From the Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea 442-721
Received for publication, October 22, 2002, and in revised form, January 29, 2003
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ABSTRACT |
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Peroxisome proliferator-activated receptor
(PPAR)- Astrocytes and microglia are cells with immune functions in the
central nervous system. They are rapidly activated in response to
pathological stimuli and lead to various inflammatory processes. Upon
activation, astrocytes and microglia change their immunophenotype as
well as the expression pattern of inflammatory mediators including cytokines, chemokines, and neurotoxic substances at the transcriptional level (1, 2). Activated glial cells can exert both beneficial and
harmful actions on brain. Although transient activation is beneficial
for defense processes, either chronic activation or overactivation may
lead to or exacerbate neuronal diseases such as Alzheimer's disease,
ischemia, and human immunodeficiency virus encephalitis (3).
Inflammatory mediators are involved in many effects of activated glial
cells. Whereas cytokines such as interleukin-10 reduce glial
cytotoxicity (4), other cytokines such as interferon- The JAK-STAT (Janus kinase-signal transducers and activators of
transcription) cascade is an essential inflammatory signaling pathway
that mediates immune responses. Specific subtypes of JAK and STAT are
activated by different signals and transduce signals from cell surface
receptors to different subsets of target genes, many of which are
involved in immune responses (6, 7). To prevent detrimental effects,
the intensity and duration of JAK-STAT activation are tightly
regulated. Recently, a family of proteins called suppressors of
cytokine signaling (SOCS) has been isolated (8-10). Generally, SOCS
are present in cells at very low levels but are rapidly transcribed
after exposure of cells to stimulus. SOCS can negatively regulate the
response of immune cells either by inhibiting JAK activity or by
competing with signaling molecules for binding to the phosphorylated
receptor (11). For example, SOCS1 and SOCS3 bind to the JAKs and
inhibit their tyrosine kinase activity (12). The ability of SOCS to
suppress cytokine signaling in vivo has been confirmed by
animal models including knock-out mice (13, 14). SOCS family is now
considered as important regulators of normal immune physiology and
immune disease (15).
Peroxisome proliferator-activated receptor (PPAR)- Reagents--
Lipopolysaccharide was purchased from Sigma, and
IFN- Cell Culture--
Primary astrocytes and microglia were cultured
from the cerebral cortices of 1-day-old Sprague-Dawley rats. The
cortices were triturated into single cells in minimal essential
medium (Invitrogen) containing 10% fetal bovine serum and incubated
for 2-3 weeks. Microglia were detached from the flasks, and the cells
remaining in the flask were harvested with 0.1% trypsin to prepare
pure astrocytes. BV2 murine microglia cells were obtained from Dr. E. J. Choi and maintained in Dulbecco's modified Eagle's medium (Invitrogen) with 5% fetal bovine serum.
Reverse Transcription (RT)-PCR Analysis--
Total RNA was
isolated using RNAzol B (TEL-TEST, Inc., Friendswood, TX), and
cDNA was prepared using AMV reverse transcriptase (Promega,
Madison, WI). The sequences of PCR primers were as follows and as
previously described (25): reverse 5'-ACACTCACTTCCGCACCTTC-3' and
forward 5'-AGCAGCTCGAAAAGGCAGTC-3' for SOCS1; reverse
5'-GTGGAGCATCATACTGATCC-3' and forward 5'-ACCAGCGCCACTTCTTCACG-3'
for SOCS3; and reverse 5'-ATGGAAGACCACTCGCATT-3' and forward
5'-CATGGACACCATACTTGAG-3' for PPAR- Real-time RT-PCR--
For transcript quantification purposes,
the LightCyclerTM system (Roche Molecular Biochemicals) was
used. The mRNA levels were determined using LightCycler-RNA Master
SYBR Green1 or LightCycler-DNA Master SYBR Green1. Glucose-6-phosphate
dehydrogenase housekeeping gene set (Roche Molecular
Biochemicals) was used as external standards, and the variability in
the initial quantities of cDNA was normalized to the internal
control, glyceraldehyde-3-phosphate dehydrogenase. Negative control was
included in each set of experiments. Melting curve analysis was
performed to enhance specificity of amplification reaction, and the
LightCycler software, version 3.5, was used to compare amplification in
the experimental samples during the log-linear phase to the standard curve.
Western Blot Analysis--
Cell lysates were separated by
SDS-PAGE and transferred to nitrocellulose membrane. The membrane was
incubated with primary antibodies and peroxidase-conjugated secondary
antibodies (Vector Laboratories, Burlingame, CA) and then visualized
using an enhanced chemiluminescence system (Promega). For Western blot
analysis and RT-PCR, cells were serum-starved at least 24 h before
drug treatment.
Luciferase Assay--
Transient transfections were performed in
duplicate on 35-mm dishes using LipofectAMINE Plus reagents
(Invitrogen). To normalize the variations in cell number and
transfection efficiency, all of the cells were co-transfected with
pCMV- Immunoprecipitation--
Cell extracts were prepared by using
modified RIPA buffer (50 mM Tris-HCl, 1% Nonidet P-40,
0.25% sodium deoxycholate, 150 mM NaCl, 1 mM
EDTA, 1 mM phenylmethylsulfonyl fluoride, 1 µg/ml leupeptin, 1 µg/ml pepstatin, 1 mM NaVO4).
500 µg lysates were incubated with 1 µg of SHP2 (Transduction
Laboratories) at 4 °C for overnight and precipitated with
protein G-agarose beads (Upstate Biotechnology) for 2 h at
4 °C. The immunoprecipitated proteins were separated by SDS-PAGE and
transferred to a nitrocellulose membrane (Schleicher & Schuell).
Western blot analysis was performed with either 4G10 (Upstate
Biotechnology) or SHP2.
To better define the mechanism of action by which PPAR- agonists are now emerging as therapeutic drugs for various
inflammatory diseases. However, their molecular mechanism of action
remains to be elucidated. Here we report a novel mechanism that
underlies the PPAR-
agonist-mediated suppression of brain
inflammation. We show that 15-deoxy-
12,14-prostaglandin
J2 (15d-PGJ2) and rosiglitazone reduce
the phosphorylation of STAT1 and STAT3 as well as Janus kinase 1 (JAK1)
and JAK2 in activated astrocytes and microglia. The PPAR-
agonist-mediated reduction in phosphorylation leads to the suppression
of JAK-STAT-dependent inflammatory responses. The effects
of 15d-PGJ2 and rosiglitazone are not mediated by activation of PPAR-
. 15d-PGJ2 and rosiglitazone rapidly
induce the transcription of suppressor of cytokine signaling (SOCS) 1 and 3, which in turn inhibit JAK activity in activated glial cells. In
addition, Src homology 2 domain-containing protein phosphatase 2 (SHP2), another negative regulator of JAK activity, is also involved in their anti-inflammatory action. Our data suggest that 15d-PGJ2 and rosiglitazone suppress the initiation of
JAK-STAT inflammatory signaling independently of PPAR-
, thus
attenuating brain inflammation.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
(IFN-
)1 cause activation
of glial cells (5), eventually leading to neuronal injury via
inflammatory cascade.
is a
ligand-dependent nuclear receptor whose ligands include several
prostanoids including 15-deoxy-
12,14-prostaglandin J2
(15d-PGJ2) (16) and antidiabetic thiazolidinediones such as
rosiglitazone (17). Although PPAR-
was originally shown to play a
key role in adipocyte differentiation and lipid metabolism (18), some
PPAR-
ligands have recently been reported to exert anti-inflammatory
actions by reducing inflammation-associated molecules such as cytokines and nitric oxides (19-24). However, the precise mechanisms of action underlying the anti-inflammatory effects of PPAR-
agonists are poorly understood. Here we provide new insights into the
anti-inflammatory actions of 15d-PGJ2 and rosiglitazone
based on their effects on JAK-STAT inflammatory signaling. We found
that there is a PPAR-
-independent link between the anti-inflammatory
action of 15d-PGJ2 and rosiglitazone and the induction of
SOCS1 and SOCS3. Our findings suggest not only a novel molecular
explanation for the therapeutic efficacy of PPAR-
agonists but also
a new potential therapeutic intervention for inflammatory diseases.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
was from Calbiochem. 15d-PGJ2 was purchased
from Biomol (Butler Pike, PA). Rosiglitazone was a kind gift from Dr.
K. S. Park (Seoul National University, Seoul, Korea). Antibodies
against STAT1, Tyr-701-phosphorylated STAT1, and Tyr-705-phosphorylated
STAT3 were from Cell Signaling Technology (Beverly, MA). Antibodies against phosphorylated JAK1 and JAK2 were from Affinity Bioreagents (Denver, CO).
.
-galactisodase.
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
agonists suppress inflammation, we examined the effects of
15d-PGJ2 and rosiglitazone on JAK-STAT inflammatory
signaling in rat brain. Pretreatment of 15d-PGJ2 or
rosiglitazone for 2 h markedly suppressed the IFN-
-stimulated
phosphorylation of STAT1 and STAT3 in rat primary astrocytes (Fig.
1a). At all of the time points
tested from 2 min to 2 h after IFN-
treatment,
phosphorylation of STAT1 and STAT3 was strongly reduced by treatment
with either of the PPAR-
agonists (data not shown). We then
investigated whether PPAR-
agonists affected the activation of JAK1
and JAK2, because phosphorylation of STATs mainly depends on the
activation of JAKs (26). The phosphorylation of JAK1 and JAK2 by
IFN-
were reduced in the presence of PPAR-
agonists (Fig.
1b). We obtained similar results with another activator of
brain inflammation, lipopolysaccharide. Stimulation with
lipopolysaccharide resulted in phosphorylation of STAT1 and STAT3, but
this was significantly inhibited by pretreatment with PPAR-
agonists
(Fig. 1c). Similar effects were observed in primary
microglia and C6 astroglioma cells (data not shown). These results show
that 15d-PGJ2 and rosiglitazone can inhibit the activation
of JAK-STAT signaling by reducing their phosphorylation.
View larger version (20K):
[in a new window]
Fig. 1.
PPAR- agonists
reduce the phosphorylation of JAKs and STATs. a,
primary astrocytes were pretreated with 15d-PGJ2 (10 µM) or rosiglitazone (20 µM) for 2 h
and stimulated with IFN-
(10 units ml
1) for 5 min.
Western blots were probed with pSTAT1 (Tyr-701) and pSTAT3 (Tyr-705)
antibody. The membrane was then stripped and analyzed with STAT1
antibody to determine loading. b, the phosphorylated level
of JAK1 and JAK2 was determined by phospho-JAK1 or JAK2 antibody.
c, rat primary astrocytes were stimulated with
lipopolysaccharide (100 ng ml
1) for 2 h in the
presence of 15d-PGJ2 (10 µM) or rosiglitazone
(20 µM). LPS, lipopolysaccharide;
15d, 15d-pGJ2; Ro,
rosiglitazone.
We further investigated the events downstream of STAT activation to
evaluate the functional importance of the reduction in phosphorylation
by 15d-PGJ2 and rosiglitazone. First, we examined the
-interferon-activated sequence (GAS) promoter activity in primary
astrocytes, because activated STAT dimers bind to GAS elements.
Transient transfection analysis showed that PPAR-
agonists significantly reduced the IFN-
responsiveness of the GAS promoter (Fig. 2a). We then examined
the mRNA level of genes whose promoters have binding sites for
STATs and act as mediators of inflammation, namely monocyte
chemoattractant protein-1 (27) and interferon-inducible protein-10
(28). IFN-
rapidly induced the transcription of both genes, but this
induction was inhibited by pretreatment with 15d-PGJ2 or
rosiglitazone (Fig. 2b). Similar patterns of transcriptional repression were observed for pro-inflammatory cytokines such as tumor
necrosis factor-
and interleukin-1
(Fig. 2c). We
further tested the effects of PPAR-
agonists at the level of protein expression. As expected, PPAR-
agonists suppressed the
IFN-
-stimulated induction of interferon regulatory factor-1 protein,
which is a regulator of host defense and has binding sites for STAT in its promoter (Fig. 2d) (29). These observations convincingly demonstrate that PPAR-
agonists can exert inhibitory actions on
JAK-STAT inflammatory signaling, thus regulating brain
inflammation.
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An important question raised by the above findings is how PPAR-
agonists influence JAK-STAT signaling. To address this question, we
examined whether PPAR-
mediates the inhibitory action of its agonists on JAK-STAT signaling. First, we determined the existence of
PPAR-
in rat primary astrocytes and microglia. Even in unstimulated cells, PPAR-
transcripts could be detected (Fig.
3a and data not shown). We
then compared the inhibitory effects of PPAR-
agonists on JAK-STAT
signaling between cells transiently transfected with PPAR-
and
vector. Interestingly, we did not observe any differences of
GAS-luciferase activity in cells with PPAR-
compared with cells with
vector (Fig. 3b). Different concentrations either of
PPAR-
constructs or of drugs also did not affect the GAS activity (data not shown). In contrast, a significant activation of
PPAR-
-responsive element (PPRE)-luciferase was observed in the same
experimental conditions (Fig. 3b). Thus, overexpression of
PPAR-
did not lessen GAS activity but enhanced PPRE activity,
indicating that PPAR-
agonists act independently of PPAR-
activation in the JAK-STAT signaling pathway. Overexpression of
PPAR-
consistently failed to improve the inhibitory effects of
PPAR-
agonists on JAK-STAT phosphorylation. In cells transiently
transfected with vector, PPAR-
, or PPAR-
, S112A (a PPAR-
active mutant) (30), PPAR-
agonists exerted equivalent effects on
the phosphorylation of STATs (Fig. 3c). To further confirm
this effect, we examined the effects of PPAR-
agonists in murine BV2
microglial cells that are reported to lack PPAR-
or express it at
very low levels (31). We could not detect the PPAR-
transcripts in
BV2 cells, but we did observe an inhibitory effect of PPAR-
agonists
on STAT phosphorylation (Fig.
4a). Furthermore, PPAR-
agonists reduced the transcription of not only IFN-
-responsive genes
but also inflammation-associated genes in BV2 cells (Fig. 4,
b and c). Thus, we conclude that the inhibitory
actions of 15d-PGJ2 and rosiglitazone on JAK-STAT signaling occur independently of PPAR-
activation in brain.
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We next focused our attention on how JAK activity might be inhibited
independently of PPAR- in cells pretreated with 15d-PGJ2 and rosiglitazone. We considered the possibility that SOCS1 and SOCS3
could be involved in these events because they have been identified as
negative regulators of JAK activation and as key regulators in the
immune system (15). Interestingly, we found that 15d-PGJ2
and rosiglitazone rapidly induced the transcription of SOCS1 as well as
SOCS3 in primary astrocytes and BV2 cells. Within 1-2 h after
treatment of either 15d-PGJ2 or rosiglitazone, the
transcript levels of SOCS1 and SOCS3 were significantly elevated in
a dose-dependent fashion
(Figs. 5 and 6). In agreement with JAK-STAT signaling events, overexpression of PPAR-
S112A failed to
increase the ability of PPAR-
agonists to induce SOCS1 and SOCS3
(Fig. 6d), indicating that elevation of SOCS transcripts occurs independently of PPAR-
. To confirm the functional role of
SOCS in brain inflammatory responses, we tested whether overexpression of SOCS1 or SOCS3 attenuated the phosphorylation of STATs in primary astrocytes. Levels of phosphorylated STAT1 and STAT3 were considerably attenuated in primary astrocytes transiently transfected with either
SOCS1 or SOCS3 compared with vector (Fig. 6e). These results suggest that SOCS1 and SOCS3 may mediate the anti-inflammatory action of 15d-PGJ2 and rosiglitazone.
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In subsequent experiments, we unexpectedly found that the
phosphorylations of JAKs and STATs were also suppressed at 5 min after
simultaneous exposure of cells to IFN- and either
15d-PGJ2 or rosiglitazone, implying that
15d-PGJ2 or rosiglitazone does not act only via the
induction of SOCS1 and SOCS3 on JAK-STAT inflammatory signaling. Thus,
we further examined the mechanism explaining the rapid inhibition of
JAK-STAT activation following treatment with 15d-PGJ2 or rosiglitazone.
Because SHP has been known to be an important negative regulator of
JAK-STAT signaling, we investigated the involvement of SHP in
anti-inflammatory action of 15d-PGJ2 and rosiglitazone.
Interestingly, we observed that SHP2 was phosphorylated within 5 min
after treatment of 15d-PGJ2 (Fig.
7). The activity of SHP2 has been
reported to correlate with its phosphorylation, and the phosphorylated
SHP2 can catalyze the tyrosine phosphorylation of JAKs, receptor, or
other cellular proteins (32). In this regard, the activation of SHP2
may be part of a mechanism involved in inhibitory action of
15d-PGJ2 and rosiglitazone.
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DISCUSSION |
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Some PPAR- agonists have been reported to effectively suppress
inflammation and are thus promising potential therapeutic agents for
chronic inflammatory diseases such as Alzheimer's disease (33). Recent
in vivo studies provide evidence for the therapeutic potential of PPAR-
agonists in various inflammatory diseases (22,
23, 34). However, the mechanisms underlying the role of PPAR-
agonists in ameliorating inflammation are poorly understood. Most of
the information on the mechanism of action of PPAR-
agonists is
based on studies of NF
B activity. PPAR-
agonists have been shown
to inhibit multiple steps in the NF
B signaling pathway through
covalent modifications of I
B kinase (31, 35, 36) and
trans-repression of NF
B, resulting in suppression of inflammation (19, 21). In this paper, we suggest a novel pathway underlying the
anti-inflammatory action of PPAR-
agonists in activated glial cells
based on the JAK-STAT signaling in inflammatory response.
The possible involvement of STAT in the anti-inflammatory action of
PPAR- agonists had been previously proposed (19), but evidence to
directly support this hypothesis was lacking. Here, we show that
15d-PGJ2 and rosiglitazone can act at two points: first by
rapidly attenuating JAK phosphorylation followed by later modulation of
JAK-STAT inflammatory signaling in brain (Figs. 1 and 2). Recent
reports indicate that JAKs and STATs play important roles in many
diverse cellular events in brain (37-39), especially in
neuroinflammatory disorders including Alzheimer's disease (25) and
experimental autoimmune encephalomyelitis (40). In this regard, it is
interesting to note that PPAR-
agonists can inhibit the activity of
JAK and STAT, which may provide an explanation for previous reports of
the beneficial actions of PPAR-
agonists in the treatment of
neuronal diseases (33).
Because of the anti-inflammatory action of PPAR- agonists, PPAR-
has received much attention as a target for the development of
anti-inflammatory drugs (24). However, whether the anti-inflammatory effects of PPAR-
agonists are PPAR-
-dependent or
independent is controversial (19, 21, 31). Thus, we investigated the involvement of PPAR-
in the inhibition of JAK-STAT phosphorylation by its agonists. In all of the signaling events that we tested, PPAR-
agonists appeared to act independently of PPAR-
activation. Previously, other researchers reported that PPAR-
agonists could reduce inflammation independently of PPAR-
via direct modulation of
NF
B activity (36, 37). Consistent with these works, our present data
indicate that PPAR-
agonists also act in JAK-STAT inflammatory
signaling independently of PPAR-
These observations support the
recent proposal by Chawla et al. (21) that PPAR-
is
required for lipid metabolism but not for anti-inflammatory effects.
How then might PPAR- agonists act independently of PPAR-
?
Interestingly, we found that PPAR-
agonists rapidly induced the transcription of SOCS1 and SOCS3, key physiological regulators of
immune responses and therapeutic targets for human immune diseases (15). One consequence of SOCS induction is the inhibition of JAK
activation, thus reducing inflammatory signaling. We also found that
overexpression of either SOCS1 or SOCS3 led to suppression of STAT
phosphorylation in primary astrocytes (Fig. 6e). Recently, Wesemann et al. (41) report that overexpression of SOCS1
inhibits CD40 expression by blocking STAT1 activation in macrophage,
resulting in the suppression of IFN-
-induced tumor necrosis
factor-
secretion and subsequent activation of NF
B. Thus, it is
possible that SOCS induction could suppress NF
B activity in addition
to JAK-STAT activity. There have been several reports regarding the
beneficial actions of SOCS in the treatment of immune diseases such as
hematological malignancies (42), inflammatory arthritis (14), and
infectious disease (43). The results we report here further support the therapeutic role of SOCS. It is interesting that 15d-PGJ2
and rosiglitazone are potent inducers of SOCS expression, because the
only SOCS-inducing agents known previously were cytokines and growth
factors (15).
These observations lead to the question of how expression of SOCS1 and
SOCS3 might be induced by 15d-PGJ2 and rosiglitazone. Although SOCS are negative feedback regulators that are rapidly transcribed in a STAT-dependent manner (15), we could not
observe the phosphorylation of JAKs and STATs by treatment of PPAR-
agonists alone for 5 min to 2 h (Fig.
8 and data not shown), indicating that
other pathways are responsible for their induction. Preliminary data
from our laboratory suggest a role for protein kinases A and C in the
induction of SOCS1 and SOCS3 by PPAR-
agonists.2 It has been
previously reported that the promoter of SOCS1 and SOCS3 contain
cAMP binding sites and that either cAMP (44) or phorbol 12-myristate
13-acetate (45) can stimulate the transcription of SOCS3. Thus, it is
conceivable that certain protein kinases may mediate the induction of
SOCS, but additional studies are needed to evaluate this
possibility.
|
Here we suggest the interesting note that there is a
PPAR--independent link between anti-inflammatory action of PPAR-
agonists and induction of SOCS. In addition to SOCS1 and SOCS3, SHP2,
another negative regulator of JAK-STAT signaling, seems to be also
involved in anti-inflammatory action of 15d-PGJ2 and
rosiglitazone. As shown in Fig. 7, SHP2 was phosphorylated upon
treatment of 15d-PGJ2. The phosphatase activity of SHPs has
been reported to depend primarily on their phosphorylation and
interaction with tyrosine-phosphorylated proteins such as JAKs,
receptor, and other cellular proteins (32). This observation is
in agreement with our recent data obtained from other experiments. We
recently revealed that the activation of SHPs may be closely related
with attenuation of brain inflammation in activated
microglia,3 which
supports that SHP2 as well as SOCS1 and SOCS3 may be involved in
the inflammatory action of 15d-PGJ2 and rosiglitazone.
Although work on the contribution of SOCS to human immune diseases is
still in its infancy, some studies suggest that the enforced expression
of SOCS might be beneficial for the treatment of some immune diseases.
Thus, our results provide a strong foundation for the future
development of therapeutic drugs for the treatment of inflammatory diseases.
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ACKNOWLEDGEMENTS |
---|
We thank Dr. J. B. Kim of Seoul National
University for providing PPAR- constructs and many helpful
discussions. We also thank Dr. Y. J. Hong of Korea Cancer Center
Hospital for help in quantitative real-time PCR using LightCycler Instrument.
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FOOTNOTES |
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* This work was supported in part by R01-2000-00164 from the Basic Research Program of the Korea Science and Engineering Foundation (KOSEF) and a grant from the Korea Ministry of Science and Technology (Critical Technology 21[01-J-LF-B-77])) (to I. J.) and by R03-2002-000-018-0 from the Basic Research program of the KOSEF (to E. J. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 82-31-219-5061;
Fax: 82-31-219-5069; E-mail: jouilo@madang.ajou.ac.kr.
Published, JBC Papers in Press, February 12, 2003, DOI 10.1074/jbc.M210819200
2 E. J. Park, S. Y. Park, E.-h. Joe, and I. Jou, unpublished observations.
3 H. Y. Kim, E. J. Park, E.-h. Joe, and I. Jou, submitted for publication.
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ABBREVIATIONS |
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The abbreviations used are:
IFN-, interferon-
;
PPAR, peroxisome proliferator-activated
receptor;
JAK, Janus kinase;
SOCS, suppressor of cytokine signaling;
STAT, signal transducers and activators of transcription;
15d-PGJ2, 15-deoxy-
12,14-prostaglandin J2;
RT, reverse transcription;
AMV, avian myeloblastosis virus;
RIPA, radioimmune precipitation assay buffer;
GAS,
-interferon-activated
sequence;
PPRE, PPAR-
-responsive element;
SHP, Src homology 2 domain-containing protein phosphatase.
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