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Institute of Medical Microbiology and Hygiene, Philipps-University, Marburg, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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as well as
IL-6- and GM-CSF-induced phosphorylation of STAT proteins. Furthermore,
IFN--induced up-regulation of MHC class II molecules was also
prevented. The same effects could be achieved by overexpression of
SOCS-1. Hence, the results indicate a substantial cross-talk between
signal pathways within cells. They provide evidence for regulative
mechanisms of Janus kinase/STAT signaling after triggering Toll-like
receptor signal pathways. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B (9). The innate
immune cell pool responding to PAMP is comprised mainly of dendritic
cells (DC) and macrophages (1). Pathogen-derived stimuli
act directly on these cells; however, responses are regulated and
influenced by a cytokine milieu containing, for example, IFN-
(10).
Bacterial DNA activates cells of the innate immune system due to the
relative abundance of unmethylated CpG motifs. Synthetic
oligodeoxynucleotides (ODN) with immunostimulative CpG motifs
mimic the effects of bacterial DNA and trigger macrophages and DC
(2, 3). Inversion of the CpG dinucleotide to GpC
completely prevents immunostimulation. As bacterial DNA, CpG-ODN
trigger activation of MAPK cascades and NF-B, resulting in
transcription of cytokine mRNA such as TNF and IL-12
(11, 12, 13). CpG signaling critically depends on the presence
of intracellular protein MyD88 and TRAF6 (14, 15).
Recently, TLR-9 has been identified as the respective receptor for
CpG-DNA, thus adding CpG-DNA to the family of TLR ligands
(6).
After triggering with CpG-DNA, intracellular signaling pathways are activated within minutes. After hours, these cells respond with production and secretion of cytokines such as IL-12 or TNF and with differentiation and activation of effector functions (16). In vivo, cytokine release shows sharp kinetics: cytokine levels burst and peak after 1–2 h, followed by subsequent down-regulation (16). Thus, initial activation of DC and macrophages is followed by counterregulative events whose mechanisms have been characterized only incompletely to date. In addition, it has been shown that macrophages down-regulate MHC class II expression after initial activation by CpG-DNA (17).
Whereas initiation of signal transduction by cytokines or natural ligands is well characterized, little is known about inactivation of signal transduction pathways. In the last years, substantial progress has been achieved toward the understanding of molecular mechanisms of activation and down-regulation of the Janus kinase (JAK)/STAT signaling pathway, which is activated in response to a variety of cytokines and hormones (18). A new family of cytokine-induced inhibitors of JAK/STAT signals has been characterized (19, 20, 21). This family is comprised of at least eight members of SH2-domain-containing proteins, which are named suppressors of cytokine signaling (SOCS 1–7) (19), and cytokine-inducible SH2(C15)-containing proteins (22). These proteins can be induced in various tissues and cell lines (23), although SOCS-1 and SOCS-3 have been recognized to be most important for regulative effects in immune cells (24, 25, 26, 27, 28). The SOCS proteins act as negative regulators of the JAK/STAT pathway either by inhibiting JAK activity or by inhibiting binding of STAT factors to the cytoplasmatic domains of the respective receptors (23). SOCS-1 and SOCS-3 are tightly regulated within immune cells, and their induction depends on de novo transcription of mRNA (29). The respective promoter regions contain defined STAT binding sites (30). Induction may occur not only through cytokines, but also through other ligands that are associated with activation of JAK/STAT pathway (23, 31). Furthermore, there are indications that SOCS proteins even can be induced by STAT-independent signals (27), suggesting that multiple signal pathways are involved in regulation of SOCS.
Because signal pathways induced by CpG-DNA are quite well
characterized, and because CpG-ODN with its internal negative control
(GpC-ODN) represents a suitable and reliable tool to trigger
TLR-related signal pathways (11, 12), we analyzed the role
of CpG-DNA on the expression of SOCS proteins. We show induction of
SOCS-1 and SOCS-3 mRNA, which was independent of protein synthesis and
could be blocked partially by inhibitors of MAPK signaling. SOCS
proteins were operative because they inhibited subsequent IFN- as
well as IL-6 and GM-CSF signaling pathways. Thus, the results indicate
that TLR-related signal pathways not only activate functional SOCS
proteins and might be responsible for down-regulative events after
triggering with PAMP, but also point to a regulative cross-talk between
distinct intracellular signaling pathways.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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J774 (American Type Culture Collection, Manassas, VA) and RAW
264.7 cells (a kind gift from R. Schumann, Universitätsklininkum
Charite, Berlin, Germany) were cultured in Clicks/RPMI 1640
supplemented with 5% FCS, 50 µM 2-ME, and antibiotics (penicillin G
(100 IU/ml of medium) and streptomycin sulfate (100 IU/ml of medium)).
Phosphothioate-modified ODN were custom synthesized by TIB Molbiol
(Berlin, Germany) and MWG Biotech (Munich, Germany). The following
sequences were used (the bold letters indicate the CpG motifs): 1668,
TCC ATG ACG TTC CTG ATG CT; SB-DG, TCC ATG ACG
TTC CTG ATG CTA GAG A; 1668GC, TCC ATG AGC TTC CTG ATG
CT (control ODN with inverted CpG motif); PZ-3, CTC CTA TTG GGG
GTT TCC TAT (G-rich ODN). LPS and chloroquine were purchased from
Sigma (Deisenhofen, Germany). Cycloheximide and the MAPK inhibitor
SB203580 were delivered by Calbiochem (Schwalbach, Germany); UO126 came
from Promega (Mannheim, Germany). IFN- was obtained from E.
Adolf (Vienna, Austria); IL-6 and GM-CSF were purchased from
Tebu (Frankfurt, Germany). Stat-1, Stat-3, and Stat-5 Ab were a kind
gift of T. Decker (Vienna, Austria). Abs to SOCS were purchased from
Santa Cruz Biotechnology (Heidelberg, Germany); other Abs were obtained
from New England Biolabs (Frankfurt, Germany). Recombinant
IFN-
, IFN-
, and neutralizing Abs against IFN- and IFN- were
obtained from PBL (New Brunswick, NJ).
Determination of cytokine secretion
Cytokine levels in culture supernatants were determined using a
commercially available ELISA kit for TNF-, according to the
manufacturer’s instructions (BD Biosciences, Heidelberg, Germany).
Each value represents mean of duplicate values.
Cell stimulation
Depending upon the experiments, 1 x
106 cells/well (RT-PCR) or 5 x
106 cells/well (Western blot) were plated in a
12-well culture plate and stimulated with different ODN in the
indicated concentrations. When using inhibitors, these were
preincubated for the indicated time before stimulation was performed.
If not otherwise indicated, cells were stimulated for 4.5 h, then
supernatants were removed and, where indicated, TNF- was measured by
ELISA.
TaqMan RT-PCR
Total RNA from the cells was isolated by using HighPure RNA kit
(Roche, Mannheim, Germany), which included DNase I digestion. A total
of 1 µg of total RNA preparation was reverse transcribed with cDNA
synthesis kit (MBI Fermentas, St. Leon-Rot, Germany) using
oligo(dT)23. cDNA was diluted 1/4, and 2.5 µl
was used as template in 25 µl TaqMan-PCR mix, according to the
manufacturer’s protocol (PE Biosystems, Weiterstadt, Germany).
MgCl2 was tested by titration and used with 5.5
mM. -actin primer (sense, CCC TGT GCT GCT CAC CGA; antisense, ACA
GTG TGG GTG ACC CCG TC), TNF- primer (sense, AAA ATT CGA GTG ACA AGC
CTG TAG; antisense, CCC TTG AAG AGA ACC TGG GAG TAG), SOCS1 primer
(sense, CAC CTT CTT GGT GCG CG; antisense, AAG CCA TCT TCA CGC TGA GC),
and SOCS3 primer (sense, GCT CCA AAA GCG AGT ACC AGC; antisense, AGT
AGA ATC CGC TCT CCT GCA G) were purchased from MWG (Munich, Germany).
Fluorogenic probes (6-carboxyfluorescein) were: -actin, CCC
CTG AAC CCT AAG GCC AAC CG; TNF-, CAC GTC GTA GCA AAC CAC CAA GTG
GA; SOCS1, TCG CCA ACG GAA CTG CTT CTT CG; SOCS3, TTG CGC ACG GCG TTC
ACC AC. Specificity of RT-PCR was controlled by no template and no
reverse-transcriptase controls.
Semiquantitative PCR results were obtained using the 
CT method
(32). Because PCR efficiencies for all four reactions were
similar (
0.95–0.98), threshold values were normalized to -actin
and set in reference to unstimulated control cells. The calculated
values represent thus the 2n-fold induction
of mRNA.
Western blot
After stimulation, cells were lysed for 30 min on ice in 250 µl of lysis buffer (50 mM Tris-HCl, pH 7.4; 1% Igepal; 0.25% sodium deoxycholate; 150 mM NaCl; 1 mM EDTA; 1 mM PMSA; 1 µg/ml each aprotinin, leupeptin, and pepstatin; 1 mM Na3VO4; and 1 mM NaF). Lysates were cleared by centrifugation at 4°C for 10 min at 11,000 x g. Equal amounts of lysates were fractionated by 12% SDS-PAGE and electrotransferred to polyvinylidene difluoride membranes. The membranes were blocked with TBS (pH 7.8)/5% nonfat dry milk/0.05% Tween 20, and were blotted with the indicated Abs. Detection was by ECL system (Amersham, Freiburg, Germany). Phosphospecific Abs to STATs and MAPK were used according to the manufacturer’s protocol. Where indicated, membranes were stripped with 0.2 M NaOH for 5 min and reprobed with Abs.
Bone marrow-derived DC (BMDDC) and peritoneal washout cells (PWC)
BMDDC from BALB/c mice were prepared as described (12). Briefly, femurs of mice were rinsed with cell culture medium using a syringe with a 27-gauge needle. Bone marrow cells (4 x 106) were seeded into a 80-cm2 tissue culture flask in culture medium with 200 U/ml GM-CSF. Nonadherent cells were used at day 9, when mature DC (CD11c+, GR-1-) represented >85% of the resulting cell population. PWC were prepared by peritoneal lavage of untreated BALB/c mice. Cells were plated in culture medium and washed 2 and 4 h after plating to remove nonadherent cells.
RNA preparation of spleen extracts
BALB/c mice were injected i.p. with 10 nmol ODN 1668 in 500 µl PBS. Mice were killed by cervical dislocation at the indicated time points. Spleens were prepared and flash-frozen in liquid nitrogen. Then spleens were homogenized on ice, and RNA was prepared using TRIzol (Life Technologies, Karlsruhe, Germany), according to the manufacturer’s protocol. To remove traces of DNA, an incubation with DNase I (Roche) was performed, and finally RNA was cleaned up in a second purification with RNeasy kit (Qiagen, Hilden, Germany). RNA was stored at -70°C before cDNA synthesis.
Flow cytometry analysis
Cells were washed in PBS/2% FCS. Fc-block was performed by
incubating with anti-FcRII/III mAbs (clone 2.4G2; PharMingen,
San Diego, CA) and 10% normal mouse serum for 15 min on ice. Then
cells were stained with FITC-conjugated anti
I-Ad/Ed mAbs (clone 2G9;
PharMingen), FITC GR-1 (clone RB6-8C5; PharMingen), or PE-conjugated
anti-CD11c Abs (clone HL3; PharMingen) for 45 min on ice. After
staining, cells were washed and fixed in PBS/1% paraformaldehyde.
Cells were analyzed on a Partec PAS flow cytometer (Dako,
Hamburg, Germany).
Generation of stable RAW 264.7 transfectants
Mammalian expression vectors for SOCS-1 and SOCS-3 were described previously (19) and were obtained from D. Hilton (Victoria, Australia). pEF-Sem, which contains a neomycin resistance cassette, was a kind gift of H. Haecker (Munich, Germany). Stable transfections were established by cotransfection of either SOCS-1, SOCS-3, or empty vector expression plasmids, and pEF-Sem in a ratio of 10 to 1.5 x 106 RAW 264.7 cells were transfected by electroporation in 500 µl final volume (RPMI, 25% FCS) at 290 V, 1050 µF in an EasyjecT plus gene pulser (PeqLab, Erlangen, Germany). Cells were plated, and 24 h after transfection they were overlaid with soft agar containing 0.8 µg/ml G418 (Life Technologies). G418-resistant clones were picked, expanded, and tested for expression of SOCS mRNA by semiquantitative RT-PCR as well as SOCS protein expression by immunoprecipitation and Western blot with anti-Flag Abs (Sigma).
Clones were selected for equal SOCS-1 and SOCS-3 mRNA overexpression. They also showed equal protein levels, as determined by anti-Flag Abs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, known to be induced by
CpG-DNA (11), and SOCS-1 and SOCS-3 in RAW 264.7
macrophage cell line (Fig. 1
A). CpG-DNA induced TNF-
mRNA as well as SOCS-1 and SOCS-3 mRNA with similar dose-response
curves. Time kinetics revealed that mRNA for TNF- peaked at 1/2–1
h, then decreased slightly, but remained elevated for 24 h (Fig. 1B). SOCS-3 mRNA expression also peaked at 1–2 h, yet
showed a second peak after 8 h. Again, sustained expression was
observed even after 24 h. Significant mRNA induction of SOCS-1 was
delayed in comparison with SOCS-3 and TNF. Expression started after
2 h and peaked at 4 h (Fig. 1B). After 48 h,
mRNA expression for SOCS and TNF declined to background values (data
not shown). Similar results were obtained with J774 macrophage cell
line for TNF and SOCS-3 mRNA expression, while SOCS-1 mRNA was
expressed at much lower levels (data not shown). mRNA expression of
SOCS-3 resulted in subsequent translation of SOCS-3 proteins, as shown
by Western blotting with extracts from J774 as well as RAW cells (Fig. 1C).
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as
well as SOCS-1 and SOCS-3, GpC ODN failed to do so (Fig. 2A). ODN containing
polyguanosine sequences but no CpG motifs (PZ-3) also were negative. In
contrast, LPS induced TNF and SOCS expression almost as efficient as
CpG-ODN. Thus, we concluded that TLR-dependent or related triggering of
innate immune cells induces expression of negative regulators of
cytokine signaling (SOCS). To exclude that SOCS mRNA is induced
indirectly by CpG-ODN, we stimulated J774 cells in the presence of
cycloheximide (Fig. 2B). Although production of TNF protein
was completely abolished, mRNA expression of TNF-, SOCS-1, and
SOCS-3 was not significantly affected (Fig. 2B). Because it
has been published that IFN- and IFN- contributes to SOCS-1
induction mediated by LPS in murine bone marrow culture-derived
macrophages in an autocrine fashion, we addressed this question by
blocking experiments. IFN- and IFN- were able to induce SOCS-1
mRNA, while SOCS-3 induction was only weak (Fig. 2C).
Addition of a neutralizing Ab completely inhibited IFN-- and
IFN--mediated SOCS induction. In contrast, the Ab did not inhibit
either SOCS-1 or SOCS-3 induction by CpG-ODN, thus ruling out an
autocrine mechanism via type I IFNs. Because the promotor region of
SOCS-3 contains putative binding sites for NF-B and AP-1, and
because CpG-ODN trigger both transcription factors (11),
yet do not induce tyrosine phosphorylation of STAT factors, we presume
that CpG-ODN directly are capable of inducing expression of SOCS
mRNA.
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, SOCS-1, SOCS-3 (Fig. 3A), as well as TNF protein
secretion (data not shown). To analyze downstream signaling events,
MAPK were blocked by specific inhibitors. SB203580, an inhibitor of the
p38 MAPK, failed to impede expression of TNF and SOCS-1 mRNA, yet
inhibited slightly SOCS-3 mRNA expression (Fig. 3B).
Corroborating previous results (11), we found that
SB203580 blocked almost completely TNF production, although mRNA
expression for TNF was not inhibited. In contrast, UO126, which
inhibits the extracellular signal-related kinase-1/2 MAPK, slightly
suppressed expression of mRNA encoding for TNF and SOCS-1 (Fig. 3).
SOCS-3 mRNA expression was more susceptible to blockade by UO126 (Fig. 3). From these experiments, we concluded that reagents known to block
the CpG ODN-triggered signaling pathways also interfered with induction
of SOCS-1 and SOCS-3 mRNA. Because we ruled out indirect mechanisms for
induction of SOCS (Fig. 2
B) and because inhibitors of
CpG-ODN signaling block expression of SOCS mRNA, we conclude
that SOCS-1 and SOCS-3 are direct target genes of CpG-ODN
signaling.
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A). Although PWC showed high
TNF- induction, SOCS-1 and SOCS-3 induction was only moderate. In
contrast, CpG-DNA induced higher amounts SOCS-1 and SOCS-3 mRNA in
BMDDC, while TNF- mRNA induction was lower. LPS induced similar mRNA
expression in BMDDC (Fig. 4B), while PWC showed a higher
SOCS induction as compared with CpG stimulation (Fig. 4B).
Comparison of mRNA induction in J774 and RAW 264.7 cell lines further
revealed cell type-specific differences (Fig. 4B). Again
SOCS mRNA data were confirmed by Western blotting for SOCS protein
expression (Fig. 4C). Taken together, primary cells as well
as cell lines showed marked induction of SOCS-1 and SOCS-3 upon
stimulation with LPS as well as with CpG-DNA.
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). TNF-
mRNA peaked at 1 h after injection; SOCS-3 also was induced as
early as after 1 h, peaking at 2 h. SOCS-1 induction was
slightly delayed, nevertheless comparable with SOCS-3 mRNA induction,
and peaked at 2 h. Thus, early kinetics of mRNA expression
obtained showed similarities to in vitro results of RAW 264.7 cells
(Fig. 1B). In contrast, mRNA expression for TNF- and SOCS
declined steadily in vivo toward basal rates at 23 h.
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, IL-6, or GM-CSF. In
control cells, tyrosine phosphorylation of STAT proteins could be
readily detected upon stimulation (Fig. 6). Whereas preincubation with CpG-ODN
for 1 h had no effect, prestimulation for 8 or 24 h blocked
almost completely phosphorylation of the respective STAT proteins (Fig. 6). Inhibition of IFN- as well as IL-6 and GM-CSF signaling
correlated with the expression of SOCS proteins (compare Figs. 1 and 6). These results were corroborated with RAW 264.7 cells overexpressing
SOCS-1 and SOCS-3. SOCS-1, but not SOCS-3, overexpression prevented
STAT-1 phosphorylation after stimulation with IFN- (data not shown).
Moreover, IL-6-induced STAT-3 phosphorylation was diminished in SOCS-1-
as well as SOCS-3-overexpressing cells (data not shown). From these
data, we conclude that CpG-ODN-induced SOCS proteins are functional in
vitro and are capable of preventing signaling via the JAK/STAT signal
pathway.
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-induced up-regulation of MHC class II molecules
by flow cytometry (Fig. 7). Treatment
with CpG-DNA alone resulted in a moderate up-regulation of MHC II
expression, while stimulation with IFN- was much more effective
(Fig. 7). However, in cells that were preincubated with CpG-DNA for
12 h, IFN- failed to induce MHC class II up-regulation (Fig. 7). Thus, pretreatment with CpG-DNA diminishes subsequent biological
effects triggered by IFN- in macrophages. This effect correlated
with induction of SOCS proteins by CpG-DNA. To further strengthen this
correlation, we examined RAW 264.7 cells overexpressing either SOCS-1
or SOCS-3. In SOCS-1-expressing cells, IFN- failed to induce
up-regulation of MHC class II molecules, while expression
of SOCS-3 had only minor inhibitory effects. (Fig. 8). Thus, SOCS-1 rather than SOCS-3
seems to play the predominant role for suppressing IFN- signaling,
which corroborates previous reports (35, 36).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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),
our data strongly suggest that pathways distinct from JAK/STAT also
trigger SOCS induction. Consistently, chloroquine, which inhibits
upstream events in CpG-ODN signaling, also completely blocks SOCS
induction by CpG-DNA. These observations fit well with recent reports
showing that endotoxin (LPS) or TNF- induces SOCS expression in
murine macrophages (37, 38). Furthermore, it has been
shown that PMA triggers SOCS expression via MAPK activation
(39). Thus, CpG-DNA induce SOCS proteins in a pathway
independent of JAK/STAT. Because LPS (37) as well as
CpG-DNA induced SOCS expression and because both stimuli trigger
TLR-dependent signaling cascades (14, 15, 40), we
concluded that expression of negative regulators of cytokine signaling
can be induced by TLR-dependent signals in innate immune cells.
Recent reports on SOCS induction by TNF or LPS showed an almost
exclusive induction of SOCS-3. We report in this study induction of
SOCS-3 as well as SOCS-1 mRNA triggered by CpG-DNA or LPS. In addition,
we provide evidence for cell type-specific SOCS induction (Fig. 4),
which in turn may explain the reported results. It has been suggested
that IFN- and IFN- may contribute to SOCS-1 induction mediated by
LPS in murine bone marrow culture-derived macrophages in an autocrine
fashion (41). Although CpG-DNA induces efficiently
production of type I IFNs (42, 43), our results do not
support an autocrine mechanism because induction of SOCS was
independent of protein synthesis and could not be inhibited by
neutralizing type I IFN Abs (Fig. 2). Moreover, time kinetics of SOCS
induction was similar to direct target genes of TLR pathways (e.g.,
TNF-). However, an autocrine pathway of SOCS induction cannot be
ruled out completely because CpG-triggered secretion of preformed
cytokines might induce SOCS transcription. Clarifying experiments using
distinct promotor/reporter construct will be needed.
SOCS-1 is important for inhibiting IFN- signaling (44),
while the role of SOCS-3 is not entirely clear. We show in this study
that STAT phosphorylations induced by multiple cytokines (IFN-,
IL-6, GM-CSF) are reduced after preincubation with CpG-DNA. We further
strengthen the importance of SOCS-1 for IFN- signaling by showing
impaired responses to IFN- in SOCS-1-overexpressing cells (Fig. 7).
It will be intriguing to analyze whether other JAK/STAT-dependent
signal pathways will also be influenced by CpG-ODN. Furthermore, it
will be interesting to examine whether SOCS also interacts with signal
molecules distinct from the JAK/STAT pathway. In this context, SOCS-1
has been reported to inhibit Tec protein kinase (45), and
SOCS-2 interferes with insulin-like growth factor-1 signaling
(46). In addition, SOCS-1 interacts with other tyrosine
kinases in yeast (47), indicating that the spectrum of
signal cascades regulated by SOCS could be much broader.
Subsequent inhibition of IFN--induced STAT-1 tyrosine
phosphorylation as well as MHC-II up-regulation after pretreatment with
CpG-ODN indicates that perception of infectious danger via PAMP not
only leads to initiation and activation of effector functions of the
innate immune system, but also simultaneously engenders intrinsic
feedback mechanisms. Although concomitant IFN-- and TLR-dependent
signals act synergistically on macrophages, we now provide evidence
that stepwise activation may result in down-regulative mechanisms. In
this context, it recently has been reported that infection of
macrophages with Listeria monocytogenes resulted in an early
enhancement of IFN- signaling, while at later time points an
inhibition was observed. This was discussed as a consequence of SOCS
induction (48). Thus, timing of different signals is of
decisive importance for distinct outcomes concerning macrophage
activation and function. Down-regulation of IFN- signaling after
CpG-ODN pretreatment could play a physiological role as protective
mechanism to excessive stimulation of innate immune cells. Furthermore,
it indicates an important intracellular cross-talk between distinct
signaling pathways that regulate the cells’ reception of extracellular
signals as well as their immune function. Collectively, our data show
that perception of infectious danger by innate immune cells not only
activates effector mechanisms, but also leads to the induction of the
negative regulatory elements SOCS, which link TLR and TLR-related
signals to the JAK/STAT signaling pathway.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Klaus Heeg, Institute of Medical Microbiology and Hygiene, Philipps-University Marburg, Pilgrimstein 2, 35037 Marburg, Germany. E-mail address: heeg{at}post.med.uni-marburg.de
3 Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern; DC, dendritic cell(s); BMDDC, bone marrow-derived DC; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; ODN, oligodeoxynucleotide(s); PWC, peritoneal washout cell(s); SOCS, suppressors of cytokine signaling; TLR, Toll-like receptor(s).
Received for publication November 2, 2000. Accepted for publication April 2, 2001.
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H. Bartz, N. M. Avalos, A. Baetz, K. Heeg, and A. H. Dalpke Involvement of suppressors of cytokine signaling in toll-like receptor-mediated block of dendritic cell differentiation Blood, December 15, 2006; 108(13): 4102 - 4108. [Abstract] [Full Text] [PDF]
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Y. Lu, S. Fukuyama, R. Yoshida, T. Kobayashi, K. Saeki, H. Shiraishi, A. Yoshimura, and G. Takaesu Loss of SOCS3 Gene Expression Converts STAT3 Function from Anti-apoptotic to Pro-apoptotic J. Biol. Chem., December 1, 2006; 281(48): 36683 - 36690. [Abstract] [Full Text] [PDF]
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N. Vazquez, T. Greenwell-Wild, S. Rekka, J. M. Orenstein, and S. M. Wahl Mycobacterium avium-induced SOCS contributes to resistance to IFN-{gamma}-mediated mycobactericidal activity in human macrophages J. Leukoc. Biol., November 1, 2006; 80(5): 1136 - 1144. [Abstract] [Full Text] [PDF]
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 V. A. Dennis, A. Jefferson, S. R. Singh, F. Ganapamo, and M. T. Philipp Interleukin-10 Anti-Inflammatory Response to Borrelia burgdorferi, the Agent of Lyme Disease: a Possible Role for Suppressors of Cytokine Signaling 1 and 3. Infect. Immun., October 1, 2006; 74(10): 5780 - 5789. [Abstract] [Full Text] [PDF]
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Y. Li, N. Chu, A. Rostami, and G.-X. Zhang Dendritic Cells Transduced with SOCS-3 Exhibit a Tolerogenic/DC2 Phenotype That Directs Type 2 Th Cell Differentiation In Vitro and In Vivo J. Immunol., August 1, 2006; 177(3): 1679 - 1688. [Abstract] [Full Text] [PDF]
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Y. Yao, Q. Xu, M.-J. Kwon, R. Matta, Y. Liu, S.-C. Hong, and C.-H. Chang ERK and p38 MAPK Signaling Pathways Negatively Regulate CIITA Gene Expression in Dendritic Cells and Macrophages J. Immunol., July 1, 2006; 177(1): 70 - 76. [Abstract] [Full Text] [PDF]
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C. Stross, S. Radtke, T. Clahsen, C. Gerlach, R. Volkmer-Engert, F. Schaper, P. C. Heinrich, and H. M. Hermanns Oncostatin M Receptor-mediated Signal Transduction Is Negatively Regulated by SOCS3 through a Receptor Tyrosine-independent Mechanism J. Biol. Chem., March 31, 2006; 281(13): 8458 - 8468. [Abstract] [Full Text] [PDF]
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 J. Sotelo, E. Briceno, and M. A. Lopez-Gonzalez Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med, March 7, 2006; 144(5): 337 - 343. [Abstract] [Full Text] [PDF]
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S. Zimmermann, P. J. Murray, K. Heeg, and A. H. Dalpke Induction of Suppressor of Cytokine Signaling-1 by Toxoplasma gondii Contributes to Immune Evasion in Macrophages by Blocking IFN-{gamma} Signaling J. Immunol., February 1, 2006; 176(3): 1840 - 1847. [Abstract] [Full Text] [PDF]
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P. Ekchariyawat, S. Pudla, K. Limposuwan, S. Arjcharoen, S. Sirisinha, and P. Utaisincharoen Burkholderia pseudomallei-Induced Expression of Suppressor of Cytokine Signaling 3 and Cytokine-Inducible Src Homology 2-Containing Protein in Mouse Macrophages: a Possible Mechanism for Suppression of the Response to Gamma Interferon Stimulation Infect. Immun., November 1, 2005; 73(11): 7332 - 7339. [Abstract] [Full Text] [PDF]
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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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J. Mostecki, B. M. Showalter, and P. B. Rothman Early Growth Response-1 Regulates Lipopolysaccharide-induced Suppressor of Cytokine Signaling-1 Transcription J. Biol. Chem., January 28, 2005; 280(4): 2596 - 2605. [Abstract] [Full Text] [PDF]
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 K. Takeda and S. Akira Toll-like receptors in innate immunity Int. Immunol., January 1, 2005; 17(1): 1 - 14. [Abstract] [Full Text] [PDF]
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J. Goral and E. J. Kovacs In Vivo Ethanol Exposure Down-Regulates TLR2-, TLR4-, and TLR9-Mediated Macrophage Inflammatory Response by Limiting p38 and ERK1/2 Activation J. Immunol., January 1, 2005; 174(1): 456 - 463. [Abstract] [Full Text] [PDF]
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A. Baetz, M. Frey, K. Heeg, and A. H. Dalpke Suppressor of Cytokine Signaling (SOCS) Proteins Indirectly Regulate Toll-like Receptor Signaling in Innate Immune Cells J. Biol. Chem., December 24, 2004; 279(52): 54708 - 54715. [Abstract] [Full Text] [PDF]
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X.-P. Yang, U. Albrecht, V. Zakowski, R. M. Sobota, D. Haussinger, P. C. Heinrich, S. Ludwig, J. G. Bode, and F. Schaper Dual Function of Interleukin-1{beta} for the Regulation of Interleukin-6-induced Suppressor of Cytokine Signaling 3 Expression J. Biol. Chem., October 22, 2004; 279(43): 45279 - 45289. [Abstract] [Full Text] [PDF]
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Y. Liu, W. Dong, L. Chen, R. Xiang, H. Xiao, G. De, Z. Wang, and Y. Qi BCL10 Mediates Lipopolysaccharide/Toll-like Receptor-4 Signaling through Interaction with Pellino2 J. Biol. Chem., September 3, 2004; 279(36): 37436 - 37444. [Abstract] [Full Text] [PDF]
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S. M. Fortune, A. Solache, A. Jaeger, P. J. Hill, J. T. Belisle, B. R. Bloom, E. J. Rubin, and J. D. Ernst Mycobacterium tuberculosis Inhibits Macrophage Responses to IFN-{gamma} through Myeloid Differentiation Factor 88-Dependent and -Independent Mechanisms J. Immunol., May 15, 2004; 172(10): 6272 - 6280. [Abstract] [Full Text] [PDF]
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J. A. Johnston Are SOCS suppressors, regulators, and degraders? J. Leukoc. Biol., May 1, 2004; 75(5): 743 - 748. [Abstract] [Full Text] [PDF]
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 F.T. Lundy and G.J. Linden NEUROPEPTIDES AND NEUROGENIC MECHANISMS IN ORAL AND PERIODONTAL INFLAMMATION Critical Reviews in Oral Biology & Medicine, March 1, 2004; 15(2): 82 - 98. [Abstract] [Full Text] [PDF]
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A. Yoshimura, H. M. M. Ohishi, D. Aki, and T. Hanada Regulation of TLR signaling and inflammation by SOCS family proteins J. Leukoc. Biol., March 1, 2004; 75(3): 422 - 427. [Abstract] [Full Text] [PDF]
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P. S. Grutkoski, Y. Chen, C. S. Chung, and A. Ayala Sepsis-induced SOCS-3 expression is immunologically restricted to phagocytes J. Leukoc. Biol., November 1, 2003; 74(5): 916 - 922. [Abstract] [Full Text] [PDF]
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 K. M. L. Hertoghs, J. H. Ellis, and I. R. Catchpole Use of locked nucleic acid oligonucleotides to add functionality to plasmid DNA Nucleic Acids Res., October 15, 2003; 31(20): 5817 - 5830. [Abstract] [Full Text] [PDF]
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M. Fukui, R. Imamura, M. Umemura, T. Kawabe, and T. Suda Pathogen-Associated Molecular Patterns Sensitize Macrophages to Fas Ligand-Induced Apoptosis and IL-1{beta} Release J. Immunol., August 15, 2003; 171(4): 1868 - 1874. [Abstract] [Full Text] [PDF]
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A. J. Gehring, R. E. Rojas, D. H. Canaday, D. L. Lakey, C. V. Harding, and W. H. Boom The Mycobacterium tuberculosis 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Regulated HLA-DR and Fc{gamma}R1 on Human Macrophages through Toll-Like Receptor 2 Infect. Immun., August 1, 2003; 71(8): 4487 - 4497. [Abstract] [Full Text] [PDF]
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R. K. Pai, M. Convery, T. A. Hamilton, W. H. Boom, and C. V. Harding Inhibition of IFN-{gamma}-Induced Class II Transactivator Expression by a 19-kDa Lipoprotein from Mycobacterium tuberculosis: A Potential Mechanism for Immune Evasion J. Immunol., July 1, 2003; 171(1): 175 - 184. [Abstract] [Full Text] [PDF]
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E. J. Park, S. Y. Park, E.-h. Joe, and I. Jou 15d-PGJ2 and Rosiglitazone Suppress Janus Kinase-STAT Inflammatory Signaling through Induction of Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 in Glia J. Biol. Chem., April 18, 2003; 278(17): 14747 - 14752. [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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C. Niemand, A. Nimmesgern, S. Haan, P. Fischer, F. Schaper, R. Rossaint, P. C. Heinrich, and G. Muller-Newen Activation of STAT3 by IL-6 and IL-10 in Primary Human Macrophages Is Differentially Modulated by Suppressor of Cytokine Signaling 3 J. Immunol., March 15, 2003; 170(6): 3263 - 3272. [Abstract] [Full Text] [PDF]
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 A. H. Dalpke and K. Heeg Synergistic and antagonistic interactions between LPS and superantigens Innate Immunity, February 1, 2003; 9(1): 51 - 54. [Abstract] [PDF]
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 K. Kitagaki, V. V. Jain, T. R. Businga, I. Hussain, and J. N. Kline Immunomodulatory Effects of CpG Oligodeoxynucleotides on Established Th2 Responses Clin. Vaccine Immunol., November 1, 2002; 9(6): 1260 - 1269. [Abstract] [Full Text] [PDF]
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R. Lang, D. Patel, J. J. Morris, R. L. Rutschman, and P. J. Murray Shaping Gene Expression in Activated and Resting Primary Macrophages by IL-10 J. Immunol., September 1, 2002; 169(5): 2253 - 2263. [Abstract] [Full Text] [PDF]
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T. Hayashi, T. Kaneda, Y. Toyama, M. Kumegawa, and Y. Hakeda Regulation of Receptor Activator of NF-kappa B Ligand-induced Osteoclastogenesis by Endogenous Interferon-beta (INF-beta ) and Suppressors of Cytokine Signaling (SOCS). THE POSSIBLE COUNTERACTING ROLE OF SOCSs IN IFN-beta -INHIBITED OSTEOCLAST FORMATION J. Biol. Chem., July 26, 2002; 277(31): 27880 - 27886. [Abstract] [Full Text] [PDF]
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A.-K. Yi, J.-G. Yoon, S.-J. Yeo, S.-C. Hong, B. K. English, and A. M. Krieg Role of Mitogen-Activated Protein Kinases in CpG DNA-Mediated IL-10 and IL-12 Production: Central Role of Extracellular Signal-Regulated Kinase in the Negative Feedback Loop of the CpG DNA-Mediated Th1 Response J. Immunol., May 1, 2002; 168(9): 4711 - 4720. [Abstract] [Full Text] [PDF]
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D. Deon, S. Ahmed, K. Tai, N. Scaletta, C. Herrero, I.-H. Lee, A. Krause, and L. B. Ivashkiv Cross-Talk Between IL-1 and IL-6 Signaling Pathways in Rheumatoid Arthritis Synovial Fibroblasts J. Immunol., November 1, 2001; 167(9): 5395 - 5403. [Abstract] [Full Text] [PDF]
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