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B1
Department of Psychiatry, University of Freiburg Medical School, Freiburg, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B, a transcription
factor involved in the control of cytokine expression. However,
activation of NF-B was not involved in SP-induced expression of
IL-6. Here, we describe p38 mitogen-activated protein kinase (p38 MAPK)
as a signal transduction component that operates independently from
NF-B activation and that mediates SP-induced IL-6 expression in the
human astrocytoma cell line U373 MG. SP induced the phosphorylation of
p38 MAPK within 10 min, and this activation persisted up to 30 min and
was independent from p42/44 MAPKs and protein kinase C activation,
which all are induced after stimulation with SP. As shown by EMSA, p38
MAPK was not involved in SP-induced activation of NF-B. p38 MAPK,
however, mediated SP-induced IL-6 expression as shown by the use of
specific inhibitors of this kinase. Our results suggest that activation
of p38 MAPK is an important component controlling neurogenic
inflammation within the CNS independently from NF-B. Drugs targeting
this MAPK may therefore interfere with SP-correlated neuropsychiatric
disorders and may represent a therapeutic approach in these
disorders. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The neuropeptide has received a lot of attention during the last years as an important mediator of neurogenic control of inflammation. SP has been shown to induce the synthesis of proinflammatory cytokines such as IL-1 and IL-6 in astrocytes and microglial cells (3, 4, 5, 6, 7). These cytokines seem to be involved in the etiopathology of different human disorders of the brain such as multiple sclerosis, AIDS dementia complex, and Alzheimer‘s disease (8, 9, 10, 11), although it is currently a matter of debate whether they play a pathogenic or a protective role in these disorders. SP could possibly initiate, exacerbate, or maintain inflammatory processes in these disorders. More recently, SP has been suggested to be involved in the etiopathology of depressive disorders since SP injections induced "depressive" behavior in animals and treatment of depressed patients with a specific SP receptor-antagonist proved to be as effective as treatment with currently used antidepressant drugs (12).
For an understanding of the biological effects of SP, it is
important to unravel the processes that follow stimulation of target
cells with SP. From molecular studies, it is well known that SP binds
to a G protein-coupled receptor of the neurokinin (NK) receptor family
and that SP has a preferential affinity to the NK-1 receptor subtype
(13, 14, 15). Intracellularly, receptor binding is followed by
phosphoinositide hydrolysis and calcium mobilization (16).
In two previous studies, we have investigated how the SP
receptor-elicited signals affect transcriptional activation and novel
inflammatory gene expression (7, 17). With respect to the
transcriptional activation of the cytokine IL-6, we showed that
SP-induced expression of IL-6 was mainly controlled by protein kinase C
(PKC) and the transcriptional activator NF of IL-6 (NF-IL-6)
(7). In another study, we showed that nanomolar
concentrations of SP potently triggered activation of NF-B, an
important transcriptional activator controlling the synthesis of many
cytokines and other proinflammatory gene products (17).
This activation required mobilization of intracellular calcium and
formation of reactive oxygen intermediates as second messengers.
Although SP potently activated NF-B, NF-B was obviously not
involved in SP-induced IL-6 gene expression as shown by the use of a
reporter gene assay (7).
In this study, we investigated the effects of SP on activation of
mitogen-activated protein kinases (MAPKs) and their relationship to
IL-6 expression and NF-B activation in the human astrocytoma cell
line U373 MG. The MAPK family of proline-directed protein Ser/Thr
kinases consists of at least three major subfamilies: 1) the p42/44
MAPKs, which are also called extracellular signal-regulated kinases
(ERK-1 and ERK-2); 2) the c-Jun NH2-terminal
kinase/stress-activated protein kinases (JNK/SAPK) including p46 JNK1
and p54 JNK2; and 3) the p38 MAPK subfamily. This third group of MAPKs
comprises kinases that are activated under stress conditions in
response to a variety of extracellular stimuli, including bacterial
LPS, oxidative stress, and the cytokines IL-1 and TNF-
(18, 19, 20, 21). We found in this study that SP activated p42/44
MAPK and p38 MAPK and that p38 MAPK functioned as a signal transduction
component that operates independently from NF-B activation and
mediates SP-induced IL-6 expression. These results suggest that
activation of p38 MAPK is an important component controlling neurogenic
inflammation within the CNS independently from NF-B. Drugs targeting
this MAPK may therefore interfere with SP-correlated neuropsychiatric
disorders and may represent a therapeutic approach in these
disorders.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The human astrocytoma cell line U373 MG was obtained from the American Type Culture Collection (Manassas, VA) and was grown in MEM-Earle’s medium (PAA Laboratories, Cölbe, Germany) containing 5% FCS, L-glutamine, antibiotics, vitamins, amino acids, and pyruvate. Confluent monolayers were passaged routinely by trypsinization. Cells were plated for RNA extraction and for detection of DNA-binding activities in 10-cm diameter dishes (Falcon; Becton Dickinson, Heidelberg, Germany) and for protein analysis in 6-well plates (Falcon; Becton Dickinson). Cultures were grown for 5–6 days at 37°C in 5% CO2, and medium was changed the day before treatment. SP, the NK-1 receptor antagonist L703606, and pyrrolidine dithiocarbamate (PDTC) were purchased from Sigma (Deisenhofen, Germany); the PKC inhibitors bis-indolylmaleimide (GF109203X) and Gö6976, the inhibitor of p38 MAPK (SB202190), and the inhibitor of p42/44 MAPKs (PD98059) were obtained from Calbiochem (Bad Soden, Germany). Stock solutions (10 mM) were prepared in DMSO and stored at -20°C. Further dilutions were conducted in distilled water. None of the inhibitors, if used in the indicated concentrations, affected the viability of the cells. DMSO concentrations were kept constant.
RNA extraction and Northern blot analysis
Total RNA was extracted by using a RNA extraction kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. Total RNA (10 µg/lane) was separated by agarose-formaldehyde gel electrophoresis and blotted onto positively charged nylon membranes (Amersham Pharmacia Biotech, Freiburg, Germany). After cross-linking at 120°C for 30 min, filters were prehybridized in 50% formamide, 0.25 M phosphate buffer, 0.25 M NaCl, 1 mM EDTA, 100 µg/ml salmon sperm DNA, and 7% SDS at 43°C for 2 h. cDNA probes were labeled with 50 µCi of [32P]dCTP (Amersham Pharmacia Biotech) using a random priming kit from Stratagene (Heidelberg, Germany). Unincorporated nucleotides were removed by using a nucleotide removal kit from Qiagen. An overnight hybridization was performed at 43°C using the same buffer as for prehybridization. Membranes were washed in 2x SSC/0.1% SDS (3 times for 20 min) at 60°C and exposed to Kodak XAR film (Kodak, Rochester, NY) at -80°C for adequate periods of time. For rehybridization, probes were removed by heating the filter at 95°C in distilled water.
Western blot analysis
U373 MG cells were exposed to SP in the presence or absence of inhibitors for the indicated periods of time. Cells were then washed with PBS and lysed in 1.3x SDS sample buffer containing 100 µM orthovanadate (22). Lysates were homogenized through a 26-gauge-needle and measured for protein content using the bicinchoninic acid method (bicinchoninic acid protein kit; Pierce, Rockford, IL, distributed by KFC Chemikalien, München, Germany). For Western blotting, 60 µg of protein from each sample was subjected to SDS-PAGE on a 12% gel under reducing conditions. Proteins were then transferred onto a polyvinylidene fluoride membrane (Millipore, Bedford, MA) by semidry blotting. The membrane was blocked overnight at 4°C using Rotiblock (Roth, Karlsruhe, Germany) and another hour at room temperature before incubation with Ab. The quantity of active p42/44 MAPK or active p38 MAPK in each sample was assessed using rabbit polyclonal Abs that only recognize the phosphorylated (and thus active) forms of these enzymes. Anti-active p42/44 MAPK (Promega, Mannheim, Germany) was diluted 1:20,000, whereas anti-active p38 MAPK, recognizing both phosphorylated residues T180 and Y182 (NEB, Schwalbach, Germany), was diluted 1:500 in TBST + 1% BSA. For the detection of IL-6 immunoreactivity, a rabbit polyclonal Ab (Endogen, Woburn, MA, distributed by Biozol, Eching, Germany) was used in a dilution of 1:1000 in TBST + 1% BSA. Subsequent detection was performed using the enhanced chemiluminescence Western blotting system (Amersham, Arlington Heights, IL) according to the manufacturer‘s instructions.
EMSAs
Total cell extracts were prepared as described elsewhere
(23). Briefly, after removing the medium, cells were lysed
in lysis buffer containing 20 mM HEPES, 0.35 M NaCl, 20% glycerol, 1%
Nonidet P-40, 1 mM MgCl2, 0.5 mM EDTA, 0.1 mM
EGTA, 5 mM DTT, and 1 mM PMSF. Cells were scraped and transferred into
tubes. Debris was pelleted by centrifugation for 10 min and the
supernatant containing nuclear proteins was collected and stored at
-80°C until use. The NF-B oligonucleotide (Promega) was labeled
with [
-32P]ATP in the presence of T4
polynucleotide kinase (Promega). After separation from unincorporated
[-32P]ATP by a nucleotide removal kit from
Qiagen, the radioactively labeled oligonucleotides (10,000 cpm/sample)
were incubated with 15 µg of protein for 10 min at room temperature.
The complexes were then separated on nondenaturing 4%
polyacrylamide gels.
Measurement of IL-6 synthesis
Cells were preincubated with the inhibitors for 30 min. Thereafter, cells were treated with SP for 18 h. Culture supernatants were harvested, centrifuged for 10 min at 10,000 x g, and levels of IL-6 in the media were measured by ELISA (Pelikine, distributed by HISS, Freiburg, Germany) according to the manufacturer’s instructions. Experiments were conducted in triplicate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effect of the neuropeptide SP on the activation of p38 and
p42/44 MAPKs was investigated in the human astrocytoma cell line U373
MG. The cells have been reported to express functional NK-1 receptors
(24, 25). To investigate the effects of SP on the
activation of p38 and p42/44 MAPK, cells were treated with 10 nM SP for
different time periods. This dose of SP was previously found to be the
optimal dose to induce IL-6 in U373 MG cells (7).
Subsequently, total cell protein was extracted and subjected to Western
blotting by using specific Abs which only recognize the activated
(i.e., phosphorylated) kinases. As shown in Fig. 1
A, p38 MAPK was activated
upon treatment of cells with SP after 5–10 min. Maximal activation was
seen after 15–20 min. Activation of p38 MAPK persisted, although on a
somewhat lower level, up to 60 min. Fig. 1B shows the
activation of p42/44 MAPK by SP. The activation of those kinases was
faster than p38 MAPK activation. Whereas activation of p44 MAPK (ERK-2)
was low and visible 5 min after SP stimulation, p42 MAPK (ERK-1)
activation was intense and already seen after 2.5 min. The activation
was transient with a maximal activation after 10 min. After 60 min of
SP treatment, only marginal activation of p42 MAPK was visible.
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). As little as 1 nM of SP activated p38
MAPK and activation was maximal with 10 nM SP, i.e., was not further
increased with concentrations of SP up to 10 µM (Fig. 2A).
Activation of p42 MAPK was induced by 1 pM SP, whereas the activation
of p44 MAPK was induced at 100 pM SP. At this dose, activation of both
p42 and p44 MAPKs was maximal.
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We further investigated whether the p38 MAPK pathway induced by SP
is independently activated from p42/44 MAPK and from another SP-induced
signal transduction pathway involving PKC and reactive oxygen
intermediates (ROIs), activators of the transcription factor NF-B.
To this end, we pretreated U373 MG astrocytoma cells with specific
inhibitors of p38 and p42/44 MAPK, the free radical scavenger (PDTC),
which prevents the formation of ROIs, and two PKC inhibitors inhibiting
all PKC isoforms (GF) or preferentially PKC and 
I (Gö) and
subsequently analyzed SP-induced p38 MAPK activation. As demonstrated
in Fig. 3, only the inhibitor of p38 MAPK
but not the inhibitors of the p42/44 MAPK, ROIs, and PKC pathways were
able to inhibit SP-induced activation of p38 MAPK. Neither the
inhibitors alone nor the vehicle DMSO had any effect on p38 MAPK
activation (data not shown). Treatment with the NK-1 receptor
antagonist L703606 completely inhibited SP-induced p38 MAPK activation
(Fig. 3).
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B
We have previously shown that SP potently triggers NF-B
activation in human astrocytoma cells (17). We therefore
tested whether p38 or p42/44 MAPKs are involved in SP-induced
activation of NF-B. Cells were pretreated with specific inhibitors
of p38 or p42/44 MAPKs and subsequently stimulated for 60 min with SP.
As shown in Fig. 4, SP caused the
appearance of a protein-DNA complex, which was specific for NF-B as
shown previously (17). Neither the use of a p38 MAPK nor
of a p42/44 MAPK inhibitor affected activation of NF-B. Furthermore,
also the PKC inhibitor GF109203X did not inhibit SP-induced activation
of NF-B. The free radical scavenger PDTC inhibited SP-induced
activation of NF-B, which is in line with the data obtained by our
previous study (7). A faster migrating, nonspecific DNA
complex was not affected by the various treatments and provided an
internal control for the amount and integrity of the cell extracts.
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The observation that p38 and p42/44 MAPKs are not involved in
NF-B activation prompted us to investigate the involvement of these
kinases in SP-induced expression of IL-6 protein and IL-6 mRNA
synthesis. SP has been shown to induce IL-6 expression time and dose
dependently in U373 MG astrocytoma cells (7). In our
study, cells were pretreated with specific inhibitors of p38 and p42/44
MAPKs at three different concentrations and then stimulated with 10 nM
SP. As shown in Fig. 5A, a
specific inhibitor of p38 MAPK (SB202190) dose-dependently inhibited
IL-6 protein synthesis induced by SP, whereas a specific inhibitor of
p42/44 MAPK (PD98059) did not affect SP-induced IL-6 synthesis. Fig. 5B demonstrates that the induction of IL-6 protein synthesis
by 10 nM SP was completely blocked by the specific NK-1 receptor
antagonist L703606. Interestingly, at a concentration of 0.1 and 1 nM,
the receptor antagonist slightly enhanced SP-induced IL-6 synthesis,
which was prevented by 10–100 nM of the antagonist.
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, SP-induced IL-6 gene expression was
dose-dependently inhibited only by the p38 MAPK inhibitor, but not by
the inhibitor of p42/44 MAPK. Inhibition of IL-6 expression by the p38
MAPK inhibitor was maximal at 1 µM, a concentration at which the
inhibitor specifically inhibits p38 MAPK and no other kinases.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B
and IL-6 expression. As a cellular system, we used the astrocytoma cell
line U373 MG which shares several characteristics with primary rat
astrocytes (16, 26, 27). U373 MG astrocytoma cells express
functional high-affinity NK-1 receptors (16, 24, 25) and
are able to express IL-6 in response to SP treatment (7, 28). Therefore, this cell line is widely used as an in vitro
model for the analysis of NK-1 receptor function. In this study, we
demonstrate that SP triggered a fast activation of p38 MAPK. To our
knowledge, this is the first report demonstrating that a neuropeptide
is able to activate such a stress-regulated kinase. p38 MAPK was
activated upon treatment with SP after 5–10 min, and activation peaked
after 15–20 min. Activation of p38 MAPK persisted, although at a lower
level, up to 60 min. This time course of p38 MAPK activation is similar
to that of TNF- stimulation of HeLa cells and mouse macrophages
(20, 29), but contrasts to reports of LPS-stimulated human
neutrophils, where p38 MAPK activity peaked at 25 min and fell toward
baseline after 40 min (19). Since SP also induces TNF-
synthesis, one might argue that the SP-induced activation of p38 MAPK
is mediated by TNF-. However, the rapid activation of p38 MAPK
within 5 min strongly suggests a direct SP effect. This is further
supported by data showing that TNF- induces the same p38 MAPK time
course in HeLa cells as SP does in astrocytoma cells (20).
Since we were able to block SP-induced p38 MAPK by a NK-1 receptor
antagonist and since the synthesis of IL-6 which follows activation of
p38 MAPK in U373 MG cells is also blocked by a selective NK-1 receptor
antagonist (3), we conclude that the SP-induced activation
of p38 MAPK in U373 MG astrocytoma cells is mediated via NK-1
receptors. Activation of p42/44 MAPK was transient with an activation that was first seen after 2.5 min, peaked after 10 min, and decreased to baseline levels after 60 min. This time course is similar to that described by other authors (30, 31).
The functional consequences of concurrent activation of p38 and p42/44
MAPKs after stimulation of astrocytoma cells with SP are not well
understood. However, our results and the results of others
(30) indicate that p38 MAPK and p42/44 MAPK mediate
different functions in astrocytes. Whereas activation of the p42/44
MAPK correlated with SP-induced mitogenesis (30),
activation of the p38 MAPK mediated SP-induced expression of the
proinflammatory cytokine IL-6 as shown here. Until now, nothing was
known about the transcriptional factors connected with MAPKs induced by
SP in astrocytoma cells. However, recent research with other cell
culture systems and other inducers indicates that activation of both
the Erk and JNK/SAPK subfamilies of the MAPK family results in
increased expression of c-fos and the trans
activation of c-jun DNA-binding activity, respectively, to increase the
transcription of TNF--responsive genes via the AP-1 transcriptional
enhancer complex (32, 33). p38 MAPK, in contrast, has been
shown to phosphorylate and trans-activate a number of other
transcription factors, including activating transcription factor 2,
ets-like protein 1, and C/EBP homologous protein (GADD153) (19, 20, 34). Additionally, p38 MAPK has been suggested to be a weak
IB kinase and may therefore potentially play a role in NF-B
activation (20). In the present study, we have studied the
involvement of p38 and p42/44 MAPKs in activation of NF-B by SP. We
focused on the activation of this transcriptional activator, since we
have previously demonstrated a strong activation of NF-B by SP,
which resulted in the expression of the chemokine IL-8
(17). We found that both kinases were not involved in this
activation. This indicates that p38 MAPK is a potent component
controlling SP-induced cytokine expression independently from
NF-B.
The upstream regulators of p38 MAPK activation after stimulation with SP are unknown. In other cell lines, at least three Thr-Tyr kinases have been identified that activate p38 MAPK: 1) MAPK kinase 3 (MKK3) that selectively activates p38 MAPK, 2) MKK4, and 3) MKK6, a specific activator of p38 MAPK related to MKK3 (for review, see Ref. 32). In the present study, we investigated whether p42/44 MAPK, ROIs, or PKC are upstream regulators of p38 MAPK. With the use of specific inhibitors of these signal transduction components, we were able to show that p38 MAPK is a signaling pathway that functions independently from the production of p42/44 MAPK, ROIs, and PKC.
Our present findings may have potential implications for the
etiopathology of several neuropsychiatric disorders. It can be
suggested from this study that activation of p38 MAPK represents a
crucial component in SP-triggered neurogenic inflammation. Activation
of this kinase represents a second switch in addition to activation of
NF-B by SP. Both factors are able to stimulate expression of
cytokines and chemotactic factors, respectively, independently from one
another and therefore act in concert to broaden up the inflammatory
responses induced by SP. Increased levels of proinflammatory cytokines
have been associated with a number of neuropsychiatric disorders, and
elevated levels of SP have often been found in these diseases
(12, 35, 36). p38 MAPK activity in these disorders has not
yet been investigated, but one may speculate that p38 MAPK activation
provides a link between SP and increased levels of cytokines in these
disorders.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bernd L. Fiebich, Department of Psychiatry, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany.
3 Abbreviations used in this paper: SP, substance P; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MKK, MAPK kinase; NK, neurokinin; PDTC, pyrrolidine dithiocarbamate; PKC, protein kinase C; ROI, reactive oxygen intermediates; JNK, c-Jun NH2-terminal kinase; SAPK, stress-activated protein kinase.
Received for publication July 8, 1999. Accepted for publication August 25, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B and B-dependent gene expression in human astrocytoma cells. J. Immunol. 159:4952.[Abstract]
B: a specific inhibitor of the NF-B transcription factor. Science 242:540. uses common and distinct signaling pathways for induction of the interleukin-6 and tumor necrosis factor genes in the human astrocytoma cell line U373. J. Neurochem. 66:1496.[Medline]
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stimulates AP-1 activity through prolonged activation of the c-Jun kinase. J. Biol. Chem. 269:26396.This article has been cited by other articles:
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  V. S. Chauhan, D. G. Sterka Jr., D. L. Gray, K. L. Bost, and I. Marriott Neurogenic Exacerbation of Microglial and Astrocyte Responses to Neisseria meningitidis and Borrelia burgdorferi J. Immunol., June 15, 2008; 180(12): 8241 - 8249. [Abstract] [Full Text] [PDF]
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 J. Sun, R. D. Ramnath, L. Zhi, R. Tamizhselvi, and M. Bhatia Substance P enhances NF-{kappa}B transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathways Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1586 - C1596. [Abstract] [Full Text] [PDF]
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