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*
Institute of Microbiology and Genetics, and
Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria; and
Department of Cellular and Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and by the invading microorganisms
or microbial products. Infection of macrophages with the Gram-positive
bacterium Listeria monocytogenes for short periods
before activation with IFN- increased the phosphorylation of
transcription factor STAT1 at S727 and thereby the expression of
IFN--induced genes. By contrast, persistent infection with viable
bacteria or treatment with heat-killed Listeria
diminished IFN--stimulated transcription and the phosphorylation of
STAT1 at Y701. Decreased IFN- signaling correlated with the
induction of suppressor of cytokine signaling 3 (SOCS3) mRNA and
protein. Contrasting our previous findings with LPS, maximal synthesis
of SOCS3 required both the immediate signals from
Listeria receptors on the cell surface and the activity
of a polypeptide secreted in response to bacterial infection. SOCS3
induction by the secreted protein could not be blocked by neutralizing
Abs to IL-10 and it did not require the presence of STAT1. Consistent
with the induction of SOCS3 activity, Listeria also
inhibited activation of STAT5 by GM-CSF. The p38 mitogen-activated
protein kinase was rapidly activated upon infection of macrophages with
L. monocytogenes. Inhibition of p38 mitogen-activated
protein kinase with the pyridinyl imidazol SB203580 abrogated both
STAT1 S727 phosphorylation and the expression of SOCS3. The data
suggest that STAT1 serine kinase and SOCS3 activity are hallmarks of
immediate and delayed phases of influence by bacterial signals on
signal transduction in response to IFN-. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, whereas the second is most often provided by
components of microbial cell walls or membranes (1, 2).
IFN- influences nuclear gene expression by binding to a
heterooligomeric, class II cytokine receptor and activating the
receptor-associated Janus tyrosine kinases
JAK13 and JAK2. These
phosphorylate the STAT1 at Y701 and cause its dimerization and
translocation to the nucleus (3, 4). STAT1 dimers then
bind to their cognate promoter DNA, the IFN- activation site (GAS),
and activate transcription (5). To act with high
efficiency as a transcription factor, STAT1 must also be phosphorylated
at S727, which lies within a potential mitogen-activated protein kinase
(MAPK) consensus motif at the C terminus, a putative transactivation
domain (6, 7). At present, the kinase(s) phosphorylating
S727 is/are not clearly defined, but the p38 MAPK was shown to be
required for LPS or stress-induced phosphorylation of STAT1 at S727
(8).
Invading microorganisms transduce signals through a variety of pattern
recognition receptors (reviewed in Ref. 9). Among these
are the recently identified Toll-like receptors (TLRs) that
discriminate between different microbial pathogens or their products
(10, 11). Whereas TLR4 is the main protein involved in
recognizing Gram-negative bacteria and LPS, TLR2 is a key component in
responses to other types of microbial pathogens, such as yeast and
Gram-positive bacteria (12, 13, 14, 15). LPS/TLR4 stimulate gene
expression predominantly through the activation of transcription factor
NF-
B (16). However, LPS also directly influences the
output of the JAK-STAT signal transduction pathway in a time-dependent
manner. Although short time exposure of macrophages to LPS increases
the activation of STAT1 via the activation of a STAT1 S727 kinase
(8, 17), prolonged treatment with LPS causes
down-regulation of IFN--mediated STAT1 tyrosine phosphorylation and
transcription. This inhibitory effect is due to an immediate and direct
signal of LPS to the suppressor of cytokine signaling 3
(socs3) gene (18). The SOCS family of proteins,
also known as cytokine-inducible Src homology 2 domain-containing
proteins, JAK-binding proteins, or STAT-induced STAT inhibitors (SSI)
(19, 20, 21), was recently described as feedback inhibitors of
cytokine signaling pathways employing JAKs and STATs (reviewed in Ref.
22). However, as demonstrated for LPS or TNF-
(17, 23, 24), SOCS also mediate negative cross-talk
between JAK-STAT pathways and other signaling routes.
The goal of our study was to investigate whether the induction of SOCS3
and/or the activation of the STAT1 serine kinase is unique to the LPS
response or whether it is a general property of pattern recognition
receptors. Therefore, we studied the impact of infection with
Listeria monocytogenes on the macrophages’ response to
IFN-. L. monocytogenes is a facultative intracellular
Gram-positive pathogen that replicates in the cytosol of mammalian
cells (reviewed in Refs. 25, 26). Once internalized,
Listeria are able to lyse the vacuolar membrane due to the
activity of a potent pore-forming toxin, listeriolysin O (LLO). Mutants
that do not express LLO are avirulent in mouse, demonstrating that
escape of the bacteria from the phagosome to the cytosol is critical
for the establishment of an infection (27, 28, 29). We report
the phosphorylation of STAT1 S727 in response to Listeria
infection and show that Listeria can enhance IFN-
signaling. Similar to LPS, the continuous presence of
Listeria reduces signal transduction in response to IFN-
through the induced synthesis of SOCS3. However, unlike LPS, SOCS3
induction by Listeria occurs in part through a secondary
response requiring the activity of a secreted cytokine.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bac1.2F5 macrophages (30), or C11 cells, a
clone of Bac1.2F5 transfected with a STAT-dependent luciferase gene
(17), were maintained in MEM- medium containing 10%
FCS and 20% L cell-conditioned medium as a source of CSF-1. Bone
marrow-derived macrophages were derived, as described previously
(31), after isolation of bone marrow from femurs of
wild-type or STAT1-deficient mice. STAT1-deficient mice were provided
by Dr. D. E. Levy, New York University School of Medicine (New
York, NY).
Bacterial strains, cytokines, and drugs
L. monocytogenes (Bof 343) and the isogenic,
nonhemolytic mutant (Bof 415), obtained from Pascale Cossart (Institute
Pasteur, Paris, France), were cultured in brain heart infusion broth
(32). Heat-killed cells of L. monocytogenes
(hkL) were prepared by incubating the viable bacterial suspension at
70°C for 10 min. For stimulation of cells, IFN- (provided by G.
Adolf, Boehringer Ingelheim, Vienna, Austria) was used at a
concentration of 10 ng/ml. GM-CSF was prepared from the
GM-CSF-producing cell line X6310 GM-CSF that was grown in RPMI medium
supplemented with 10% FCS for 2 days, and the supernatant was
collected and sterile filtered and used at a concentration of 1:100.
LPS (Sigma, St. Louis, MO) was from Salmonella minnesota and
used at a concentration of 1 µg/ml. The p38 MAPK inhibitor SB203580
was provided by Ken Murray (SmithKline Beecham, Philadelphia, PA) and
was used at 10 µM. The drug was added 30 min before further
treatment.
Cell infection
Bac1.2F5 macrophages were infected with L. monocytogenes wild-type, mutant (both derived from overnight culture), or heat-killed bacteria at multiplicity of infection of 10:1 and incubated for 1 h at 37°C in a humidified 5% CO2 atmosphere. Extracellular bacteria were removed by washing with PBS and killed with gentamicin-containing medium (final concentration 50 µg/ml). After another 60 min, medium was changed to medium containing 10 µg/ml gentamicin. This concentration was shown not to affect survival of intracellular Listeria during the period of treatment (33).
Antibodies
The antisera to the STAT1 C terminus and to phospho-S727-STAT1
have recently been described (17). Rabbit antiserum to
Y701-phosphorylated STAT1 was purchased from New England Biolabs
(Beverly, MA) and used at a dilution of 1:1000. Rabbit anti-SOCS3
antiserum was produced by immunization with a GST fusion protein of
SOCS3 (the plasmid was provided by Jim Johnston, DNAX Research
Institute, Palo Alto, CA). It was used at a 1:1000 dilution in Western
blots. A mAb to SOCS3 was derived from spleen cells of mice after
immunization with the GST-SOCS3 fusion protein by standard techniques.
Hybridoma supernatants were screened for specific Ab by ELISA with
GST-SOCS3-coated wells and subsequently by Western blotting of extracts
from SOCS3-transfected 293 cells. Undiluted hybridoma supernatants were
used for the experiment shown in Fig. 5
C. A polyclonal Ab
against Y694/Y699-phosphorylated STAT5a/b was purchased from Upstate
Biotechnology (Lake Placid, NY). The antiserum specific for the STAT5a
isoform (and its use in Western blot experiments) was recently
described (34). Neutralizing Abs to IL-10 were purchased
from Strathmann Biotech (Hannover, Germany). They were used at a
dilution of 1:200, which neutralizes 2 ng/ml of IL-10. The amount
secreted by LPS-treated monocytes or macrophages into the culture
medium was reported to be at least 4-fold lower (35, 36).
Abs specific for the phosphorylated form of p38 MAPK, or against p38
MAPK, were bought from New England Biolabs. Pan-extracellular
signal-related kinase mAbs were purchased from Transduction
Laboratories (Lexington, KY) and used at a dilution of 1:2000 in
Western blots. For FACS analysis, a biotin-labeled rat mAb recognizing
the -chain of the murine IFN- receptor was obtained from
PharMingen (San Diego, CA). PE-labeled streptavidin was used as a
secondary reagent. Rabbit antisera to JAK1 and JAK2 kinases were a gift
from Dr. Andrew Zimiecki (Laboratory for Clinical and Experimental
Cancer Research, Bern, Switzerland). They were used at 1:100 dilution
for immuno-precipitation and 1:1000 dilution for Western blots.
Polyclonal Abs against inhibitory protein that dissociates from NF-B
(I-B) were used in Western blots at a dilution of 1:1000.
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We have recently described protocols for these procedures (17).
EMSA
An end-labeled, double-stranded oligonucleotide corresponding to
the GAS sequence of the 
-casein promoter was used. The assay was
performed with whole cell extracts, as recently described (37, 38).
Luciferase assay
Extracts from C11 macrophages were assayed for luciferase
activity according to standard procedures (39). Results
are stated as inducibility, the ratio obtained by dividing cpm light
emission from IFN- and/or L. monocytogenes-treated and
unstimulated cells.
Northern blot
An amount of 15 µg of total RNA from Bac1.2F5 cells was separated on agarose gels and blotted to membrane using standard procedures. The blots were probed using SOCS3 cDNA labeled by random priming.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In macrophages, phosphorylation of STAT1 S727 occurs in response
to LPS, the outer membrane constituent of Gram-negative bacteria
(17). To determine whether Gram-positive bacteria that
signal through a distinct TLR family member cause STAT1 S727
phosphorylation, we infected macrophages with L.
monocytogenes. The experiment shown in Fig. 1A demonstrates rapid
phosphorylation of STAT1 S727 in response to infection with
Listeria, which persisted throughout the tested period.
Therefore, like LPS, infection with Gram-positive bacteria targets
STAT1 at S727. IFN- also caused phosphorylation of STAT1 at S727,
and the effects of Listeria and IFN- in phosphorylating
STAT1 were approximately additive.
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and
both in vitro and in vivo (40, 41, 42). Infection with
L. monocytogenes caused rapid activation of p38 MAPK (Fig. 1
B). A potential role of p38 MAPK in phosphorylating STAT1
S727 was tested using SB203580 (Fig. 1C). The drug inhibited
STAT1 S727 phosphorylation in response to hkL and LPS in macrophages by
70%. This suggests a role for p38 MAPK, because macrophages
mainly express this isoform (43). However, macrophages
also express the SB203580-insensitive p38 MAPK
. Therefore, the
incomplete suppression of STAT1 S727 phosphorylation by SB203580, which
was also noted in the case of LPS (8), may result from
activation of this p38 MAPK isoform, or be due to other
SB203580-insensitive kinases participating in STAT1
phosphorylation. Prolonged infection with Listeria inhibits STAT1 tyrosine phosphorylation
To investigate whether L. monocytogenes infection
affects STAT1 tyrosine phosphorylation by IFN-, we performed EMSA
experiments. Infection of Bac1.2F5 macrophages (Fig. 2A, lanes 3–8), or
bone marrow-derived macrophages (data not shown) with
Listeria for more than 4 h strongly reduced the
dimerization of STAT1 in response to a subsequent IFN- stimulus.
Furthermore, not only viable bacteria, but also hkL could significantly
down-regulate STAT1 DNA-binding activity (lanes
9–14). Consistent with the EMSA results, pretreatment with viable
wild-type or listeriolysin-deficient Listeria, or with
hkL, reduced the tyrosine phosphorylation of STAT1 in
response to IFN-, as determined by Western blot with an antiserum
against STAT1 phosphorylated on Y701 (Fig. 2B). Although
some reduction of STAT1 protein expression was noted upon persistent
Listeria infection or hkL treatment, control blots with
pan-extracellular signal-related kinase antiserum showed that the
reduced STAT1 tyrosine phosphorylation was not primarily caused by a
decrease in the relative amount of cellular STAT1 protein. Furthermore,
suppression of STAT1 tyrosine phosphorylation occurred at both
saturating and limiting doses of IFN- (Fig. 2C). Long
exposures of our blots indicated that despite the ability of
Listeria to down-regulate IFN--induced STAT1 tyrosine
phosphorylation, a low level of STAT1 tyrosine phosphorylation was
caused by stimulation with Listeria alone (data not
shown).
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. In fact,
Mycobacterium avium was reported to diminish expression of
the IFN-R1 receptor chain (44). In the case of L.
monocytogenes, we observed a slight reduction in the expression of
IFN-R1 on the cell surface, as determined by flow cytometry (Fig. 3A). It is not nearly as
pronounced as that observed with M. avium and insufficient
to explain the much stronger effect on STAT1 tyrosine phosphorylation
by IFN-. Expression of the JAK1 and JAK2 kinases as analyzed by
Western blot was not significantly altered (Fig. 3B). This
suggests that reduced activity rather than reduced expression of signal
transducers might be responsible for the negative effect of
Listeria on STAT1 activation.
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and LPS
(18), a brief costimulation of the cells with both IFN-
and Listeria resulted in increased STAT1 transcriptional
activity, compared with stimulation by IFN- alone. This is the
effect expected from increased phosphorylation at S727. By contrast,
longer treatment converted the stimulatory effect of
Listeria on the IFN- response into suppressive activity
(Fig. 4). S727 phosphorylation by
Listeria persists for many hours (Fig. 1). Therefore, the
reduced stimulatory activity of IFN- on transcription seen between
0.5 and 4 h of pretreatment with Listeria is most
likely due to the inhibitory effect on IFN--induced STAT1 tyrosine
phosphorylation (Fig. 2B).
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The inhibition of STAT1 tyrosine phosphorylation prompted us to
investigate a possible role of SOCS proteins in
Listeria-mediated signaling. Two members of this family,
SOCS1/JAK-binding protein/SSI1 and SOCS3/cytokine-inducible Src
homology 2 domain-containing protein 3/SSI3, have been associated with
inhibition of the IFN- response (18, 45, 46, 47). Northern
blots with RNA from Bac1.2F5 macrophages infected with L.
monocytogenes for various periods demonstrated increased
expression of SOCS3 mRNA (Fig. 5A). Maximal levels of SOCS3
mRNA were reached after 4 h of Listeria treatment.
Interestingly, the induction was only in part resistant to inhibition
of protein synthesis by cycloheximide. After short treatment with
Listeria (2 h), the induction was fully resistant to
cycloheximide. Longer periods of infection with Listeria (4
h) led to a partial dependence on protein synthesis. SOCS3 protein was
induced by L. monocytogenes as well as hkL with maximal
levels after 6 h (Fig. 5B). This result argues for a
causal effect of SOCS3 on suppression of IFN--induced signal
transduction, in which a clear effect on STAT1 tyrosine phosphorylation
is evident after 4 h and a maximal effect after 8–12 h (Fig. 2).
L. monocytogenes infection of macrophages causes
I-B degradation and the secretion of a SOCS3-inducing polypeptide
NF-B is a major player in the transcription of antibacterial
and proinflammatory genes. Consistent with a role of NF-B in
regulating the expression of Listeria-induced genes, its
inhibitor, I-B, was rapidly degraded after stimulation of
macrophages with heat-killed bacteria (Fig. 6A). Thus, NF-B is a
candidate transcription factor for the rapid and direct stimulation of
SOCS3 mRNA expression by L. monocytogenes.
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B).
L. monocytogenes was previously shown to induce the
synthesis of IL-10 (48) and IL-10 was reported to induce
SOCS3 mRNA (49). To investigate whether the secreted,
SOCS3-inducing peptide might be IL-10, we infected macrophages with
Listeria in the presence of neutralizing Abs to IL-10. This
treatment did not decrease SOCS3 mRNA expression (Fig. 5A).
Type I IFN were previously shown to be important intermediates in the
transcription of the inducible NO synthase gene in response to
Leishmania major infection (50). Macrophages
isolated from STAT1-deficient mice responded to Listeria
infection with SOCS3 synthesis at similar amounts and with similar
kinetics, thus ruling out a similar role for type I IFN for
Listeria infection and the induction of SOCS3 (Fig. 6C). In conclusion, neither IL-10 nor type I IFN appears to
be involved in the stimulation of the socs3 gene. Therefore,
the cause for sensitivity to cycloheximide after extended periods of
Listeria infection is still not clear.
Like the phosphorylation of STAT1S727, Listeria-induced SOCS3
expression was also SB203580 sensitive (Fig. 6D). SB203580
in this case caused complete inhibition of SOCS3 expression.
Together the data establish SOCS3 as a direct and indirect Listeria target gene, induced by Listeria-responsive transcription factors or mRNA stabilization, and a secreted polypeptide.
Listeria infection inhibits GM-CSF-mediated JAK-STAT signal transduction
SOCS3 is known to inhibit signaling of a broad array of stimuli,
such as prolactin, leptin, growth hormone, GM-CSF, and, as confirmed
before, IFN- (reviewed in Ref. 51). To confirm SOCS3
activity in Listeria-infected cells, STAT5 activation by
GM-CSF was tested in Western blot experiments. Bac1.2F5 macrophages
were preinfected with Listeria for the indicated periods and
subsequently stimulated with GM-CSF for 25 min. Already after 3 h
of pretreatment with Listeria, a decrease in STAT5 tyrosine
phosphorylation could be observed in response to GM-CSF when compared
with STAT5 expression in the control blot (Fig. 7). This effect is consistent with
results obtained from EMSA experiments (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Together with our recent findings (8, 18), the results presented in this study suggest that the enhancement of STAT1 activity after a brief contact with macrophages and the suppression of activity after chronic exposure are hallmarks of responses to probably all types of bacteria. They also imply that Gram-negative and Gram-positive bacteria, while using different pattern recognition receptors, elicit signaling pathways that converge at the level of STAT1 activation. p38 MAPK is activated and required for the phosphorylation of STAT1 at S727 not only in response to LPS (8), but also to Gram-positive bacteria such as L. monocytogenes.
Viable bacteria are neither required for the induction of STAT1 S727
kinase nor are they necessary for the inhibition of STAT1 tyrosine
phosphorylation. Avirulent mutant Listeria that lack the
pore-forming toxin LLO, as well as hkL, reproduce the effects of live
bacteria by significantly reducing the level of tyrosine
701-phosphorylated STAT1. This indicates that the bacterial
component(s) that initiates inhibition of the IFN- response is (are)
constitutively expressed and not triggered upon infection of the host
cell. The bacterial membrane and its interaction with, e.g., the
corresponding TLR, appear entirely sufficient to cause the effects on
IFN- signal transduction.
As in the case of LPS, SOCS3 mRNA and protein induction in response to Listeria is most likely responsible for the inhibition of STAT1 tyrosine phosphorylation. As a member of a family of feedback inhibitors of cytokine signaling pathways, SOCS3 was shown to be induced by a broad array of stimuli (reviewed in Ref. 51). IL-10 is among these stimuli, but was shown in our studies not to be responsible for the partial sensitivity of SOCS3 mRNA expression to cycloheximide after treatment with Listeria for more than 4 h. Moreover, SOCS3 mRNA was induced in absence of STAT1, ruling out a transcriptional response to type I or type II IFN in this particular aspect of L. monocytogenes infection. In contrast, our data clearly imply an unidentified, secreted cytokine in SOCS3 synthesis. In this aspect, Listeria differs from LPS, in which induction is exclusively due to direct effects on the socs3 gene (18).
Likewise, the signals and transcription factors induced by
Listeria to cause direct (i.e., cycloheximide-resistant)
SOCS3 expression remain to be clarified. The Toll family receptor TLR2
and postreceptor signals (NF-B?) are likely candidates. Like STAT1
phosphorylation at S727, the expression of SOCS3 protein in response to
Listeria or LPS is also p38 MAPK dependent, confirming the
important role of the enzyme during macrophage activation. At present,
we do not know whether p38 MAPK is required for SOCS3 transcription,
mRNA stability, or protein translation.
Our studies suggest that STAT S727 kinase activation and SOCS3
induction are general aspects of the antimicrobial response of
macrophages. These responses can be caused by cell wall components (LPS
or heat-killed bacteria) and therefore do not require active
participation of the bacteria. Therefore, it seems unlikely that they
represent part of a bacterial survival strategy. We speculate that in
an initial phase of infection, it is immunologically meaningful to
achieve maximal macrophage activation to eliminate invaders with
maximal efficiency. Activation of the STAT1 S727 kinase is part of this
host cell strategy because it enhances the output of IFN--induced
genes. Upon persistent infection with bacteria, the effects of chronic
macrophage activation, hence inflammation, may be detrimental to the
host organism. Therefore, deactivation mechanisms are implemented, and
intracellular SOCS3 activity is part of these. IL-10-induced SOCS3
production is part of its deactivating activity, but our studies show
that both LPS and Gram-positive bacteria can stimulate SOCS3 synthesis
directly and independently of deactivating cytokines.
While stressing the significance of Listeria-induced SOCS3 for lowering the inflammatory potential of chronically activated macrophages, our data and results from other labs also suggest a general alteration of the macrophage’s cytokine responsiveness by intracellular SOCS3. This is very evident from the inability of SOCS3-expressing cells to mount a proper response to GM-CSF. The full implications of SOCS3 activity for the physiology of macrophages remain to be determined in future studies.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas Decker, Vienna Biocenter, Institute of Microbiology and Genetics, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria.
3 Abbreviations used in this paper: JAK, Janus kinase; GAS, IFN- activation site; hkL, heat-killed cells of Listeria monocytogenes; I-B, inhibitory protein that dissociates from NF-B; LLO, listeriolysin O; MAPK, mitogen-activated protein kinase; SOCS, suppressor of cytokine signaling; SSI, STAT-induced STAT inhibitor; TLR, Toll-like receptor.
Received for publication March 31, 2000. Accepted for publication September 28, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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K.-i. Uchiya and T. Nikai Salmonella Pathogenicity Island 2-Dependent Expression of Suppressor of Cytokine Signaling 3 in Macrophages Infect. Immun., September 1, 2005; 73(9): 5587 - 5594. [Abstract] [Full Text] [PDF]
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H. Feng, D. Zhang, D. Palliser, P. Zhu, S. Cai, A. Schlesinger, L. Maliszewski, and J. Lieberman Listeria-Infected Myeloid Dendritic Cells Produce IFN-{beta}, Priming T Cell Activation J. Immunol., July 1, 2005; 175(1): 421 - 432. [Abstract] [Full Text] [PDF]
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S. Stockinger, B. Reutterer, B. Schaljo, C. Schellack, S. Brunner, T. Materna, M. Yamamoto, S. Akira, T. Taniguchi, P. J. Murray, et al. IFN Regulatory Factor 3-Dependent Induction of Type I IFNs by Intracellular Bacteria Is Mediated by a TLR- and Nod2-Independent Mechanism J. Immunol., December 15, 2004; 173(12): 7416 - 7425. [Abstract] [Full Text] [PDF]
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C. Gomez-Guerrero, O. Lopez-Franco, G. Sanjuan, P. Hernandez-Vargas, Y. Suzuki, G. Ortiz-Munoz, J. Blanco, and J. Egido Suppressors of Cytokine Signaling Regulate Fc Receptor Signaling and Cell Activation during Immune Renal Injury J. Immunol., June 1, 2004; 172(11): 6969 - 6977. [Abstract] [Full Text] [PDF]
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J. A. Gold, Y. Hoshino, S. Hoshino, M. B. Jones, A. Nolan, and M. D. Weiden Exogenous Gamma and Alpha/Beta Interferon Rescues Human Macrophages from Cell Death Induced by Bacillus anthracis Infect. Immun., March 1, 2004; 72(3): 1291 - 1297. [Abstract] [Full Text] [PDF]
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D. J. Mitchell, H. Q. Huynh, P. J. M. Ceponis, N. L. Jones, and P. M. Sherman Helicobacter pylori Disrupts STAT1-Mediated Gamma Interferon-Induced Signal Transduction in Epithelial Cells Infect. Immun., January 1, 2004; 72(1): 537 - 545. [Abstract] [Full Text] [PDF]
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P. J. M. Ceponis, D. M. McKay, R. J. Menaker, E. Galindo-Mata, and N. L. Jones Helicobacter pylori Infection Interferes with Epithelial Stat6-Mediated Interleukin-4 Signal Transduction Independent of cagA, cagE, or VacA J. Immunol., August 15, 2003; 171(4): 2035 - 2041. [Abstract] [Full Text] [PDF]
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S. P. Coller, J. M. Mansfield, and D. M. Paulnock Glycosylinositolphosphate Soluble Variant Surface Glycoprotein Inhibits IFN-{gamma}-Induced Nitric Oxide Production Via Reduction in STAT1 Phosphorylation in African Trypanosomiasis J. Immunol., August 1, 2003; 171(3): 1466 - 1472. [Abstract] [Full Text] [PDF]
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S. Bertholet, H. L. Dickensheets, F. Sheikh, A. A. Gam, R. P. Donnelly, and R. T. Kenney Leishmania donovani-Induced Expression of Suppressor of Cytokine Signaling 3 in Human Macrophages: a Novel Mechanism for Intracellular Parasite Suppression of Activation Infect. Immun., April 1, 2003; 71(4): 2095 - 2101. [Abstract] [Full Text]
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P. J. M. Ceponis, D. M. McKay, J. C. Y. Ching, P. Pereira, and P. M. Sherman Enterohemorrhagic Escherichia coli O157:H7 Disrupts Stat1-Mediated Gamma Interferon Signal Transduction in Epithelial Cells Infect. Immun., March 1, 2003; 71(3): 1396 - 1404. [Abstract] [Full Text] [PDF]
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S. Stockinger, T. Materna, D. Stoiber, L. Bayr, R. Steinborn, T. Kolbe, H. Unger, T. Chakraborty, D. E. Levy, M. Muller, et al. Production of Type I IFN Sensitizes Macrophages to Cell Death Induced by Listeria monocytogenes J. Immunol., December 1, 2002; 169(11): 6522 - 6529. [Abstract] [Full Text] [PDF]
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 M. J. Scott, C. J. Godshall, and W. G. Cheadle Jaks, STATs, Cytokines, and Sepsis Clin. Vaccine Immunol., November 1, 2002; 9(6): 1153 - 1159. [Full Text] [PDF]
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M. D. Lehner, F. Schwoebel, A. Kotlyarov, M. Leist, M. Gaestel, and T. Hartung Mitogen-Activated Protein Kinase-Activated Protein Kinase 2-Deficient Mice Show Increased Susceptibility to Listeria monocytogenes Infection J. Immunol., May 1, 2002; 168(9): 4667 - 4673. [Abstract] [Full Text] [PDF]
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I. Woldman, L. Varinou, K. Ramsauer, B. Rapp, and T. Decker The Stat1 Binding Motif of the Interferon-gamma Receptor Is Sufficient to Mediate Stat5 Activation and Its Repression by SOCS3 J. Biol. Chem., November 30, 2001; 276(49): 45722 - 45728. [Abstract] [Full Text] [PDF]
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A. H. Dalpke, S. Opper, S. Zimmermann, and K. Heeg Suppressors of Cytokine Signaling (SOCS)-1 and SOCS-3 Are Induced by CpG-DNA and Modulate Cytokine Responses in APCs J. Immunol., June 15, 2001; 166(12): 7082 - 7089. [Abstract] [Full Text] [PDF]
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