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J. Biol. Chem., Vol. 277, Issue 17, 14884-14893, April 26, 2002
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From the Program in Cell Biology, Department of Pediatrics,
National Jewish Medical and Research Center,
Denver, Colorado 80206
Received for publication, December 9, 2001, and in revised form, February 4, 2002
Phagocytosis of apoptotic cells by macrophages
results in the production of transforming growth factor- Removal of apoptotic cells by macrophages not only prevents the
release of potentially toxic and immunogenic intracellular contents
from the apoptotic cells into the surrounding tissues but also produces
an anti-inflammatory phenotype, with transcriptional down-regulation of pro-inflammatory chemokines, such as interleukin-8, MIP-2,1 MIP-1 TGF- p38 MAPK is activated by pro-inflammatory cytokines, osmotic stress,
and UV irradiation (24). Following activation, p38 MAPK is capable of
modulating functional responses through phosphorylation of
transcription factors, such as ATF-2, and activation of other kinases.
It has been reported that p38 MAPK is involved in the transcriptional
regulation of interleukin-1- Previously we have demonstrated that the suppression of inflammatory
mediator production (through the induction of TGF- Antibodies and Reagents--
TGF- Cell Culture and Stimulation--
RAW 264.7 (obtained from the
American Type Culture Collection) was cultured in Dulbecco's modified
Eagle's medium supplemented with 10% heat-inactivated endotoxin free
fetal bovine serum, 2 mM L-glutamine, 100 µg/ml streptomycin and 100 units/ml penicillin under a humidified 5%
CO2 atmosphere at 37 °C. The drugs were dissolved in
dimethyl sulfoxide. An aliquot of each drug solution was added to the
medium, and the final concentration of the vehicle in the medium was
adjusted to 0.1% (v/v). The control medium contained the same amount
of the vehicle.
Immunoblotting Analysis--
Immunoblotting analysis was carried
out as described previously with some modification (24). Briefly, RAW
264.7 cells (3.0 × 105 cells/well) were plated in
each well of a 12-well tissue culture plate and incubated overnight.
Following stimulation, the cells were lysed in lysis buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM
dithiothreitol, 0.5% Triton X-100, and 1 × Protease Inhibitor Mixture Set I), resolved on 10% SDS-PAGE, and blotted to
nitrocellulose membranes. The membranes were probed with
phospho-specific antibodies at 4 °C overnight and incubated with
either horseradish peroxidase-conjugated anti-rabbit or anti-mouse
secondary antibodies for 1 h at room temperature. The proteins
were visualized by enhanced chemiluminescence (Amersham Biosciences)
according to the manufacturer's instructions. To confirm equal loading
of proteins in each lane, the membranes were incubated in stripping
buffer (62.5 mM Tris-HCl, pH 7.8, 100 mM
p38 MAPK Immunoprecipitation and Kinase Activity Assay--
p38
MAPK activity measurements were performed essentially as described
(24). Briefly, RAW 264.7 cells (1 × 106 cells/well)
were plated in each well of a 12-well tissue culture plate and
incubated overnight. After stimulation, the cells were lysed in 500 µl of RIPA buffer supplemented with protease inhibitors. p38 MAPK was
immunoprecipitated with 2 µg/ml anti-p38 (c-20) antibody and protein
A-Sepharose beads. The immunoprecipitates were resuspended in 50 µl
of kinase reaction mix containing 20 mM HEPES (pH 7.6), 200 µM MgCl2, 20 µM ATP, 20 µCi
of [ Transient Cell Transfection and Reporter Gene
Assays--
pNF- Immunostaining of Nuclear Accumulation of MKP-1--
RAW 264.7 cells were plated at a density of 3 × 105 cells/well
in a 4-well tissue culture plate on glass coverslips and incubated overnight. The cells were incubated in the presence or absence of PD
98059 (50 µM) for 60 min, followed by TGF- Effects of TGF- Effect of TGF-
In contrast, treatment of RAW 264.7 cells with TGF- Cross-talk between MAPKs in TGF-
We next examined whether TGF- TGF- TGF- TGF-
It has been reported that the selective protein kinase C inhibitor, Ro
31-8220, inhibits MKP-1 expression (39). To further support the
involvement of MKP-1 in inactivation of p38 MAPK by TGF- TGF- In this study, we provide evidence that TGF- Even without the addition of TGF- Thus, blockade of ERK activation using the MEK-1/2 inhibitor PD 98059 resulted in complete prevention of TGF- The induction of inflammatory mediators, as well as activity of the
NF- In neutrophils, we have shown that LPS stimulation results in
activation of MKK-3, which in turn activates p38 MAPK (47). The same
upstream kinase was implicated herein for p38 MAPK activation in RAW
264.7 cells, i.e. LPS-stimulated activation of p38 MAPK was
preceded by activation of MKK-3. On the other hand, we show that
TGF- The most likely explanation for the inhibition of p38 MAPK is by the
action of protein phosphatases. Regulation of MAPK by dual specificity
MAPK phosphatases have been widely studied and discussed (37, 38, 48,
49). Among nine distinct mammalian MAPK phosphatase family members,
MPK-1 (CL 100/3CH 134), MKP-2, and PAC-1 (phosphatase of
activated cells-1) are localized
primarily in the nuclear compartment, encoded by immediate-early genes, which are rapidly and highly inducible by many of the stimuli that
activate MAPKs. They have distinct patterns of substrate specificity.
MKP-1 is known to be up-regulated by ERK and preferentially inactivates
p38 MAPK and SAPK/JNK. PAC-1 inactivates p38 MAPK but not JNK. However,
PAC-1 was undetectable in RAW 264.7 cells (data not shown). MKP-2 was
not considered in this study, because it does not inactivate p38 MAPK
(37, 38, 50). That led us to focus on the role of MKP-1 in the p38 MAPK inhibition.
Accordingly, we present evidence to show that TGF- Production of the CC chemokine MCP-1 is known to be predominantly
controlled by AP-1 rather than NF- Although many studies show functional interaction between members of
the Smad family and MAPK signaling pathways (52-55), we did not find
any effects of PD 98059 on TGF- In conclusion, our results support the concept that TGF- We acknowledge Jay Westcott for provision of
the enzyme-linked immunosorbent assay plates and Lindsay Guthrie for
performing the enzyme-linked immunosorbent assays.
*
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.
Published, JBC Papers in Press, February 12, 2002, DOI 10.1074/jbc.M111718200
The abbreviations used are:
MIP, macrophage
inflammatory protein;
TNF, tumor necrosis factor;
MAPK, mitogen-activated protein kinase;
MKK, MAPK kinase;
ERK, extracellular
signal-regulated kinase;
MEK, MAPK/ERK kinase;
SAPK, stress-activated
protein kinase;
JNK, c-Jun N-terminal kinase;
MKP-1, MAPK
phosphatase-1;
TGF, transforming growth factor;
LPS, lipopolysaccharide;
ATF-2, activated transcription factor 2;
PBS, phosphate-buffered saline.
Cross-talk between ERK and p38 MAPK Mediates Selective
Suppression of Pro-inflammatory Cytokines by Transforming Growth
Factor-
*
ABSTRACT
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
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DISCUSSION
REFERENCES
(TGF-),
which plays an important role in induction of an anti-inflammatory
phenotype and resolution of inflammation. In this study, we show that
TGF- prevents pro-inflammatory cytokine production through
inhibition of p38 mitogen-activated protein kinase (MAPK) and NF-
B.
Blockade of extracellular signal-regulated kinase (ERK) signaling by
the MEK-1/2 inhibitor PD 98059 reversed the inhibitory effects of TGF-, suggesting that cross-talk between MAPKs is essential for this
response. Further investigation indicated that TGF- activated ERK,
which in turn up-regulated MAPK phosphatase-1, thereby inactivating p38
MAPK. On the other hand, TGF- maintained or slightly increased production of the CC chemokine MCP-1, which is regulated predominantly by AP-1. Although SB 203580, an inhibitor of p38 MAPK, and
dominant-negative p38 MAPK both increased AP-1 transcription, lack of
effect of TGF- on lipopolysaccharide-stimulated SAPK/JNK
phosphorylation along with a demonstrated inhibition of TGF--induced
AP-1 activation by dominant-negative Smad3 suggest that
TGF--stimulated AP-1 activation was not caused by inhibition of p38
MAPK but rather through the activation of Smads. Our data provide
evidence that TGF- selectively inhibits inflammatory cytokine
production through cross-talk between MAPKs.
INTRODUCTION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
, and KC in human or mouse
macrophages and partial transcriptional regulation of
TNF-. Macrophage interaction with
apoptotic cells increases production of TGF- and leaves production
and secretion of the CC chemokine MCP-1 (1, 2) either unchanged or
slightly increased. We have previously reported that the uptake of
apoptotic cells by macrophages can be mediated by a
phosphatidylserine receptor and that triggering this receptor is
responsible for the increased production of TGF-. The findings that
anti-TGF--neutralizing antibodies largely reversed the inhibitory
effect of apoptotic cell uptake and that exogenous TGF-
down-regulated the synthesis of the same pro-inflammatory mediators
indicated that TGF- plays an important role in the suppressive
effect of interaction between apoptotic cells and macrophages (3).
is a multifunctional cytokine that regulates numerous
physiological processes, including cell growth, differentiation, apoptosis, adhesion, early embryonic development, and extracellular matrix protein synthesis (4-6). TGF- exerts its effects through heteromeric receptor complex consisting of type I and type II transmembrane serine/threonine kinase receptors. Upon ligand binding, the type II receptor transphosphorylates the type I receptor within its
GS domain, enabling it to transmit signals from TGF- (7, 8).
Smad family members (7, 9, 10), and MAPKs have been implicated in the
signaling by TGF- in regulation of growth, apoptosis, and gene
expression (11-16). Although TGF- has been shown to regulate
several MAPK pathways, the mode of activation appears to be highly
variable and cell type-dependent (13, 17-23).
, interleukin-6, and interleukin-8
expression (25-27). Furthermore, translational regulation of cytokine
mRNA by p38 MAPK has also been suggested (28, 29). Most of the
pro-inflammatory cytokines are regulated by NF-B, and recently, it
has been found that p38 MAPK regulates NF-B-driven gene expression,
in part, by increasing the association of the basal transcriptional
factor, TATA-binding protein, with the C terminus of p65 subunit of
NF-B and increasing the binding of TATA-binding protein to the TATA
box (30).
) in macrophages
that have ingested apoptotic cells is a general phenomenon that does
not depend on the nature of apoptotic target, the macrophage activation
state, or the type of stimulus used (2). In the present study, we
employed an LPS-stimulated macrophage cell line, RAW 264.7, to
investigate the signaling pathway used by TGF- for inhibition of p38
MAPK and regulation of NF-B- or AP-1-dependent
transcription and hence pro-inflammatory mediator production. Using LPS
to activate ERK, p38 MAPK, and JNK in RAW 264.7 cells, we demonstrate
that the balance between ERK and p38 MAPK is dysregulated by
simultaneous TGF--stimulated ERK activation, which results in the
up-regulation of MAPK phosphatase (MKP)-1, thereby causing the
dephosphorylation of LPS-stimulated p38 MAPK. Reduced p38 MAPK
activation is then associated with decreased NF-B-driven gene
transcription and pro-inflammatory cytokine production. On the other
hand, under these conditions the LPS/JNK/c-Jun pathway and TGF-/Smad
pathway synergistically increased AP-1-driven gene transcription.
EXPERIMENTAL PROCEDURES
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DISCUSSION
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1 was from R & D Systems.
LPS (Escherichia coli 0111:B4) was from List Biological
Laboratories. SB 203580, PD 98059, Ro 31-8220, Dapi, and 1 × Protease Inhibitor Mixture Set I were from Calbiochem-Novabiochem.
LipofectAMINE Plus reagent was from Invitrogen. Anti-p38 MAPK
phospho-specific antibody was from Calbiochem-Novabiochem. Phospho-ERK
(E-4), ERK-2 (K 23), p38 (c-20), MEK-3 (N-20), MEK-6 (N-19) (K-19),
MKP-1 (v-15) antibodies, and recombinant fragment of activated
transcription factor 2 (ATF-2-(1-96)) were from Santa Cruz
Biotechnology. Phospho-SAPK/JNK (Thr183/Tyr185)
antibody was from New England Biolabs. Rabbit anti-MKK-6 polyclonal antibody was from Chemicon International. Phospho-MKK-3/MKK-6 (Ser189/207) was from Cell Signaling. Purified anti-mouse
CD16/CD32 (Fc
III/II Receptor) (2.4G2) was from Pharmingen.
-mercaptoethanol, 2% SDS) for 30 min at 50 °C and reprobed with
corresponding antibodies against the native proteins.
-32P]ATP, 2 mM dithiothreitol, 100 µM sodium orthovanadate, 25 mM -glycerolphosphate, and 500 ng of ATF-2-(1-96) for 30 min at 30 °C. The reactions were terminated with 4× Laemmli buffer, and the proteins were separated by 10% SDS-PAGE and blotted to
nitrocellulose membrane. p38 MAPK activity was visualized as the
phosphorylation of the ATF-2 fragment by autoradiography.
B-Luc (B4, 6x, CLONTECH) and
pAP-1-Luc (AP-1, 7x, Stratagene) luciferase reporter gene constructs
were kindly provided by Dr. Annemie Van Linden. cDNA for p38 was
amplified by PCR from an HL60 cDNA library (Stratagene) and cloned
into the BamHI/XhoI sites of pBC KS
(Stratagene). The K287M mutation was made using the Altered Sites II
in vitro mutagenesis system (Promega) to produce a
kinase-dead form of p38. The resulting
BamHI/XhoI fragments were inserted into
pcDNA3 downstream of a FLAG epitope tag to yield dominant-negative
pcDNA3-FLAG-p38()KM plasmid. The wild-type pXL-Smad3 and
dominant-negative pXL-Smad3A were described previously (31). RAW 264.7 cells (3.0 × 105 cells/well) in Dulbecco's modified
Eagle's medium supplemented with 10% heat-inactivated fetal bovine
serum were plated in each well of a 12-well tissue culture plate and
cultured overnight. Transfection was carried out by using LipofectAMINE
Plus reagent according to the manufacturer's instructions.
pSV--galactosidase vector (Promega) was co-transfected as internal
control to measure differences in transfection efficiency. Luciferase
and -galactosidase activities were measured 4 h after LPS
stimulation using a luciferase assay system (Promega) and Galacto-Light
(Tropix), respectively.
(10 ng/ml)
for 60 min. The cells were then stimulated with LPS (100 ng/ml) for 15 min and fixed in phosphate-buffered saline (PBS) containing 4%
glutaraldehyde and 0.2% saponin. The fixed cells were incubated in
blocking buffer (PBS containing 10 µg/ml anti-mouse CD16/CD32 (Fc
III/II Receptor) (2.4G2), 2% bovine serum albumin, and 0.2% Triton
X-100) for 30 min at room temperature, washed once with PBS, and
incubated for additional 30 min in PBS containing 2% bovine serum
albumin, 0.2% saponin, and 1:100 dilution of anti-MKP-1. The cells
were then washed three times with PBS and incubated for 30 min in PBS
containing 2% bovine serum albumin, 0.2% saponin, 1:1000 Dapi, and
1:1000 Cy3-conjugated F(ab')2 goat anti-rabbit IgG, Fc
fragment-specific (Jackson ImmunResearch). The cells were then
rinsed three times in PBS, and the coverslips were mounted onto the
slides. The mounted RAW cells were viewed with a fluorescence microscope using a 63× Zeiss water objective. Confocal images were
achieved using Slidebook v.3.0.4.5 (Intelligent Imaging Innovations, Inc.).
RESULTS
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
on LPS-induced NF-B- and AP-1-driven Gene
Transcription in RAW 264.7 Cells--
Previously, we demonstrated that
in human macrophages or mouse J774 macrophages, apoptotic cell binding
and ingestion results in the early release of TGF- and that this
cytokine contributes to the decreased production of TNF- and several
chemokines (1, 2). Here we show that blockade of p38 MAPK by the p38
inhibitor SB 203580 also inhibited the LPS-stimulated generation of
TNF- and MIP-2, whereas once again the CC chemokine MCP-1 was
increased (Fig. 1). Because of the facts
that most of the pro-inflammatory mediators are regulated by the
transcription factor NF-B and that MCP-1 is known to be regulated
through AP-1 (32-34), we then examined the role of TGF- in
regulating NF-B- and AP-1-driven gene transcription by measuring
NF-B- and AP-1-dependent promoter activity. RAW 264.7 cells were transfected with pNF-B-luc or pAP-1-luc reporter
construct, and 48 h later, the cells were pretreated with SB
203580 or TGF- for 1 h. Reporter gene activity was determined 4 h after LPS stimulation. As shown in Fig.
2A, LPS increased NF-B-driven luciferase activity by 5-fold. However, in the cells pretreated with either SB 203580 or TGF-, LPS-induced luciferase activity was markedly inhibited. In contrast, either LPS or TGF- alone slightly increased the luciferase activity for AP-1, but the
combination of LPS and TGF- resulted in about 10-fold increase (Fig.
2B). We next sought to confirm that p38 MAPK was involved in
the regulation of NF-B-driven gene transcription in RAW 264.7 cells.
The cells were transfected with an empty vector or the dominant-negative pcDNA3-FLAG-p38()KM plasmid. Overexpression of
the transfected p38 MAPK was evaluated using Western blot analysis based on the different molecular weights of the transfected
FLAG-tagged p38 MAPK and endogenous p38 MAPK (Fig. 2C). As
shown in Fig. 2D, LPS significantly increased luciferase
activity for NF-B in cells co-transfected with pNF-B-luc and an
empty vector. The luciferase activity for NF-B was markedly
suppressed in cells transfected with dominant-negative p38 MAPK. These
results indicated that p38 MAPK inhibition induces a pattern of
pro-inflammatory mediator regulation remarkably similar to the effect
of TGF- in macrophages. From these observations, it seemed likely
that TGF- might act in part by inhibiting p38 MAPK activation.
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Fig. 1.
Effects of SB 203580 on LPS-stimulated
chemokine and TNF- release. RAW 264.7 cells were initially cultured for 60 min in the presence or absence of
SB 203580 (10 µM) and subsequently cultured in the
presence or absence of LPS (1 ng/ml) for 12 h. Culture
supernatants were analyzed by enzyme-linked immunosorbent assay for
MIP-2, TNF-, and MCP-1. The values are the means ± S.E. of
three separate experiments presented as percentages of inhibition or
increases relative to LPS alone (MIP-2, 216.25 ± 3.75 ng/ml;
TNF-, 70.80 ± 2.20 ng/ml; MCP-1, 294.35 ± 3.65 ng/ml).
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Fig. 2.
Effects of TGF- on
NF-B- and AP-1-driven gene transcription.
RAW 264.7 cells were transiently transfected with pNF-B-luc
(A) or pAP-1-luc (B). After 48 h, the cells
were incubated in the presence or absence of SB 203580 (10 µM) or TGF- (10 ng/ml) for 60 min, followed by
incubation with LPS (100 ng/ml) for 4 h. C, RAW 264.7 cells were transiently transfected with an empty vector or
dominant-negative p38 MAPK expression vector. After 48 h, the
cells were harvested, and equal amounts of proteins were subjected to
Western blot analysis with anti-p38 (c-20) antibody. The results shown
are representative of three experiments. D, overexpression
of dominant-negative p38 MAPK inhibited NF-B-driven gene
transcription. RAW 264.7 cells were transiently co-transfected with
pNF-B-luc, together with either an empty vector or the
dominant-negative p38 MAPK expression vector. After 48 h, the
cells were stimulated with LPS (100 ng/ml) for 4 h and harvested.
All the luciferase assays, which were normalized to -galactosidase,
are expressed as fold increase from control. The values are the
means ± S.E. from three separate experiments.
on LPS-stimulated MAPK
Activation--
Initially, the time course of LPS-stimulated
macrophage activation was determined (Fig.
3A). RAW 264.7 cells were
stimulated with LPS (100 ng/ml) at various time points before
measurement of ERK, p38 MAPK, and JNK phosphorylation. ERK
phosphorylation was observed at 5 min, reached maximum at 15 min, and
declined at 60 min. Phosphorylation of p38 MAPK was detectable at 5 min, reached maximum at 15 min, and declined rapidly from 30 min to control level at 60 min. Phosphorylation of JNK, however, was only
observed at 15 and 30 min. Pretreatment of RAW 264.7 cells with TGF-
for 1 h dose-dependently inhibited LPS-stimulated p38 MAPK phosphorylation (Fig. 3B, upper panel), and
this effect was confirmed in p38 MAPK activity assays (Fig.
3B, lower panel).
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Fig. 3.
Effects of TGF- on
LPS-stimulated MAPK activation. A, time course for
phosphorylation of ERK, p38 MAPK and JNK by LPS. RAW 264.7 cells were
stimulated with LPS (100 ng/ml) for the times indicated. Cell lysates
were immunoblotted with phospho-ERK (E-4), phospho-p38 MAPK, and
phospho-SAPK/JNK (Thr183/Tyr185) antibodies,
respectively. B, TGF- inhibited both phosphorylation and
activation of p38 MAPK. RAW 264.7 cells were pretreated with the
indicated concentrations of TGF- for 1 h and then stimulated
with LPS (100 ng/ml) for 15 min. The cell lysates were immunoblotted
with phospho-p38 MAPK antibody. Equal loading of proteins in each lane
was confirmed by reprobing the same blot with anti-p38 (c-20)
(upper panel). p38 MAPK was immunoprecipitated, and its
activity was measured using [-32P]ATP and ATF-2 as a
substrate. The phosphorylated ATF-2 was detected after SDS-PAGE by
autoradiography. Equal amount of p38 MAPK immunoprecipitated for each
lane was confirmed by reprobing the same blot with anti-p38 (c-20)
(lower panel). C, time course for phosphorylation
of ERK by TGF-. RAW 264.7 cells were stimulated with TGF- (10 ng/ml) for the times indicated. the cell lysates were immunoblotted
with phospho-ERK (E-4) antibody. The results shown are representative
of at least three experiments.
induced
phosphorylation of ERK even in the absence of LPS. This reached a
maximum at 60 min and declined at 120 min (Fig. 3C). No
detectable phosphorylation of p38 MAPK or JNK was seen with TGF-
alone (data not shown).
Inhibition of p38
MAPK--
Blockade of ERK activation by PD 98059, a specific inhibitor
of its upstream activator MEK-1/2, increased the LPS-stimulated p38
phosphorylation (Fig. 4A).
This finding suggested that cross-talk between ERK and p38 might
contribute to the TGF- effects. In addition, inhibition of
LPS-stimulated p38 MAPK by SB 203580 resulted in a reciprocal increase
of ERK and JNK phosphorylation, showing the potential for
cross-inhibition in the other direction (from p38 to ERK or JNK) as
well (Fig. 4A).
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Fig. 4.
TGF- inhibits p38
MAPK via activating ERK. A, cross-talk between MAPKs.
RAW 264.7 cells were pretreated for 60 min with either TGF- (10 ng/ml), SB 203580 (10 µM), or PD 98059 (50 µM) and then stimulated with LPS (100 ng/ml) for 15 min.
The cell lysates were immunoblotted with phospho-ERK (E-4), phospho-p38
MAPK, and phospho-SAPK/JNK (Thr183/Tyr185)
antibodies, respectively. B, TGF--stimulated ERK
phosphorylation was blocked by PD 98059. RAW 264.7 cells were
pretreated with indicated concentrations of PD 98059 for 60 min and
then stimulated with TGF- (10 ng/ml) for 60 min. The cell lysates
were immunoblotted with phospho-ERK (E-4) antibody. C, PD
98059 reversed the inhibition of p38 MAPK by TGF-. RAW 264.7 cells
were pretreated with the indicated concentrations of PD 98059 for 60 min and of TGF- (10 ng/ml) for another 60 min. The cells were then
stimulated with LPS (100 ng/ml) for 15 min. Afterward, p38 MAPK was
immunoprecipitated, and its activity was measured. All of the results
shown are representative of three experiments.
inhibits p38 MAPK by activating ERK.
As shown in Fig. 4B, the TGF--stimulated ERK
phosphorylation was blocked by PD 98059, confirming that TGF-
stimulates ERK activation through MEK/ERK pathway. Importantly,
preincubation of RAW 264.7 cells with PD 98059 for 60 min before
treatment of the cells with TGF- resulted in reversal of the
TGF--mediated suppression of p38 MAPK activity (Fig. 4C).
These findings suggested that TGF- inhibits p38 MAPK by activating
ERK.
Inhibits LPS-induced NF-B-driven Gene Transcription
through ERK-driven Suppression of p38 MAPK--
To determine whether
TGF- inhibits LPS-induced NF-B-driven gene transcription through
effects on ERK, we transfected RAW 264.7 cells with a pNF-B-luc
plasmid and pretreated the transfected cells with PD 98059 for 60 min
before TGF- and LPS treatment. As shown in Fig.
5, PD 98059 pretreatment in the absence
of TGF- had no effect on LPS-induced luciferase activity. Consistent
with the finding that PD 98059 reversed the inhibitory effect of
TGF- on p38 MAPK activation, the inhibitory effect of TGF- on
LPS-induced luciferase activity for NF-B was completely abrogated by
PD 98059 pretreatment. Moreover, the inhibitory effect of TGF- on
LPS-stimulated MIP-2 or TNF- production was completely abrogated by
PD 98059 pretreatment (data not shown).
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Fig. 5.
PD 98059 reverses the inhibitory effect of
TGF- on NF-B-driven
gene transcription. RAW 264.7 cells were transiently transfected
with pNF-B-luc. After 48 h, the cells were incubated in the
presence or absence of PD 98059 (50 µM) for 60 min,
followed by incubation with TGF- (10 ng/ml) for 60 min. The cells
were then stimulated with LPS (100 ng/ml) for 4 h and harvested.
The luciferase assays, which were normalized to -galactosidase, are
expressed as fold increase from control. The values are the means ± S.E. from three separate experiments.
Inhibition of LPS-stimulated p38 MAPK Is Not at the Level
of MKK-3 or -6--
It has been demonstrated that MKK kinases
and MKKs are the upstream activators for p38 MAPK phosphorylation (35).
Because both MKK-3 and MKK-6 activate p38 MAPK, we performed Western
blots using a phospho-MKK-3,6 antibody to see whether the suppression of p38 MAPK by TGF- is through its upstream activators. As shown in
Fig. 6A, LPS-stimulated
phosphorylation of MKK-3 and MKK-6 (seen as a single band) reached a
maximum at 15 min. To determine which of the MKKs is responsible for
the LPS-stimulated phosphorylation, RAW 264.7 cells were lysed and
immunoprecipitated with MKK-3 or MKK-6 antibody before blotting with
phospho-MKK-3,6 antibody. A detectable increase in phosphorylation of
MKK-3 was observed in cells exposed to LPS when compared with
unstimulated cells, whereas no phosphorylation of MKK-6 was detected
(Fig. 6B). In addition, Western blot performed on the whole
cell lysates using three different MKK-6-specific antibodies (see
"Antibodies and Reagents") failed to detect the protein (data not
shown), suggesting that MKK-6 is not constitutively expressed in
macrophages. We next evaluated whether TGF- also inhibits
LPS-stimulated MKK-3 phosphorylation. No inhibition was seen (Fig.
6C). To our surprise, both TGF- and SB 203580 caused an
increase in LPS-stimulated phosphorylation of MKK-3 (Fig.
6C). These findings suggested that the blockade of p38 MAPK
by TGF- is at the level of p38 MAPK itself, e.g. not
through inhibition of its upstream protein kinases. Moreover, it raises
the possibility of a negative feedback loop to regulate the upstream
activator MKK-3 by p38 MAPK itself.
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Fig. 6.
Effect of TGF- on
the phosphorylation of MKK-3. A, time course for
phosphorylation of MKK-3 and MKK-6 by LPS. RAW 264.7 cells were
stimulated with LPS (100 ng/ml) for the times indicated. The cell
lysates were immunoblotted with phospho-MKK-3,6 antibody. Equal loading
of proteins in each lane was confirmed by reprobing the same blot with
MKK-3 antibody. B, LPS stimulates the phosphorylation of
MKK-3. RAW 264.7 cells were stimulated with LPS (100 ng/ml) for 15 min
and immunoprecipitated (IP) with MKK-3 and MKK-6 antibodies,
respectively. The presence of phosphorylated MKK-3 or MKK-6 was
examined by immunoblotting with phospho-MKK-3,6 antibody. C,
TGF- and SB 203580 increase LPS-stimulated phosphorylation of MKK-3.
RAW 264.7 cells were incubated in the presence or absence of SB 203580 (10 µM) or TGF- (10 ng/ml) for 60 min and then
stimulated with LPS (100 ng/ml) for 15 min. The cell lysates were
immunoblotted with phospho-MKK-3,6 antibody. Equal loading of proteins
in each lane was confirmed by reprobing the same blot with MKK-3
antibody. Fold increase determined by densitometric analysis is
expressed relative to the level of LPS alone as the means ± S.E.
from three separate experiments. The results shown are representative
of three experiments.
Inhibits p38 MAPK through Up-regulation of MAPK
Phosphatase-1--
ERK, p38 MAPK, and JNK activation requires dual
phosphorylation of threonine and tyrosine residues within the motifs
TGY, TEY, and TPY, respectively (36). Dephosphorylation of either residue results in the complete loss of their activity. Inhibition of
MAPKs is principally mediated in vivo by members of a family of dual specificity phosphatases. Among them, MPK-1 is up-regulated by
ERK and preferentially inactivates p38 MAPK and SAPK/JNK (37, 38). To
evaluate its potential role in TGF--mediated p38 MAPK inhibition, we
initially examined levels of MKP-1 after TGF- treatment. TGF-
alone resulted in induction of MKP-1, which was detectable at 30 min
and reached maximum at 1 h (Fig.
7A, top panel). LPS
stimulation resulted in induction of MKP-1 from 30 min (Fig.
7A, middle panel). Pretreatment with TGF- for
1 h before LPS stimulation caused an earlier induction of MKP-1 at
15 min and reached maximum at 30 min (Fig. 7A, bottom
panel). To determine whether TGF- induction of MKP-1 plays a
role in the inactivation of p38 MAPK, the MEK-1/2 inhibitor was first
examined for its ability to prevent MKP-1 up-regulation. As shown in
Fig. 7B, the increase in MKP-1 (which is correlated with the
inhibition of p38 MAPK by TGF- was reversed by PD 98059. The effect
of TGF- in MKP-1 induction was also observed by nuclear staining. As
shown in Fig. 7C, LPS stimulation caused a slight increase
in nuclear accumulation/up-regulation of MKP-1 compared with
unstimulated control. TGF- alone or in combination with LPS
treatment resulted in a significant increase in nuclear accumulation of
MKP-1, which was reduced to control level by PD 98059 pretreatment.
View larger version (30K):
[in a new window]
Fig. 7.
TGF- -induced MKP-1
expression is involved in inactivation of p38 MAPK. A,
time course for up-regulation of MKP-1. RAW 264.7 cells were incubated
with TGF- (10 ng/ml) for the times indicated (top panel).
The cells were incubated in the presence or absence of TGF- (10 ng/ml) for 1 h and then stimulated with LPS (100 ng/ml) for the
times indicated (middle and bottom panels). The
cell lysates were immunoblotted with MKP-1 antibody. B,
blockade of TGF--induced up-regulation of MKP-1 by PD 98059 coincides with the reversal of p38 MAPK. RAW 264.7 cells were incubated
in the presence or absence of PD 98059 (50 µM) for 60 min
followed by incubation with TGF- (10 ng/ml) for 60 min. The cells
were then stimulated with LPS (100 ng/ml) for 15 min. The cell lysates
were immunoblotted with MKP-1 and phospho-p38 MAPK antibodies,
respectively. C, TGF--induced nuclear accumulation of
MKP-1 is blocked by PD 98059. RAW 264.7 cells were plated at a density
of 3 × 105 cells/well in a 4-well tissue culture
plate on glass coverslips and incubated overnight before stimulation
(as described for B) and nuclear staining for MKP-1.
D, the inhibitory effect of TGF- on p38 MAPK is abrogated
by Ro 31-8220. RAW 264.7 cells were incubated in the presence or
absence of Ro 31-8220 (10 µM) for 30 min and then with
TGF- (10 ng/ml) for 60 min. The cells were subsequently
stimulated with LPS (100 ng/ml) for 15 min. The cell lysates were
immunoblotted with MKP-1 and phospho-p38 MAPK antibodies, respectively.
The results shown are representative of at least three
experiments.
, we
pretreated RAW 264.7 cells with Ro 31-8220 for 30 min to see whether
blocking expression of MKP-1 could reverse the TGF--mediated
inhibition of p38 MAPK. As shown in Fig. 7D, Ro 31-8220 blocked the production of MKP-1, which in turn was correlated with
reversal of TGF--mediated inhibition of p38 MAPK.
Increases LPS-induced AP-1-driven Gene Transcription
Independent of p38 MAPK Suppression--
Because the combination of
LPS and TGF- resulted in a significant increase of luciferase
activity for AP-1 (Fig. 2B), we sought to determine whether
TGF- increases AP-1 activation through suppression of p38 MAPK
activation. We co-transfected the pAP-1-luc plasmid either with an
empty vector or with the dominant-negative pcDNA3-FLAG-p38()KM
plasmid. As shown in Fig. 8, LPS
increased luciferase activity for AP-1 in cells co-transfected with
pAP-1-luc reporter and an empty vector (to control for the p38
construct), and this effect was significantly increased in cells
co-transfected with a dominant-negative p38 MAPK expression vector.
Stimulation of RAW 264.7 cells with LPS results in phosphorylation of
JNK, which can phosphorylate c-Jun and thus increase AP-1-driven gene transcription. Inhibition of p38 MAPK by SB 203580 resulted in increase
of JNK phosphorylation (Fig. 4A), indicating the presence of
a suppressive signal from p38 MAPK to JNK. Therefore, inhibition of p38
MAPK might account for the effect of dominant-negative p38 MAPK in
causing an increase of AP-1 activation. However, although TGF- and
SB 203580 were shown to inhibit p38 MAPK, TGF- had no effect on JNK
activation (Fig. 4A). Because the TGF-/Smad signal
pathway has been implicated in AP-1-driven gene transcription as well
(40), we co-transfected the pAP-1-luc reporter construct either with
wild-type or dominant-negative Smad3 plasmid into RAW 264.7 cells. As
shown in Fig. 9, co-transfection of
wild-type Smad3 with the reporter construct resulted in no change for
AP-1 activation compared with that in Fig. 2B. However, when
a dominant-negative Smad3 was co-transfected with the reporter gene,
the AP-1 activation induced by TGF- alone or in combination with LPS
was significantly inhibited. As control, the dominant-negative Smad3
had no effect on LPS-induced AP-1 activation alone. Notably, lack of
inhibition of TGF--induced or TGF- plus LPS-induced AP-1
activation by PD 98059 (data not shown) indicated that TGF--induced
AP-1 activation is independent of ERK in macrophages. Taken together,
we suggest that TGF--induced AP-1-driven gene transcription is via
the Smad complex but not through p38 MAPK suppression.
View larger version (9K):
[in a new window]
Fig. 8.
Dominant-negative p38 MAPK increases
AP-1-driven gene transcription. RAW 264.7 cells were transiently
co-transfected with pAP-1-luc, together with either an empty vector or
the dominant-negative p38 MAPK expression vector. After 48 h, the
cells were stimulated with LPS (100 ng/ml) for 4 h and harvested.
The luciferase assays, which were normalized to -galactosidase, are
expressed as fold increase from control. The values are the means ± S.E. from three separate experiments.
View larger version (11K):
[in a new window]
Fig. 9.
Dominant-negative Smad3 inhibits
TGF- alone or in combination with LPS-induced
AP-1-driven gene transcription. RAW 264.7 cells were transiently
co-transfected with pAP-1-luc and either wild-type pXL-Smad3 or the
dominant-negative pXL-Smad3A expression vector. After 48 h, the
cells were stimulated with LPS (100 ng/ml) for 4 h and harvested.
The luciferase assays, which were normalized to -galactosidase, are
expressed as fold increase from control. The values are the means ± S.E. from three separate experiments.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
blocks
inflammatory cytokine production from macrophages through inhibition of
p38 MAPK and NF-B. In contrast, the CC chemokine MCP-1, regulated by
AP-1 and the Smad complex, demonstrated a potential for enhanced production after exposure to TGF-, implying a selective effect of
TGF- on NF-B-mediated transcription. The key point of action for
the suppression is suggested to be at the level of MAPKs and, more
importantly, by ERK-dependent inhibition of p38 MAPK.
, the time course of LPS-stimulated
MAPK phosphorylation showed a decline in phosphorylation of p38 MAPK as
ERK activation increased. Inhibition of ERK (by blocking the activity
of the upstream kinases MEK1/2) led to increased phosphorylation of p38
MAPK. TGF- alone stimulated ERK phosphorylation but had no direct
effects on p38 MAPK and JNK. However, when TGF- was combined with
LPS stimulation, ERK activation was enhanced over either stimulus alone
and was accompanied by a concomitant decrease in phosphorylation and
activation of p38 MAPK. This allowed examination of the possible
effects of TGF--activated ERK on the degree or extent of p38 MAPK
activation, as well as the extent of cross-talk between the different
classes of MAPKs.
-mediated suppression of p38
MAPK activation. On the other hand, blocking p38 MAPK by SB 203580 resulted in a reciprocal increase in phosphorylation of ERK and JNK,
which suggests cross-inhibition from p38 to ERK as well. In addition,
even although SB 203580 is an inhibitor of p38 MAPK activity, it was
also seen to reduce p38 MAPK phosphorylation. Although unexplained at
this point, the observation has been made previously (41). These
inhibitor experiments do support the now widely recognized concept that
considerable cross-talk occurs between the different MAPKs, including
interactions between inflammatory/stress-activated signal pathways and
hormone/growth factor-activated signal pathways (42).
B luciferase reporter construct in response to macrophage stimulation by LPS was shown to be dependent on p38 MAPK activity based
on blockade by inhibitor of p38 MAPK and, in addition, by transfection
of the cells with a dominant-negative p38 MAPK construct. Although p38
MAPK has been suggested to act at various points in NF-B activation,
nuclear translocation, and transcriptional regulation of inflammatory
mediators (30, 43), at issue here is the potential regulation of p38
MAPK activity itself and the role of TGF--stimulated ERK activity in
this process. Thus, TGF- inhibition of both p38 MAPK activation and
NF-B luciferase reporter expression was reversed by pretreatment of
the cells with PD 98059 to prevent ERK activation. The observations are
consistent with MEK/ERK inhibition of NF-B-driven transcription via
suppression of p38 MAPK (44). On the other hand these observations do
not support the suggestion that pretreatment of mouse macrophages with
TGF- for 24 h inhibits LPS-stimulated expression of
inflammatory cytokines through down-regulation of AP-1 and CD14
receptor expression (45). In macrophages that have ingested apoptotic
cells, TGF- production is rapid (within 60 min) (46). In the present
study, LPS-stimulated phosphorylation of ERK and JNK were not
inhibited by TGF-. Moreover, TGF- combined with LPS
synergistically increased luciferase activity for AP-1, indicating
intact signaling for LPS via TLR4 and, putatively, CD14. We treated
both human monocyte-derived macrophages and J774 cells with TGF- and
then measured CD14 expression. It is not up-regulated nor is it
down-regulated (data not shown). Therefore, it seems unlikely
that the inhibition of CD14 expression accounts for these early
inhibitory effects of
TGF-.
View larger version (22K):
[in a new window]
Fig. 10.
Schematic diagram of the regulation
of NF- B- and AP-1-driven gene transcription by
TGF-.
had no effect on MKK-3 phosphorylation, suggesting that its
effect was on p38 MAPK itself rather than on the upstream activators.
Interestingly, blockade of p38 with either TGF- stimulation or the
p38 MAPK inhibitor seemed to enhance MKK-3 phosphorylation. This may
imply that p38 MAPK by itself can serve as a negative regulator of its
own activation in macrophages. Although the mechanism and physiological
significance of the negative feedback is not clear, it could play a
role in shut-off and/or control of the inflammatory signal after some
period of inflammation.
can induce
up-regulation of MKP-1 and that this depended on MEK and ERK. Importantly, LPS stimulation alone did induce a increase in MKP-1 levels, in keeping with the suggested balance between activation and
inhibition of p38 activity discussed above. The addition of TGF-,
however, led to increased and prolonged up-regulation and nuclear
localization of the phosphatase. TGF- alone (no LPS) increased
up-regulation (Fig. 7A, top panel) and nuclear
localization of MKP-1 very similar to that of TGF- plus LPS (Fig.
7C); this might explain why TGF- activates ERK but not
p38 MAPK and SAPK/JNK in macrophages. As expected, TGF--induced
up-regulation of MKP-1 was prevented by the inhibitor of the MEK/ERK
pathway. We took two approaches to definitively demonstrate that MKP-1
was responsible for the decreased p38 MAPK phosphorylation.
Unfortunately, attempts to use MKP-1 antisense constructs were not
successful in reducing the levels of this protein and were therefore
not useful. On the other hand, Ro 318220, an inhibitor of protein
kinase C that has been reported to inhibit MKP-1 expression independent
of protein kinase C inhibition (39), was found to inhibit
TGF--induced up-regulation of MKP-1. Taken together, the data
support a pathway in which TGF- activates (and/or enhances the
activation of) ERK with subsequent up-regulation of MKP-1. This in turn
dephosphorylates and thence limits the amount and extent of p38 MAPK
activation with subsequent reduction of NF-B-dependent
inflammatory mediator production (Fig. 10). Although not addressed
herein, reduced p38 MAPK activity would also be expected to alter
additional p38 MAPK-dependent effects within the cell,
including known roles in control of protein translation.
B (32-34), and as noted earlier,
TGF- was not effective in blocking production of this chemokine. We
have suggested that this observation may be important in the sequelae
of apoptotic cell clearance during inflammation because, as a monocyte
chemoattractant, MCP-1 may be needed to maintain monocyte emigration
into resolving lesions to complete the clearance process (2). This
would be in keeping with the synergistic activation of AP-1 reporter
activity seen with TGF- and LPS co-stimulation (Fig. 2B).
Because JNK-induced phosphorylation of c-Jun can lead to activation of
AP-1 (51) and inhibition of p38 MAPK by SB 203580 caused an increase in
the phosphorylation of JNK, the TGF--induced enhancement of AP-1
might proceed via this mechanism. We found a similar
enhancement of AP-1 reporter activity after transfection with
dominant-negative p38 MAPK. However, when TGF- was examined, despite
its increased effects on AP-1, no alteration was seen in LPS-stimulated
JNK phosphorylation at 15 min (Fig. 3D) and 30 min (data not
shown). This suggests that TGF- effects on AP-1 activation in the
presence of LPS are not proceeding through cross inhibition of JNK by
p38 MAPK. We suggest that the reason for the inability of TGF- to
mimic the effect of SB 203580 to increase JNK activation might be due
to the ERK-induced increase in MKP-1, which is known to inactivate
SAPK/JNK as well as p38 MAPK.
- or TGF- plus LPS-induced AP-1
activation. It has been reported that c-Jun homodimers and c-Jun-c-Fos
heterodimers activate transcription through their ability to interact
directly with the AP-1-binding site and that the same is true with the
complex of Smad2/Smad3 and Smad4 (40). Furthermore, following TGF-
stimulation, the Smad complex itself binds to AP-1 and results in
transcription from the AP-1 binding site (10). Our results with
dominant-negative Smad3 support such an interaction in macrophages.
Thus, LPS and TGF- added separately would activate AP-1 via the JNK
and Smad pathway, respectively. The synergistic activation of AP-1 by
TGF- and LPS together might then be caused by the combined effects
of three signaling processes: LPS/JNK/AP-1, TGF-/Smads, and the
complex of AP-1 with Smads (Fig. 10).
inhibits
inflammatory cytokine production through the cross-talk between MAPKs,
specifically ERK-dependent inhibition of p38 MAPK caused by
up-regulation of MKP-1. The ability of apoptotic cells to initiate
TGF- production during their recognition and uptake through a
specific receptor for phosphatidylserine has been shown to suppress
inflammatory mediators in vitro (3) and in vivo (46) with resultant resolution of the inflammatory process (46). Presumably, TGF- could be acting via these signaling
pathways not only to enhance resolution of inflammation but also
perhaps to prevent its occurrence in the first place during removal of apoptotic cells in development and tissue remodeling.
ACKNOWLEDGEMENTS
FOOTNOTES
To whom correspondence should be addressed: National Jewish
Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1380; Fax: 303-398-1381; E-mail:
hensonp@njc.org.
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DISCUSSION
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 D. J. Weiss and C. D. Souza REVIEW PAPER: Modulation of Mononuclear Phagocyte Function by Mycobacterium avium subsp. paratuberculosis Vet. Pathol., November 1, 2008; 45(6): 829 - 841. [Abstract] [Full Text] [PDF]
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 H. Chi and R. A. Flavell Acetylation of MKP-1 and the Control of Inflammation Sci. Signal., October 14, 2008; 1(41): pe44 - pe44. [Abstract] [Full Text] [PDF]
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 Y. Q. Xiao, C. G. Freire-de-Lima, W. P. Schiemann, D. L. Bratton, R. W. Vandivier, and P. M. Henson Transcriptional and Translational Regulation of TGF-{beta} Production in Response to Apoptotic Cells J. Immunol., September 1, 2008; 181(5): 3575 - 3585. [Abstract] [Full Text] [PDF]
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 H. T. Lee, S. W. C. Chen, T. C. Doetschman, C. Deng, V. D. D'Agati, and M. Kim Sevoflurane protects against renal ischemia and reperfusion injury in mice via the transforming growth factor-{beta}1 pathway Am J Physiol Renal Physiol, July 1, 2008; 295(1): F128 - F136. [Abstract] [Full Text] [PDF]
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N. Nacu, I. G. Luzina, K. Highsmith, V. Lockatell, K. Pochetuhen, Z. A. Cooper, M. P. Gillmeister, N. W. Todd, and S. P. Atamas Macrophages Produce TGF-{beta}-Induced ({beta}-ig-h3) following Ingestion of Apoptotic Cells and Regulate MMP14 Levels and Collagen Turnover in Fibroblasts J. Immunol., April 1, 2008; 180(7): 5036 - 5044. [Abstract] [Full Text] [PDF]
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H. T. Lee, M. Kim, J. H. Song, S. W. C. Chen, G. Gubitosa, and C. W. Emala Sevoflurane-mediated TGF-{beta}1 signaling in renal proximal tubule cells Am J Physiol Renal Physiol, February 1, 2008; 294(2): F371 - F378. [Abstract] [Full Text] [PDF]
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 J. J. Gills, S. S. Castillo, C. Zhang, P. A. Petukhov, R. M. Memmott, M. Hollingshead, N. Warfel, J. Han, A. P. Kozikowski, and P. A. Dennis Phosphatidylinositol Ether Lipid Analogues That Inhibit AKT Also Independently Activate the Stress Kinase, p38{alpha}, through MKK3/6-independent and -dependent Mechanisms J. Biol. Chem., September 14, 2007; 282(37): 27020 - 27029. [Abstract] [Full Text] [PDF]
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 S. Xie, M. B. Sukkar, R. Issa, N. M. Khorasani, and K. F. Chung Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L245 - L253. [Abstract] [Full Text] [PDF]
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 R. A. Boon, J. O. Fledderus, O. L. Volger, E. J.A. van Wanrooij, E. Pardali, F. Weesie, J. Kuiper, H. Pannekoek, P. ten Dijke, and A. J.G. Horrevoets KLF2 Suppresses TGF-{beta} Signaling in Endothelium Through Induction of Smad7 and Inhibition of AP-1 Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 532 - 539. [Abstract] [Full Text] [PDF]
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I. D'Alimonte, V. Flati, M. D'Auro, E. Toniato, S. Martinotti, M. P. Rathbone, S. Jiang, P. Ballerini, P. Di Iorio, F. Caciagli, et al. Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and beta Amyloid in Mouse Microglia Cells J. Immunol., January 15, 2007; 178(2): 720 - 731. [Abstract] [Full Text] [PDF]
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C. G. Freire-de-Lima, Y. Q. Xiao, S. J. Gardai, D. L. Bratton, W. P. Schiemann, and P. M. Henson Apoptotic Cells, through Transforming Growth Factor-beta, Coordinately Induce Anti-inflammatory and Suppress Pro-inflammatory Eicosanoid and NO Synthesis in Murine Macrophages J. Biol. Chem., December 15, 2006; 281(50): 38376 - 38384. [Abstract] [Full Text] [PDF]
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W. Qi, X. Chen, J. Holian, E. Mreich, S. Twigg, R. E. Gilbert, and C. A. Pollock Transforming growth factor-beta1 differentially mediates fibronectin and inflammatory cytokine expression in kidney tubular cells Am J Physiol Renal Physiol, November 1, 2006; 291(5): F1070 - F1077. [Abstract] [Full Text] [PDF]
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I.-K. Hong, Y.-J. Jin, H.-J. Byun, D.-I. Jeoung, Y.-M. Kim, and H. Lee Homophilic Interactions of Tetraspanin CD151 Up-regulate Motility and Matrix Metalloproteinase-9 Expression of Human Melanoma Cells through Adhesion-dependent c-Jun Activation Signaling Pathways J. Biol. Chem., August 25, 2006; 281(34): 24279 - 24292. [Abstract] [Full Text] [PDF]
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M. Cvetanovic, J. E. Mitchell, V. Patel, B. S. Avner, Y. Su, P. T. van der Saag, P. L. Witte, S. Fiore, J. S. Levine, and D. S. Ucker Specific Recognition of Apoptotic Cells Reveals a Ubiquitous and Unconventional Innate Immunity J. Biol. Chem., July 21, 2006; 281(29): 20055 - 20067. [Abstract] [Full Text] [PDF]
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J. C. Lewthwaite, E. R. Bastow, K. J. Lamb, J. Blenis, C. P. D. Wheeler-Jones, and A. A. Pitsillides A Specific Mechanomodulatory Role for p38 MAPK in Embryonic Joint Articular Surface Cell MEK-ERK Pathway Regulation J. Biol. Chem., April 21, 2006; 281(16): 11011 - 11018. [Abstract] [Full Text] [PDF]
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W. Yang, Y. Chen, Y. Zhang, X. Wang, N. Yang, and D. Zhu Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinase Pathway Is Involved in Myostatin-Regulated Differentiation Repression Cancer Res., February 1, 2006; 66(3): 1320 - 1326. [Abstract] [Full Text] [PDF]
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Y. Q. Xiao, C. G. Freire-de-Lima, W. J. Janssen, K. Morimoto, D. Lyu, D. L. Bratton, and P. M. Henson Oxidants Selectively Reverse TGF-{beta} Suppression of Proinflammatory Mediator Production J. Immunol., January 15, 2006; 176(2): 1209 - 1217. [Abstract] [Full Text] [PDF]
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 H. He, H.-T. Cho, W. Li, T. Kawakita, L. Jong, and S. C. G. Tseng Signaling-Transduction Pathways Required for Ex Vivo Expansion of Human Limbal Explants on Intact Amniotic Membrane Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 151 - 157. [Abstract] [Full Text] [PDF]
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 D. A. Sawatzky, D. A. Willoughby, P. R. Colville-Nash, and A. G. Rossi The Involvement of the Apoptosis-Modulating Proteins ERK 1/2, Bcl-xL and Bax in the Resolution of Acute Inflammation in Vivo Am. J. Pathol., January 1, 2006; 168(1): 33 - 41. [Abstract] [Full Text] [PDF]
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 S. L. House, K. Branch, G. Newman, T. Doetschman, and J. E. J. Schultz Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2167 - H2175. [Abstract] [Full Text] [PDF]
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B. Teng, W. Qin, H. R. Ansari, and S. J. Mustafa Involvement of p38-mitogen-activated protein kinase in adenosine receptor-mediated relaxation of coronary artery Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2574 - H2580. [Abstract] [Full Text] [PDF]
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T. Q. Nhan, W. C. Liles, and S. M. Schwartz Role of Caspases in Death and Survival of the Plaque Macrophage Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 895 - 903. [Abstract] [Full Text] [PDF]
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 H. Shiratsuchi and M. D. Basson Activation of p38 MAPK{alpha} by extracellular pressure mediates the stimulation of macrophage phagocytosis by pressure Am J Physiol Cell Physiol, May 1, 2005; 288(5): C1083 - C1093. [Abstract] [Full Text] [PDF]
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S. Pastore, F. Mascia, F. Mariotti, C. Dattilo, V. Mariani, and G. Girolomoni ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation J. Immunol., April 15, 2005; 174(8): 5047 - 5056. [Abstract] [Full Text] [PDF]
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S. Xie, M. B. Sukkar, R. Issa, U. Oltmanns, A. G. Nicholson, and K. F. Chung Regulation of TGF-{beta}1-induced connective tissue growth factor expression in airway smooth muscle cells Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L68 - L76. [Abstract] [Full Text] [PDF]
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R. A. K. Singh and J. Z. Zhang Differential Activation of ERK, p38, and JNK Required for Th1 and Th2 Deviation in Myelin-Reactive T Cells Induced by Altered Peptide Ligand J. Immunol., December 15, 2004; 173(12): 7299 - 7307. [Abstract] [Full Text] [PDF]
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L. Luo, D.-Q. Li, A. Doshi, W. Farley, R. M. Corrales, and S. C. Pflugfelder Experimental Dry Eye Stimulates Production of Inflammatory Cytokines and MMP-9 and Activates MAPK Signaling Pathways on the Ocular Surface Invest. Ophthalmol. Vis. Sci., December 1, 2004; 45(12): 4293 - 4301. [Abstract] [Full Text] [PDF]
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A. J. K. Williamson, B. C. Dibling, J. R. Boyne, P. Selby, and S. A. Burchill Basic Fibroblast Growth Factor-induced Cell Death Is Effected through Sustained Activation of p38MAPK and Up-regulation of the Death Receptor p75NTR J. Biol. Chem., November 12, 2004; 279(46): 47912 - 47928. [Abstract] [Full Text] [PDF]
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S. J. Gardai, B. B. Whitlock, Y. Q. Xiao, D. B. Bratton, and P. M. Henson Oxidants Inhibit ERK/MAPK and Prevent Its Ability to Delay Neutrophil Apoptosis Downstream of Mitochondrial Changes and at the Level of XIAP J. Biol. Chem., October 22, 2004; 279(43): 44695 - 44703. [Abstract] [Full Text] [PDF]
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Y. Le, P. Iribarren, W. Gong, Y. Cui, X. Zhang, and J. M. Wang TGF-{beta}1 Disrupts Endotoxin Signaling in Microglial Cells through Smad3 and MAPK Pathways J. Immunol., July 15, 2004; 173(2): 962 - 968. [Abstract] [Full Text] [PDF]
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D. J. Weiss, O. A. Evanson, M. Deng, and M. S. Abrahamsen Gene Expression and Antimicrobial Activity of Bovine Macrophages in Response to Mycobacterium avium subsp. paratuberculosis Vet. Pathol., July 1, 2004; 41(4): 326 - 337. [Abstract] [Full Text] [PDF]
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 B. Veres, B. Radnai, F. Gallyas Jr., G. Varbiro, Z. Berente, E. Osz, and B. Sumegi Regulation of Kinase Cascades and Transcription Factors by a Poly(ADP-Ribose) Polymerase-1 Inhibitor, 4-Hydroxyquinazoline, in Lipopolysaccharide-Induced Inflammation in Mice J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 247 - 255. [Abstract] [Full Text] [PDF]
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M. C. Maiuri, G. Tajana, T. Iuvone, D. De Stefano, G. Mele, M. T. Ribecco, M. P. Cinelli, M. F. Romano, M. C. Turco, and R. Carnuccio Nuclear Factor-{kappa}B Regulates Inflammatory Cell Apoptosis and Phagocytosis in Rat Carrageenin-Sponge Implant Model Am. J. Pathol., July 1, 2004; 165(1): 115 - 126. [Abstract] [Full Text] [PDF]
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 D. E. Shifflett, S. L. Jones, A. J. Moeser, and A. T. Blikslager Mitogen-activated protein kinases regulate COX-2 and mucosal recovery in ischemic-injured porcine ileum Am J Physiol Gastrointest Liver Physiol, June 1, 2004; 286(6): G906 - G913. [Abstract] [Full Text] [PDF]
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 M. W. Feinberg, K. Shimizu, M. Lebedeva, R. Haspel, K. Takayama, Z. Chen, J. P. Frederick, X.-F. Wang, D. I. Simon, P. Libby, et al. Essential Role for Smad3 in Regulating MCP-1 Expression and Vascular Inflammation Circ. Res., March 19, 2004; 94(5): 601 - 608. [Abstract] [Full Text] [PDF]
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K. M. Stuhlmeier and C. Pollaschek Differential Effect of Transforming Growth Factor {beta} (TGF-{beta}) on the Genes Encoding Hyaluronan Synthases and Utilization of the p38 MAPK Pathway in TGF-{beta}-induced Hyaluronan Synthase 1 Activation J. Biol. Chem., March 5, 2004; 279(10): 8753 - 8760. [Abstract] [Full Text] [PDF]
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 B. Maier, W. Gluba, B. Bernier, T. Turner, K. Mohammad, T. Guise, A. Sutherland, M. Thorner, and H. Scrable Modulation of mammalian life span by the short isoform of p53 Genes & Dev., February 1, 2004; 18(3): 306 - 319. [Abstract] [Full Text] [PDF]
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M. Cvetanovic and D. S. Ucker Innate Immune Discrimination of Apoptotic Cells: Repression of Proinflammatory Macrophage Transcription Is Coupled Directly to Specific Recognition J. Immunol., January 15, 2004; 172(2): 880 - 889. [Abstract] [Full Text] [PDF]
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T. Ohshima and K. Shimotohno Transforming Growth Factor-{beta}-mediated Signaling via the p38 MAP Kinase Pathway Activates Smad-dependent Transcription through SUMO-1 Modification of Smad4 J. Biol. Chem., December 19, 2003; 278(51): 50833 - 50842. [Abstract] [Full Text] [PDF]
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 N. C. Weber, S. B. Blumenthal, T. Hartung, A. M. Vollmar, and A. K. Kiemer ANP inhibits TNF-{alpha}-induced endothelial MCP-1 expression--involvement of p38 MAPK and MKP-1 J. Leukoc. Biol., November 1, 2003; 74(5): 932 - 941. [Abstract] [Full Text] [PDF]
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 N. Kaminski, J. A. Belperio, P. B. Bitterman, L. Chen, S. W. Chensue, A. M.K. Choi, S. Dacic, J. H. Dauber, R. M. du Bois, J. J. Enghild, et al. Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): S1 - 105. [Full Text] [PDF]
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 Y. Dai, S. Datta, M. Novotny, and T. A. Hamilton TGF{beta} inhibits LPS-induced chemokine mRNA stabilization Blood, August 15, 2003; 102(4): 1178 - 1185. [Abstract] [Full Text] [PDF]
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C. Ropert, M. Closel, A. C. L. Chaves, and R. T. Gazzinelli Inhibition of a p38/Stress-Activated Protein Kinase-2-Dependent Phosphatase Restores Function of IL-1 Receptor-Associated Kinase-1 and Reverses Toll-Like Receptor 2- and 4-Dependent Tolerance of Macrophages J. Immunol., August 1, 2003; 171(3): 1456 - 1465. [Abstract] [Full Text] [PDF]
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W.-C. Lai, M. Zhou, U. Shankavaram, G. Peng, and L. M. Wahl Differential Regulation of Lipopolysaccharide-Induced Monocyte Matrix Metalloproteinase (MMP)-1 and MMP-9 by p38 and Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinases J. Immunol., June 15, 2003; 170(12): 6244 - 6249. [Abstract] [Full Text] [PDF]
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G.-D. Sharma, J. He, and H. E. P. Bazan p38 and ERK1/2 Coordinate Cellular Migration and Proliferation in Epithelial Wound Healing: EVIDENCE OF CROSS-TALK ACTIVATION BETWEEN MAP KINASE CASCADES J. Biol. Chem., June 6, 2003; 278(24): 21989 - 21997. [Abstract] [Full Text] [PDF]
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R. M. Hobbs and F. M. Watt Regulation of Interleukin-1{alpha} Expression by Integrins and Epidermal Growth Factor Receptor in Keratinocytes from a Mouse Model of Inflammatory Skin Disease J. Biol. Chem., May 23, 2003; 278(22): 19798 - 19807. [Abstract] [Full Text] [PDF]
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K. C. Malcolm and G. S. Worthen Lipopolysaccharide Stimulates p38-dependent Induction of Antiviral Genes in Neutrophils Independently of Paracrine Factors J. Biol. Chem., April 25, 2003; 278(18): 15693 - 15701. [Abstract] [Full Text] [PDF]
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M. Bakovic, K. Waite, and D. E. Vance Oncogenic Ha-Ras Transformation Modulates the Transcription of the CTP:Phosphocholine Cytidylyltransferase alpha Gene via p42/44MAPK and Transcription Factor Sp3 J. Biol. Chem., April 18, 2003; 278(17): 14753 - 14761. [Abstract] [Full Text] [PDF]
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 N. Vartiainen, G. Goldsteins, V. Keksa-Goldsteine, P. H. Chan, and J. Koistinaho Aspirin Inhibits p44/42 Mitogen-Activated Protein Kinase and Is Protective Against Hypoxia/Reoxygenation Neuronal Damage Stroke, March 1, 2003; 34(3): 752 - 757. [Abstract] [Full Text] [PDF]
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P. Chen, J. Li, J. Barnes, G. C. Kokkonen, J. C. Lee, and Y. Liu Restraint of Proinflammatory Cytokine Biosynthesis by Mitogen-Activated Protein Kinase Phosphatase-1 in Lipopolysaccharide-Stimulated Macrophages J. Immunol., December 1, 2002; 169(11): 6408 - 6416. [Abstract] [Full Text] [PDF]
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W. Ning, R. Song, C. Li, E. Park, A. Mohsenin, A. M. K. Choi, and M. E. Choi TGF-beta 1 stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L1094 - L1102. [Abstract] [Full Text] [PDF]
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