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1
Institutes of
*
Microbiology and Genetics, and
Molecular Pathology, Vienna Biocenter, Vienna, Austria; and
DNAX Research Institute, Palo Alto, CA 94304
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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.
Pretreatment of macrophages with LPS for <2 h increased the
transcriptional response to IFN-. In contrast, simultaneous
stimulation with IFN- and LPS, or pretreatment with LPS for >4 h,
suppressed Stat1 tyrosine 701 phosphorylation, dimerization, and
transcriptional activity in response to IFN-. Consistently, the
induction of MHCII protein by IFN- was antagonized by LPS
pretreatment. Neutralizing Abs to IL-10 were without effect on
LPS-mediated suppression of Stat1 activation. Decreased IFN- signal
transduction after LPS treatment corresponded to a direct induction of
suppressor of cytokine signaling3 (SOCS3) mRNA and protein. Under the
same conditions socs1, socs2, and
cis genes were not transcribed. In transfection assays,
SOCS3 was found to suppress the transcriptional response of macrophages
to IFN-. A causal link of decreased IFN- signaling to SOCS3
induction was also suggested by the LPS-dependent reduction of
IFN--mediated Janus kinase 1 (JAK1) activation. Further consistent
with inhibitory activity of SOCS3, LPS also inhibited the
JAK2-dependent activation of Stat5 by GM-CSF. Our results thus link the
deactivating effect of chronic LPS exposure on macrophages with its
ability to induce SOCS3. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, whereas the second is most often provided by microbial
products like LPS, the outer membrane constituent of Gram-negative
bacteria (1, 2). IFN- influences nuclear gene
expression by activating the IFN- receptor-associated Janus tyrosine
kinases (JAK),3 JAK1
and JAK2. These phosphorylate transcription factor Stat1 on Y701 and
cause its dimerization and translocation to the cell nucleus (3, 4). Stat1 dimers bind to the IFN- activation site (GAS) in
the promoters of target genes and activate transcription
(5). On the other hand, LPS stimulates gene expression
predominantly through the activation of transcription factor NF-
B
(6). However, LPS also exerts a direct and rapid effect on
IFN--mediated Stat1 activation by increasing the activity of a Stat1
S727 kinase (7). Phosphorylation of S727 strongly augments
the transcription factor activity of Stat1 (7, 8).
In this study, we investigated the effect of prolonged LPS stimulation
on the IFN- response of macrophages, a situation that may occur if
bacteria are not rapidly cleared from a site of infection. We report
the inhibition of signal transduction in response to IFN- through
the LPS-induced synthesis of the suppressor molecule, suppressor of
cytokine signaling 3 (SOCS3). The SOCS family of proteins, also known
as cytokine-inducible SH2 domain-containing protein (CIS)/JAK-binding
protein (JAB) or STAT-induced STAT inhibitors (SSI)
(9, 10, 11), was recently described as feed-back inhibitors of
cytokine signaling paths and appears to have a widespread role in their
negative regulation (reviewed in Refs. 12, 13). The
ability of socs genes to respond to cytokine-activated Stats
explains how Jak-Stat signal transduction autoregulates in a negative
feed-back loop (14). In addition, SOCS proteins can
mediate negative crosstalk between distinct signaling avenues. Here, we
establish socs3 as an LPS target gene, thus linking its
regulation to a signaling path not employing Stats. We suggest that via
SOCS3 the persistent presence of bacteria and their products exerts a
direct suppressive effect on macrophage activation by IFN-. Our
findings stress the importance of timing immunologically relevant
extracellular stimuli with respect to each other.
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Materials and Methods |
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Bac1.2F5 macrophages (15), or C11 cells, a clone of
Bac1.2F5 transfected with a Stat-dependent luciferase gene
(7), were maintained in MEM-
medium containing 10% FCS
and 20% L cell-conditioned medium as a source of CSF-1. 293 kidney
fibroblasts were cultured in DMEM containing 10% FCS.
Antibodies
The antiserum to the Stat1 C terminus has recently been
described (7). Rabbit antiserum to Y701-phosphorylated
Stat1 was purchased from New England Biolabs (Beverly, MA) and used at
a dilution of 1:1000. A mAb recognizing the -chain of the murine
IFN- receptor was obtained from PBL Biomedical Laboratories (New
Jersey, NJ) and used at a 1:50 dilution for flow cytometry. To
visualize binding of the anti-IFN- receptor Ab, PE-coupled
rabbit anti-rat antiserum was used. FITC-conjugated Ab (clone
AMS32.1) to the MHC class II protein IAd was
purchased from PharMingen (San Diego, CA). The Py20 Ab to
phosphotyrosine was purchased from Transduction Laboratories
(Lexington, KY) and used at 3 µg/ml. Rabbit antisera to JAK1 and JAK2
kinases were a kind gift from Dr. Andrew Zimiecki (Laboratory for
Clinical and Experimental Cancer Research, Bern, Switzerland). They
were used at 1:100 dilution for immunoprecipitation and 1:1000 dilution
for Western blots. Rabbit anti-SOCS3 antiserum was produced by
immunization with a peptide corresponding to amino acids 5–21 of human
SOCS3 protein. It was used at a 1:100 dilution in immunoprecipitation
and a 1:500 dilution in Western blots. A polyclonal Ab specific for the
two Stat5 isoforms, Stat5a and Stat5b, was recently described
(16). It was used for EMSA supershift analysis at a final
dilution of 1:100. A mAb recognizing Stat3 was kindly provided by David
Levy (Department of Pathology, New York University School of Medicine,
New York, NY). It was used for EMSA supershift at a final concentration
of 10 ng/ml. 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 (17, 18). As control Abs, an equal
dilution of an antiserum raised against human IFN- was
used.
Immunoprecipitation and Western blot
A protocol for these procedures has recently been described (7). Abs were used as indicated in the figure legends.
EMSA
An end-labeled, double-stranded oligonucleotide corresponding to
the GAS sequence of the ß-Casein promoter was used in most
experiments. To determine Stat3 binding, an acute phase response
element (APRE) oligonucleotide corresponding to the sequence in the rat
2 macroglobulin promoter was used (19). The assay was
performed with whole cell extracts, as recently described (20, 21).
Transfection assays
293 cells and Bac1.2F5 macrophages were transfected using
Superfect reagent according to the manufacturer’s instructions
(Quiagen, Munich, Germany). Transfected plasmids contained a luciferase
reporter gene under control of the IFN--responsive IFP53 promoter
(22) or, in cotransfections, the IFN--responsive
reporter gene and expression plasmids for either SOCS1, -2, and -3 or
CIS. Luciferase assays were performed according to standard procedures.
Results are stated as inducibility, the ratio obtained by dividing cpm
light emission from IFN- and/or LPS-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 SOCS or CIS cDNAs labeled by random priming.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-stimulated gene expression
Transcriptional activity of Stat1 was determined in Bac1.2F5
macrophages stably transfected with a Stat1-dependent reporter gene. In
this experimental situation, we have previously shown that a short
pretreatment with LPS causes an increase in Stat1-dependent
transcription, due to the stimulation of a Stat1 S727 kinase
(7). Consistent with our previous observation, a brief
costimulation (up to 3 h) of the cells with both IFN- and LPS
resulted in increased Stat1 transcriptional activity, compared with
stimulation with IFN- alone. By contrast, treatment beyond 4 h
converted the stimulatory effect of LPS on the IFN- response into
suppressive activity (Fig. 1
A). This suppressive effect
of LPS was confirmed when the cells were first pretreated with LPS for
various periods, followed by 2 h of stimulation with IFN- (Fig. 1B).
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B sites and can be
directly stim-ulated by LPS (23, 24, 25, 26). By contrast, MHCII
protein induction is an exclusive property of IFN-. Since
the crucial transcription factor for MHCII induction by IFN-, CIITA,
is a Stat1 target gene, the expression of MHCII is indirectly dependent
on Stat1 (27). To test whether enhanced MHCII expression,
an important attribute of activated macrophages, is influenced by LPS
pretreatment similar to our reporter gene, we analyzed MHCII expression
by flow cytometry. Relative to untreated controls, Bac1.2F5 macrophages
showed moderate but significant enhancement of MHCII expression by
IFN- within 48 h. This increase was strongly inhibited by
12 h of pretreatment with LPS (Fig. 1
C). The same
result was obtained in primary bone marrow macrophages (data not
shown). It is consistent with reporter gene expression and confirms
that the block in transcriptional responsiveness to Stat1 affects
target genes relevant for macrophage activation in their proper genomic
context.
Prolonged LPS treatment inhibits Stat1 activation and decreases
JAK1 tyrosine phosphorylation by IFN-
To determine whether decreased transcription was due to
LPS-mediated down-regulation of Stat1 activation, we performed EMSA
experiments. Consistent with results on Stat1-mediated transcription,
costimulation with IFN- and LPS caused a more transient appearance
of Stat1 DNA-binding activity, compared with IFN- alone (Fig. 2A), and pretreatment with LPS for more than 4 h
strongly reduced the dimerization of Stat1 in response to IFN- (Fig. 2B). Consistent with the EMSA results, pretreatment with LPS
also reduced the tyrosine phosphorylation of Stat1 in response to
IFN-, as indicated by Western blot with an antiserum reactive with
Stat1 phosphorylated on Y701 (Fig. 2C). Control cells
treated for 6 h with LPS alone (Fig. 2A, lane 7)
produced a Stat complex with lower mobility than Stat1. This complex is
analyzed in detail below.
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-mediated Stat1 activation, we treated
macrophages with LPS in the presence of control Abs, or of neutralizing
Abs to IL-10, followed by a brief pulse of IFN-. Stat1 activation
was assayed by EMSA (Fig. 2D). The reduction of Stat1
activation by a 12-h LPS treatment was found similarly strong in
samples without Ab (lanes 3 and 4), the
control Abs (lanes 7 and 8), or IL-10 Abs
(lanes 5 and 6). Treatment with IL-10 Abs
for 12 h (lanes 9 and 10) did not per
se reduce IFN--mediated Stat1 activation, a possibility suggested by
a recent report (28). Together, the data in Fig. 2D demonstrate that the suppressive activity toward Stat1
activation by IFN- stems mostly from LPS directly, not from
LPS-induced IL-10.
To study possible causes of the LPS effect on Stat1 activation, we
first determined IFN- receptor expression by flow cytometry.
Expression in normal or LPS-pretreated macrophages was virtually
identical (Fig. 3). By contrast, LPS
affected an early step in IFN- signaling, the activation of the
receptor-associated tyrosine kinase JAK1, as indicated by diminished
tyrosine phosphorylation in response to IFN- (Fig. 4). Densitometric analysis after
normalization to expression levels indicated a reduction of JAK1
tyrosine phosphorylation after 8 h of LPS pretreatment of 
70%.
Inhibition of JAK1 activation was always observed. In a total of six
independent experiments, four showed no effect of LPS on JAK2 tyrosine
phosphorylation, while two showed a somewhat reduced activation of
JAK2. We have at present no explanation for this variation because
there were no apparent differences in the experimental protocol.
Importantly, normal JAK2 activation in response to IFN-, as shown in
Fig. 4, confirms that LPS did not affect the expression of the IFN-
receptor. Moreover, the control lanes of the blots shown in Figs. 2C and 4 indicate that LPS caused no significant reduction
of either JAK or Stat1 protein.
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The inhibition of JAK1 phosphorylation prompted us to investigate
the possible role of the previously described inhibitors of JAK
activity, the SOCS/CIS/SSI proteins. Particularly one member of this
family, SOCS1/JAB/SSI1, has been associated with inhibition of the
IFN- response, and another one, SOCS3, was similarly shown to
inhibit Stat1 activation (29, 30). Consistent with these
published results, SOCS1 and SOCS3, but not the family members SOCS2 or
CIS, inhibited reporter gene expression in response to IFN- in
transformed 293 kidney fibroblasts (Fig. 5A) and in macrophages (Fig. 5B). Northern blots with RNA from macrophages treated with
LPS for various periods demonstrated increased expression of SOCS3 mRNA
(Fig. 6A), but not of SOCS1,
SOCS2, or CIS mRNA (data not shown). Maximal levels of SOCS3 mRNA were
reached after 4 h of LPS treatment, and induction was resistant to
the inhibition of protein synthesis by cycloheximide. This establishes
SOCS3 as a direct LPS target gene, induced by LPS-responsive
transcription factors like NF-B, and/or responsive to LPS-mediated
mRNA stabilization as in the case of many mRNAs encoding
proinflammatory cytokines. SOCS3 protein was induced by LPS with
maximal levels after 6 h (Fig. 6B). This result argues
for a causal effect of SOCS3 on suppression of IFN--induced signal
transduction where a clear effect on Stat1 tyrosine phosphorylation is
evident after 4 h and a maximal effect after 8–12 h (Fig. 2).
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signaling is therefore unlikely. LPS inhibits GM-CSF-mediated JAK-Stat signal transduction
Recent publications suggest an ability of SOCS3 to inhibit
prolactin, leptin, and growth hormone-induced signal transduction
(32, 33, 34). All corresponding receptors signal via JAK2.
Therefore, we tested whether SOCS3 induction by LPS in macrophages
causes a general inhibition of cytokine responses employing JAK2. The
GM-CSF receptor employs a JAK2-Stat5 signaling path to elicit immediate
gene expression (20, 35). Rapid activation of Stat5 by
GM-CSF in Bac1.2F5 macrophages was strongly suppressed after 5 h
of LPS pretreatment (Fig. 7A).
This adds GM-CSF-induced signal transduction to the list of
SOCS3-inhibitable cellular responses and further demonstrates the
activity of the inhibitory protein in LPS-treated macrophages.
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, LPS treatment for
4 h or longer caused the appearance of a Stat complex with lower
mobility, compared with Stat1. The same observation is documented in
Fig. 7A. LPS does not directly activate Stats (Ref.
7 , and Refs. therein). Consistently, the slow appearance
and cycloheximide-sensitivity (data not shown) of the LPS-induced
complex indicated that it is activated indirectly by an LPS-induced
cytokine. Careful analysis revealed the LPS-induced band to represent
two closely spaced complexes. To identify the relevant Stats, we
reacted the extracts from LPS-treated macrophages with an APRE probe
that strongly binds Stat3, but associates only weakly with Stat5 and
with the ß-Casein promoter probe, which shows the opposite behavior.
Coupled with EMSA supershift analysis using specific Abs to Stat3 and
the Stat5 isoforms, we could demonstrate that the LPS-induced complexes
consist of Stat3 and Stat5 dimers (Fig. 7B). The
transcription experiment in Fig. 1B suggests that the
LPS-induced complexes do not possess a strong potential to activate a
Stat-dependent reporter gene. This is not surprising because Stat
tyrosine phosphorylation was shown in a number of situations to produce
dimers capable of binding to DNA, but without an inductive effect on
target gene transcription (16, 20, 36). LPS-mediated
generation of Stat3 and Stat5 complexes occurs in the presence of
intracellular SOCS3. This indicates that signal transduction in
response to the responsible LPS-induced cytokine(s) is either not
inhibited by SOCS3, or that activation levels would be much higher if
the same concentration of cytokine(s) would be acting on cells not
treated with LPS. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Stat1 knockout mice demonstrate the crucial
importance of the protein for macrophage activation in vivo (37, 38). SOCS3 induction by LPS inhibits Stat1 activation, thereby
interfering with the ability of macrophages to produce their complete
arsenal of antibacterial responses.
The induction of SOCS3 mRNA was previously reported to occur in
response to IL-6 and IL-10 (9, 39). Particularly IL-10 is
found in culture supernatants of LPS-activated macrophages. IL-10 is a
potent activating stimulus for Stat3 (40), and this
protein was part of the Stat complex found after long LPS stimulation
in macrophage extracts (Fig. 7). As shown for LPS in this study, SOCS3
produced in response to IL-10 was similarly suggested to down-regulate
Stat1 activation by IFN- (39). For these reasons, it
was important to neutralize IL-10 activity in culture supernatants and
to assess the residual suppressive effect of LPS on the IFN-
response. This experiment, documented in Fig. 2D, indicates
that IL-10 is not required for LPS to down-regulate Jak-Stat signal
transduction in response to IFN-. Therefore, despite the ability of
both agents to induce SOCS3 and interfere with an IFN- response,
macrophage deactivation after long LPS treatment and after IL-10
stimulation is likely to be different. For example, IL-10 directly
activates transcriptionally active Stat3 (40) and induces
a set of genes that partially overlaps with that induced by
IFN--activated Stat1. This became apparent from our recent study on
the expression of the FcRI gene in macrophages. It demonstrated not
only a direct induction of this gene by IL-10 and IFN- individually,
but an additive effect on induction by the simultaneous presence of
both cytokines (41). Therefore, both LPS- and
IL-10-treated macrophages will be refractory to activation by IFN-,
but the IL-10-treated cell will express part of the IFN--responsive
genes through the activity of Stat3, while the LPS-treated cell
will not.
From our recent findings (7) and the results presented
here, we propose a dual time-dependent effect of LPS on macrophage
activation by IFN-. A brief exposure to LPS enhances
IFN--mediated macrophage activation through its specific target
genes and through the activation of a Stat1 S727 kinase, which
increases the transcriptional potential of Stat1 dimers. However, the
continuous presence of LPS before the Th1 cytokine inhibits the
responsiveness to IFN- and thus counteracts macrophage activation.
Long exposure to LPS also causes macrophages to become tolerant to LPS
itself (42). However, LPS-mediated LPS tolerance involves
the formation of NF-B p50 dimers (43) and differs in
kinetics and dose-dependency from LPS-mediated tolerance to IFN-
(our unpublished observations). Therefore, the two phenomena appear to
be mechanistically unrelated.
The mechanism of SOCS3 action is currently unclear. While all reports
agree with respect to the ability of the family member SOCS1 to bind to
and inhibit JAK1 and JAK2 kinases (44), some studies
suggest a similar ability of SOCS3, while others find a very limited
potential of SOCS3 to directly inhibit JAKs, and therefore consider
alternative ways by which SOCS proteins might interfere with cytokine
signaling (13, 45). Assuming a direct SOCS3-JAK
interaction, the predominant effect on JAK1 displayed in Fig. 4 of this
paper may indicate that SOCS3 binds to JAK1 and inhibits its activity.
This would resemble the situation recently described for the IL-2
response of T lymphocytes (46). Alternatively, SOCS3 may
bind to tyrosine-phosphorylated JAK2 and inhibit its kinase activity,
with the possible consequence that JAK1 tyrosine phosphorylation and
activation by cross-phosphorylation cannot occur. The latter assumption
is consistent with our results, showing an inhibition of
Jak-2-dependent Stat5 activation by GM-CSF and the ability of SOCS3 to
inhibit Stat5 activation by IL-3 (46). Pull-down assays
employing GST-SOCS3 have not been successful, either because of
insufficient sensitivity of the assay or because SOCS3 does not stably
associate with complexes containing JAKs (our unpublished
observations). Recent publications suggest an ability of SOCS3 to
inhibit prolactin, IL-6, LIF, leptin, growth hormone, IFN-, IFN-,
and IL-2-induced signal transduction (30, 32, 33, 34, 39, 45, 46). Therefore, SOCS3 interferes with both JAK2-dependent and
JAK2-independent cytokine responses.
Thus, while the details of SOCS3 activity remain to be clarified, our studies emphasize the important role of this protein in mediating inhibitory crosstalk not only between signals from different cytokine receptors, but also between cytokine signals and those derived from bacteria during infection.
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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. E-mail address:
3 Abbreviations used in this paper: JAK, Janus kinase; GAS, IFN activation site; SOCS, suppressor of cytokine signaling; APRE, acute phase response element; CIS, cytokine-inducible SH2 domain-containing protein; JAB, JAK-binding protein; SSI, STAT-induced STAT inhibitors.
Received for publication April 28, 1999. Accepted for publication June 28, 1999.
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References |
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B with predominance of p50 homodimers. J. Biol. Chem. 269:17001.This article has been cited by other articles:
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