R. Jagirdar, L. Zhu, N. Inohara, J. Bertin, et al. Distinct Roles of TLR2 and the Adaptor ASC in IL-1beta/IL-18 Secretion in Response to Listeria monocytogenes J. Immunol., April 1, 2006; 176(7): 4337 - 4342. [Abstract] [Full Text] [PDF]
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A. K. Behera, E. Hildebrand, R. T. Bronson, G. Perides, S. Uematsu, S. Akira, and L. T. Hu MyD88 Deficiency Results in Tissue-Specific Changes in Cytokine Induction and Inflammation in Interleukin-18-Independent Mice Infected with Borrelia burgdorferi Infect. Immun., March 1, 2006; 74(3): 1462 - 1470. [Abstract] [Full Text] [PDF]
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 Y.-T.A. Teng Protective and Destructive Immunity in the Periodontium: Part 1--Innate and Humoral Immunity and the Periodontium Journal of Dental Research, March 1, 2006; 85(3): 198 - 208. [Abstract] [Full Text] [PDF]
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 L. Romics Jr, A. Dolganiuc, A. Velayudham, K. Kodys, P. Mandrekar, D. Golenbock, E. Kurt-Jones, and G. Szabo Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni- bacterium acnes J. Leukoc. Biol., December 1, 2005; 78(6): 1255 - 1264. [Abstract] [Full Text] [PDF]
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S. B. Su, P. B. Silver, R. S. Grajewski, R. K. Agarwal, J. Tang, C.-C. Chan, and R. R. Caspi Essential Role of the MyD88 Pathway, but Nonessential Roles of TLRs 2, 4, and 9, in the Adjuvant Effect Promoting Th1-Mediated Autoimmunity J. Immunol., November 15, 2005; 175(10): 6303 - 6310. [Abstract] [Full Text] [PDF]
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 K. Fuse, G. Chan, Y. Liu, P. Gudgeon, M. Husain, M. Chen, W.-C. Yeh, S. Akira, and P. P. Liu Myeloid Differentiation Factor-88 Plays a Crucial Role in the Pathogenesis of Coxsackievirus B3-Induced Myocarditis and Influences Type I Interferon Production Circulation, October 11, 2005; 112(15): 2276 - 2285. [Abstract] [Full Text] [PDF]
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Y. Sasaki, T. Yoshimoto, H. Maruyama, T. Tegoshi, N. Ohta, N. Arizono, and K. Nakanishi IL-18 with IL-2 protects against Strongyloides venezuelensis infection by activating mucosal mast cell-dependent type 2 innate immunity J. Exp. Med., September 6, 2005; 202(5): 607 - 616. [Abstract] [Full Text] [PDF]
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Y. Naiki, K. S. Michelsen, N. W. J. Schroder, R. Alsabeh, A. Slepenkin, W. Zhang, S. Chen, B. Wei, Y. Bulut, M. H. Wong, et al. MyD88 Is Pivotal for the Early Inflammatory Response and Subsequent Bacterial Clearance and Survival in a Mouse Model of Chlamydia pneumoniae Pneumonia J. Biol. Chem., August 12, 2005; 280(32): 29242 - 29249. [Abstract] [Full Text] [PDF]
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R. E. Berg, E. Crossley, S. Murray, and J. Forman Relative Contributions of NK and CD8 T Cells to IFN-{gamma} Mediated Innate Immune Protection against Listeria monocytogenes J. Immunol., August 1, 2005; 175(3): 1751 - 1757. [Abstract] [Full Text] [PDF]
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 G. I Lancaster, Q. Khan, P. Drysdale, F. Wallace, A. E Jeukendrup, M. T Drayson, and M. Gleeson The physiological regulation of toll-like receptor expression and function in humans J. Physiol., March 15, 2005; 563(3): 945 - 955. [Abstract] [Full Text] [PDF]
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R. M. O'Connell, S. A. Vaidya, A. K. Perry, S. K. Saha, P. W. Dempsey, and G. Cheng Immune Activation of Type I IFNs by Listeria monocytogenes Occurs Independently of TLR4, TLR2, and Receptor Interacting Protein 2 but Involves TANK-Binding Kinase 1 J. Immunol., February 1, 2005; 174(3): 1602 - 1607. [Abstract] [Full Text] [PDF]
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J. Schmieg, G. Yang, R. W. Franck, N. Van Rooijen, and M. Tsuji Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion PNAS, January 25, 2005; 102(4): 1127 - 1132. [Abstract] [Full Text] [PDF]
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J. Liu, X. Guan, T. Tamura, K. Ozato, and X. Ma Synergistic Activation of Interleukin-12 p35 Gene Transcription by Interferon Regulatory Factor-1 and Interferon Consensus Sequence-binding Protein J. Biol. Chem., December 31, 2004; 279(53): 55609 - 55617. [Abstract] [Full Text] [PDF]
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H. Hata, T. Yoshimoto, N. Hayashi, T. Hada, and K. Nakanishi IL-18 together with anti-CD3 antibody induces human Th1 cells to produce Th1- and Th2-cytokines and IL-8 Int. Immunol., December 1, 2004; 16(12): 1733 - 1739. [Abstract] [Full Text] [PDF]
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R. Janssen, A. van Wengen, M. A. Hoeve, M. ten Dam, M. van der Burg, J. van Dongen, E. van de Vosse, M. van Tol, R. Bredius, T. H. Ottenhoff, et al. The Same I{kappa}B{alpha} Mutation in Two Related Individuals Leads to Completely Different Clinical Syndromes J. Exp. Med., September 7, 2004; 200(5): 559 - 568. [Abstract] [Full Text] [PDF]
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R. M. O'Connell, S. K. Saha, S. A. Vaidya, K. W. Bruhn, G. A. Miranda, B. Zarnegar, A. K. Perry, B. O. Nguyen, T. F. Lane, T. Taniguchi, et al. Type I Interferon Production Enhances Susceptibility to Listeria monocytogenes Infection J. Exp. Med., August 16, 2004; 200(4): 437 - 445. [Abstract] [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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N. Liu, R. R. Montgomery, S. W. Barthold, and L. K. Bockenstedt Myeloid Differentiation Antigen 88 Deficiency Impairs Pathogen Clearance but Does Not Alter Inflammation in Borrelia burgdorferi-Infected Mice Infect. Immun., June 1, 2004; 72(6): 3195 - 3203. [Abstract] [Full Text] [PDF]
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G. Mancuso, A. Midiri, C. Beninati, C. Biondo, R. Galbo, S. Akira, P. Henneke, D. Golenbock, and G. Teti Dual Role of TLR2 and Myeloid Differentiation Factor 88 in a Mouse Model of Invasive Group B Streptococcal Disease J. Immunol., May 15, 2004; 172(10): 6324 - 6329. [Abstract] [Full Text] [PDF]
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M. G. Netea, C. van der Graaf, J. W. M. Van der Meer, and B. J. Kullberg Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system J. Leukoc. Biol., May 1, 2004; 75(5): 749 - 755. [Abstract] [Full Text] [PDF]
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D. Torres, M. Barrier, F. Bihl, V. J. F. Quesniaux, I. Maillet, S. Akira, B. Ryffel, and F. Erard Toll-Like Receptor 2 Is Required for Optimal Control of Listeria monocytogenes Infection Infect. Immun., April 1, 2004; 72(4): 2131 - 2139. [Abstract] [Full Text] [PDF]
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C. A. Scanga, A. Bafica, C. G. Feng, A. W. Cheever, S. Hieny, and A. Sher MyD88-Deficient Mice Display a Profound Loss in Resistance to Mycobacterium tuberculosis Associated with Partially Impaired Th1 Cytokine and Nitric Oxide Synthase 2 Expression Infect. Immun., April 1, 2004; 72(4): 2400 - 2404. [Abstract] [Full Text] [PDF]
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S. J. Skerrett, H. D. Liggitt, A. M. Hajjar, and C. B. Wilson Cutting Edge: Myeloid Differentiation Factor 88 Is Essential for Pulmonary Host Defense against Pseudomonas aeruginosa but Not Staphylococcus aureus J. Immunol., March 15, 2004; 172(6): 3377 - 3381. [Abstract] [Full Text] [PDF]
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M. Kursar, H.-W. Mittrucker, M. Koch, A. Kohler, M. Herma, and S. H. E. Kaufmann Protective T cell response against intracellular pathogens in the absence of Toll-like receptor signaling via myeloid differentiation factor 88 Int. Immunol., March 1, 2004; 16(3): 415 - 421. [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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C. G. Feng, C. A. Scanga, C. M. Collazo-Custodio, A. W. Cheever, S. Hieny, P. Caspar, and A. Sher Mice Lacking Myeloid Differentiation Factor 88 Display Profound Defects in Host Resistance and Immune Responses to Mycobacterium avium Infection Not Exhibited by Toll-Like Receptor 2 (TLR2)- and TLR4-Deficient Animals J. Immunol., November 1, 2003; 171(9): 4758 - 4764. [Abstract] [Full Text] [PDF]
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S. Shi, C. Nathan, D. Schnappinger, J. Drenkow, M. Fuortes, E. Block, A. Ding, T. R. Gingeras, G. Schoolnik, S. Akira, et al. MyD88 Primes Macrophages for Full-Scale Activation by Interferon-{gamma} yet Mediates Few Responses to Mycobacterium tuberculosis J. Exp. Med., October 6, 2003; 198(7): 987 - 997. [Abstract] [Full Text] [PDF]
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L. Lefrancois, A. Marzo, and K. Williams Sustained Response Initiation Is Required for T Cell Clonal Expansion But Not for Effector or Memory Development In Vivo J. Immunol., September 15, 2003; 171(6): 2832 - 2839. [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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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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H. Nakano, H. Tsutsui, M. Terada, K. Yasuda, K. Matsui, S. Yumikura-Futatsugi, K.-i. Yamanaka, H. Mizutani, T. Yamamura, and K. Nakanishi Persistent secretion of IL-18 in the skin contributes to IgE response in mice Int. Immunol., May 1, 2003; 15(5): 611 - 621. [Abstract] [Full Text] [PDF]
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), IFN-
), IL-12/IL-18 DKO (DKO; 
), IL-12 KO
(
), IL-18 KO (
), and WT (•) mice after i.v. injection of 5
x 105 (A), 5 x 104
(B), or 5 x 103 (C) CFU
of LM/mouse are shown. Survival was assessed every 12 h for 14
days. Each experimental group consisted of eight (A) or
five (B and C) mice. Similar results were
obtained in two independent experiments.