Swammerdam Institute for Life Sciences, University of Amsterdam, 1090 GB Amsterdam, The Netherlands
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ABSTRACT |
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In a previous study, it was found that
exposure to tumor necrosis factor- (TNF-
) potentiated the
electrophysiological response to carbachol in a time-dependent and
cycloheximide-sensitive manner. It was deduced that the potentiation
could be due to protein kinase C activity because of increased
1,2-diacylglycerol. It was also observed that propranolol could
decrease the electrophysiological response to carbachol (Oprins JC,
Meijer HP, and Groot JA. Am J Physiol Cell Physiol 278:
C463-C472, 2000). The aim of the present study was to investigate
whether the phospholipase D (PLD) pathway plays a role in the carbachol
response and the potentiating effect of TNF-
. The
transphosphatidylation reaction in the presence of the primary alcohol
1-butanol [leading to stable phosphatidylbutanol (Pbut) formation]
was used to measure activity of PLD. The phosphatidic acid (PA) levels
were also measured. Muscarinic stimulation resulted in an increased
formation of Pbut and PA. TNF-
decreased levels of PA.
intestinal epithelia; protein kinase C; phosphatidic acid; thin-layer chromatography
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INTRODUCTION |
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CL
secretion across intestinal epithelium plays an important role in
regulating water secretion into intestinal lumen and is under close
regulation of hormonal, neuronal, and paracrine mediators. A disturbed
regulation of Cl
secretion can result in a change in the
water balance and cause pathophysiological situations like diarrhea, in
which excessive water secretion occurs. In patients suffering
inflammatory bowel diseases (IBD) like Crohn's disease (CD) and
ulcerative colitis, severe diarrhea occurs. Little is known about the
pathogenesis of this diarrhea. The role of the cytokine tumor necrosis
factor-
(TNF-
) has drawn increased attention. In patients with
CD, enhanced numbers of TNF-
-expressing cells and increased
concentrations of TNF-
have been found (6, 32).
Moreover, therapy using antibodies against TNF-
reduced the symptoms
of diarrhea, suggesting a crucial role for TNF-
in the pathogenesis
of diarrhea in IBD (38, 45). However, the precise
mechanism of action of TNF-
on intestinal epithelium is still
unknown. Several studies have shown that cytokines are able to alter
ion transport and barrier properties of intestinal epithelium, which
could contribute to the diarrhea (23, 26, 36). We recently
demonstrated that TNF-
did not affect the basal Cl
secretion in the intestinal epithelial cell line HT29cl.19A. Also,
neither the cAMP-dependent, the Ca2+-dependent, nor the
protein kinase C (PKC)-dependent Cl
secretion was
affected by TNF-
. However, Cl
secretion induced by
muscarinic receptor activation by carbachol was potentiated after
exposure to TNF-
(30). This phenomenon had not been
previously described and deserves further investigation. This effect
occurred only after at least 2 h of incubation with TNF-
and
was cycloheximide sensitive.
It has been widely documented that activating the muscarinic receptor
with carbachol results in hydrolysis of the membrane phospholipid
phosphatidylinositol 4,5-bisphosphate (PIP2) by the phospholipase C pathway (PLC), generating two signaling molecules: 1,2-diacylglycerol (DAG) and D-myo-inositol
1,4,5-trisphosphate (IP3) (15).
IP3 liberates Ca2+ from the stores in the
endoplasmic reticulum, thereby increasing the intracellular
Ca2+ concentration levels
([Ca2+]i). DAG, with or without
Ca2+, can stimulate various members of the PKC family. In
the human intestinal epithelial cell line HT29cl.19A, it has been
described that carbachol activates the Cl secretion in
these cells via increases of [Ca2+]i and DAG
and activation of isotype PKC-
(3). We have recently provided additional evidence for the involvement of PKC in the carbachol response in these cells (30).
Increases in DAG, and therefore subsequent activation of PKC, are not
solely controlled by the PI-PLC (phosphatidylinositol-specific PLC) pathway. DAG can also be derived from PLC acting on
phosphatidylcholine (PC) (13). Additionally, DAG can be
generated by phospholipase D (PLD) that hydrolyzes structural lipids
like PC to phosphatidic acid (PA). The latter is subsequently broken
down by the enzyme PA phosphatase (PAP) to DAG. On the
contrary, DAG can be phosphorylated by DAG kinase to return PA. A
schematic presentation of the cell signaling pathways involved
in muscarinic receptor activation is shown in Fig.
1.
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The involvement of PLD in muscarinic receptor-related signaling has
been widely studied. Muscarinic receptor-stimulated PLD activity is
reported in several cell types, including lacrimal gland acini,
neuroblastoma cells, and tracheal smooth muscle cells (24, 33,
47). Recently, we showed that the carbachol-induced Cl secretion in human intestinal epithelium is diminished
by propranolol, a putative inhibitor of PAP (30). Hence,
these results suggest a role for the PLD pathway in the
carbachol-induced ion secretion in HT29cl.19A cells. Moreover, the
potentiating action of TNF-
was completely abolished by propranolol.
This strongly suggests that TNF-
exerts its effect via the PLD
pathway, so that more DAG is generated and more PKC is activated, which
then generates an increased Cl
conductance and consequent
Cl
secretion.
The aim of the present study was to investigate the possible
involvement of the PLD pathway in the carbachol response in the colonic
epithelial cell line HT29cl.19A and the possible upregulation of this
pathway by TNF-. The activity of PLD can be measured by using the
unique feature of the enzyme to transphosphatidylate its substrate
(46). In the presence of a primary alcohol like 1-butanol,
PLD is able to form the stable product phosphatidylbutanol (Pbut) in
addition to its physiological product PA. The level of Pbut can be used
as a relative measure for the activity of PLD.
Here, we show that muscarinic receptor activation in HT29cl.19A cells
results in activation of PLD. PLD could also be activated by phorbol
ester, which shows that PLD activation could be downstream of PLC
activation. However, in contrast to the phorbol ester-induced PLD
activation, the muscarinic receptor-activated PLD could not be blocked
by the PKC inhibitor GF-109203X. Furthermore, we show that TNF-
affects the PLD pathway by decreasing the level of PA. This could
result in an increased formation of DAG and subsequent PKC activation,
which may explain the potentiating effect of TNF-
on the secretory
response to carbachol in these cells.
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MATERIALS AND METHODS |
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Cell culture.
HT29cl.19A cells were cultured as described previously
(2). Briefly, cells (passages 16-32) were
grown in DMEM, supplemented with 10% fetal bovine serum, 8 mg/l
ampicillin, and 10 mg/l penicillin/streptomycin. They were seeded in
25-cm2 flasks and passaged every week. For experiments,
cells were subcultured on 25-mm Falcon filters for 14 days, and medium
was replaced every other day. Labeling of the cells with
32Pi and TNF- incubations were performed in
culture media in the incubator for the indicated time.
Labeling, stimulation, and lipid extraction.
Cells were labeled in culture medium for 24 h with 1.85 × 106 3.7 × 106 Bq of
carrier-free 32Pi (Amersham International)
added to the mucosal side of the cells. Cells were then washed with
mannitol Ringer at 37°C to remove the label that was not
incorporated. The composition of the Ringer was (in mM) 117.5 NaCl, 5.7 KCl, 25.0 NaHCO3, 1.2 NaH2PO4, 2.5 CaCl2, 1.2 MgSO4, and 28.0 mannitol. Cells were
stimulated with carbachol in the presence of 0.05%
1-butanol for 30 min with or without preexposure to
different blockers. The stimulation procedure was optimized as
described in Time and dose-response curves of 1-butanol
stimulation. The reaction was stopped by adding 0.1 M HCl, and
lipids were extracted as previously described by Munnik et al.
(27). Extracted lipids were separated on heat-activated TLC plates (Merck; 20 × 20 × 0.1 cm) using a modified ethyl
acetate solvent system [ethyl acetate/isooctane/formic acid/water
(13:2:3:10, by vol)] (28). The levels of
[32P]PA and [32P]Pbut were quantified by
phosphoimaging (Storm; Molecular Dynamics).
Materials.
TNF-, GF-109203X (bisindolylmaleimide I), 4-
-phorbol
12,13-dibutyrate (PDB), and DAG kinase inhibitors I and II (R59022 and
R59949) were from Calbiochem. Propranolol, carbachol, and 1-butanol
were purchased from Sigma, Brunschwig, and Brocades, respectively.
Silica 60 TLC plates and reagents for lipid extraction were from Merck.
[32P]orthophosphate (32Pi;
carrier free) was from Amersham International. TNF-
, propranolol, and carbachol were dissolved in water. PDB, GF-109203X, R59022, and
R59949 were dissolved in DMSO and used at a maximal concentration of
the solvent of 0.01% (vol/vol). Maximal concentrations of solvents were without electrophysiological effects on the cells.
Statistics. Data are presented as means ± SE of the means. Statististical significance was calculated, comparing two groups using a paired Student's t-test as indicated in figure legends.
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RESULTS |
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Muscarinic receptor activation with carbachol results in activation
of PLD.
To establish whether in intestinal epithelial cells (HT29cl.19A cells)
the PLD activity is increased after activating the muscarinic receptor
with carbachol, we studied the formation of Pbut, which is used as a
measure for PLD activity (46). The level of
[32P]Pbut was increased after incubating the cells with
100 µM carbachol. Figure 2A
shows that application of carbachol resulted in an increased level of
[32P]Pbut to 124 ± 6%, compared with controls
without carbachol (100%) (P < 0.001;
n = 21). The level of [32P]PA is
increased to 242 ± 11%, compared with control (P < 0.001; n = 21) (Fig. 2B). These results
illustrate that in HT29cl.19A cells, application of a muscarinic
receptor agonist activates PLD.
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Time and dose-response curves of 1-butanol stimulation.
To determine the time dependence of [32P]Pbut formation,
cells were incubated with carbachol plus 1-butanol (0.05%
vol/vol) for different time intervals. Figure
3 shows that at time (t) = 30 min, the maximal levels of Pbut and PA are seen. Therefore, in all
following experiments, cells were incubated during 30 min with
1-butanol. To determine the concentration of 1-butanol to be used,
electrophysiological experiments were performed with concentrations of
1-butanol varying between 0.05% and 0.5%. We found that 1-butanol
concentrations >0.05% induced a transient increase in transepithelial
potential of 0.6 mV (for 0.15%) and 3 mV (for 0.5%). At 0.5%
1-butanol, the carbachol response was significantly inhibited with
37 ± 4%. The concentration of 0.05% did not show
electrophysiological effects and was, therefore, used in these
experiments.
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Propranolol increases PA levels.
In electrophysiological experiments, we observed that the short-circuit
current induced by carbachol could be inhibited 47% by adding 100 µM
propranolol (30). This inhibitor was claimed to block PAP
activity (39). Figure
4A shows that the presence of
propranolol (100 µM) induced an increase in the basal
[32P]PA levels (208 ± 9%) and in the
carbachol-induced [32P]PA levels (136 ± 12%
compared with carbachol alone) (P < 0.05; n = 5). Neither the basal nor the carbachol-induced
levels of [32P]Pbut were significantly affected by
incubation with propranolol (Fig. 4B). These results
confirm that exposure to 100 µM propranolol in these cells inhibits
PAP activity.
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TNF- affects PA levels.
Since electrophysiological experiments revealed that the potentiation
of the carbachol response by TNF-
could be prevented by propranolol,
we proposed that TNF-
could exert its effect via the PLD pathway in
HT29cl.19A cells (30). To test this, cells were exposed to
10 ng/ml TNF-
during the 24-h labeling period. TNF-
did not have
an effect on the total labeling of the cells [control 5.4 ± 1.4 × 108 arbitrary units (AU) vs. 4.7 ± 1.2 × 108 AU TNF-
; n =42]. After
exposure to TNF-
, basal levels of [32P]PA were
decreased to 87 ± 1% (P < 0.05;
n = 6) compared with control levels (100%), and the
carbachol-stimulated levels were also attenuated to 87 ± 4%
(P < 0.05; n = 6), as shown in Fig. 5A. In Fig. 5B, the
effect of TNF-
on the level of [32P]Pbut is shown. The
basal levels of [32P]Pbut (100%) were not significantly
affected after exposure to TNF-
(95 ± 5%; n = 6). However, the carbachol-induced levels were slightly but
significantly decreased after exposure to TNF-
to 92 ± 3%,
compared with control (100%) (P < 0.05;
n = 6).
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Phorbol ester-induced PKC activation increases PLD activation.
PKC is known to upregulate PLD activity in many different tissues and
cells (14). To establish whether PKC activated by phorbol
esters can activate the PLD pathway in these cells as well, we
incubated the cells during 30 min with 1 µM of the phorbol ester PDB
(4) and measured the formation of [32P]Pbut.
Figure 6A shows that the level
of [32P]Pbut was increased to 128 ± 6%
(P < 0.05; n = 8) and that the PKC
inhibitor GF-109203X (1 µM) (41) could inhibit this
increased [32P]Pbut formation completely. This suggests
that also in these intestinal epithelial cells, stimulating PKC with
phorbol ester increases PLD activity.
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Inhibition of PKC does not affect carbachol-induced PLD activation. We next asked whether in these cells, PKC, which can be activated via carbachol-induced stimulation of PI-PLC, was involved in the carbachol-stimulated PLD activity as well. Before addition of carbachol, cells were incubated for 30 min with 1 µM of the PKC-inhibitor GF-109203X bilaterally. As shown in Fig. 6B, the PKC inhibitor did not show an effect on the basal or on the carbachol-induced levels of [32P]Pbut (n = 7). These results imply that in HT29.cl19A cells, carbachol does not activate PLD downstream of PKC activation.
The source of PA. PA can be formed by DAG kinase from DAG generated by PI-PLC and by PC-PLC. To investigate whether DAG kinase was involved in PA formation, cells were preincubated with 10 µM DAG kinase inhibitor I (R59022) or 5 µM DAG kinase inhibitor II (R59949) 30 min before carbachol addition (9, 10). Neither DAG kinase inhibitor I (293 ± 6% carbachol vs. 285 ± 13% R59022 + carbachol; n = 4) nor DAG kinase inhibitor II (244 ± 13% carbachol vs. 243 ± 8% carbachol + R59949; n = 4) had an effect on the carbachol-induced level of [32P]PA.
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DISCUSSION |
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In a previous study, we found that exposure to TNF- potentiated
the electrophysiological response to carbachol in a time-dependent and
cycloheximide-sensitive manner. We deduced that the potentiation could
be due to increased PKC activity because of increased DAG (30). We also observed that propranolol could decrease the
electrophysiological response to carbachol. The aim of the present
study was to investigate whether the PLD pathway plays a role in the
carbachol response and the potentiating effect of TNF-
.
Therefore, we analyzed the changes in levels of 32P-labeled
PA and 32P-labeled Pbut as a consequence of exposure to
carbachol and/or TNF-. Although the level of PA can be increased
because of a large number of mechanisms, it is claimed that the
transphosphatidylation of primary alcohols is a unique feature of PLD
(46). The increase of the percentage of
[32P]Pbut by carbachol in these cells is, therefore,
evidence that muscarinic receptor activation can increase the activity
of PLD in these cells. A similar observation has been made in
transfected HEK-293 cells (34), submandibular acinar cells
(8), thyroid cells (19), and in a number of
nonepithelial cells like tracheal smooth muscle cells, neuroblastoma
cells, and astrocytes (17, 24, 33), respectively. The
increase of the PA level may, therefore, be partly the result of the
increased formation through PLD. Another pathway for PA formation is
from DAG via DAG kinase. Experiments using inhibitors of DAG kinase did
not show an effect on PA levels. This could imply that DAG kinase is
not involved in the generation of PA. However, we cannot exclude the
possibility that the inhibitors used are not effective in our cell
system. Nine isotypes of DAG kinase are now known, and it is unknown
which isotypes are present in our cells and whether these are
effectively inhibited by the mentioned inhibitors (40).
One of the goals of this study was to establish whether propranolol
reduced the electrophysiological response to carbachol via inhibition
of the conversion of PA to DAG. In the presence of propranolol, PA
levels were further increased, which is consistent with the postulated
inhibitory role of propranolol on PAP (39). An important
observation is that the potentiation of the carbachol-induced secretory
response by TNF-
is totally prevented by propranolol
(30). This indicates that the PLD pathway plays a crucial
role in the potentiating effect of TNF-
.
We reasoned, from electrophysiological experiments, that exposure to
TNF- could augment the response to carbachol by increased formation
of DAG. Thus TNF-
might have increased the activity of PLD or PAP or
decreased the activity of DAG kinase. In the present study, we observed
that TNF-
decreased basal and carbachol-induced [32P]PA levels. Because Pbut cannot be a substrate for
PAP, the observed decrease of Pbut after TNF-
and carbachol exposure
requires another explanation. It is known that PLD activity can be
enhanced by PA and by PIP2, which is formed by the
PA-dependent PIP kinase (16, 31). Therefore, when PA level
is decreased by exposure to TNF-
, PLD may be activated to a lesser
extent, which results in a decreased level of [32P]Pbut
after TNF-
plus carbachol exposure. From these observations, we
propose that muscarinic receptor activation and TNF-
exposure act
synergistically in that they increase the activity of PLD and modulate
the level of PA in this cell line. The decrease in PA level may be due
to increased activity of PAP or decreased activity of DAG kinase. In
this context, it is intriguing that recently the presence of PLD and
PAP in specific membrane compartments have been described
(37).
As reported for many other cell types (14), we
demonstrated that also in this cell line PLD activity can be increased
by PDB-induced PKC activation. However, we revealed that carbachol does
not activate PLD downstream of PKC activation in HT29cl.19A cells. It
may be that this is due to lack of activation of the specific PKC
isotype required for PLD activation by carbachol. Another possibility
is that the activation of PLD by the muscarinic receptors occurs via
another route. A detailed study of this dual activation of PLD by
muscarinic receptors and by phorbol ester-activated PKC in HEK-293
cells has given insight into this phenomenon (35, 43). In
these cells, phorbol ester-stimulated PLD activity appeared to be
dependent on Ral GTPases, whereas muscarinic receptor-mediated PLD
activation was dependent on Rho kinase-activated Rho protein and
PIP2. Similarly, Mamoon et al. (24) concluded
that the PLD stimulation in tracheal smooth muscle by muscarinic
receptor activation is not solely due to PKC, and this was also
observed in neuroblastoma cells (33). Thus our observation
in the intestinal cell line seems to fit in a rather general mechanism
where activation of the muscarinic receptor leads to activation of PLD.
This may lead to the slow but prolonged increase of DAG, which was
described for the first time in astrocytoma cells by Martinson et al.
(25). Surprisingly, as far as we know, this pathway has
gained no attention in studies of Cl secretion by
intestinal epithelium.
Recently, in a study of protein transport through the apical membrane using the same intestinal cell line as the present study, Auger et al. (1) concluded that carbachol did not activate PLD (and that carbachol-induced increase of PA was solely via the PC-PLC/DAG-kinase pathway). One differences between their methods and ours is that they used a very high concentration of ethanol (3%) as substrate for the transphosphatidylation instead of the 0.05% 1-butanol we used in the present study. Furthermore, they labeled lipids with [3H]myristic acid, a less sensitive method to detect phospholipids than 32Pi labeling, as used in the present study.
To our knowledge, this is the first study that suggests that TNF-
might affect PAP activity. Interestingly, it has been recently shown
that other cytokines can affect the activity of PAP. In rat
hepatocytes, transforming growth factor-
increases the activity of
PAP, probably by increased enzyme synthesis or decreased degradation (12). In human mesangial cells, interleukin-1 rapidly
stimulates PAP activity (7). However, the mechanism of the
regulation of PAP remains unclear.
Regulation of PAP activity/expression can influence the PA levels and consequently PA/DAG ratios following PLD activation. Although DAG is known to be an important second messenger, and lately, more attention is paid to the role of PA as a second messenger, not much is known about the mechanisms of regulation of PAP yet. Waggoner et al. (44) reviewed that PAP has putative regulation sites on COOH and NH2 termini, but the mechanisms of regulation remain poorly understood.
PLD activity is shown to be present at different sites of the
intestinal system. Enterocytes express PLD activity in the
mitochondria, and their activity is regulated by nitric oxide,
polyamines, monoamines, and Ca2+ (20-22).
Furthermore, PLC and PLD signaling have been extensively studied in
intestinal smooth muscle cells (29). But as mentioned before, not much is known about the role the PLD pathway can play in
the Cl secretion in intestinal epithelium. To our
knowledge, only one study showed that the primary product of the PLD
pathway, i.e., PA, although exogenously applied, did modulate the
Cl
secretion in another intestinal epithelial cell line,
T84 (42).
A role for TNF- in PLD signaling has been proposed earlier, but
these studies focus on TNF-
as a mediator involved in
apoptosis (5, 11, 18). In the HT29cl.19A cells,
TNF-
in the concentration used (10 ng/ml) does not induce
apoptosis (30).
In summary, we have shown that PLD activity is present in human
intestinal epithelial cells and that this PLD activity is increased by
muscarinic receptor activation and phorbol ester-induced PKC activation
leading to augmented PA levels. We propose that the de novo enzyme
synthesis-dependent potentiation of the electrophysiological response
to carbachol after TNF- exposure may be due to enhanced activity of
PAP. The increased PAP activity, acting on the augmented substrate
level, may lead to increased DAG-dependent PKC activity and,
consequently, to increased Cl
conductivity. The testing
of this hypothesis remains to be done.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. C. J. Oprins, Swammerdam Institute for Life Sciences, Univ. of Amsterdam, P.O. Box 94084, 1090 GB Amsterdam, The Netherlands (E-mail: oprins{at}bio.uva.nl).
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.
Received 19 July 2000; accepted in final form 25 October 2000.
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