Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor, Michigan 48109
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ABSTRACT |
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Helicobacter pylori
and proinflammatory cytokines have a direct stimulatory effect on
gastrin release from isolated G cells, but little is known about the
mechanism by which these factors regulate gastrin gene expression. We
explored whether tumor necrosis factor (TNF)- and interleukin (IL)-1
directly regulate gastrin gene expression and, if so, by what
mechanism. TNF-
and IL-1 significantly increased gastrin mRNA in
canine G cells to 181 ± 18% and 187 ± 28% of control,
respectively, after 24 h of treatment. TNF-
and IL-1 stimulated
gastrin promoter activity to a maximal level of 285 ± 12% and
415 ± 26% of control. PD-98059 (a mitogen-activated protein
kinase kinase inhibitor), SB-202190 (a p38 kinase inhibitor), and
GF-109203 (a protein kinase C inhibitor) inhibited the
stimulatory action of both cytokines on the gastrin promoter. In
conclusion, both cytokines can directly regulate gastrin gene
expression via a mitogen-activated protein kinase- and protein kinase
C-dependent mechanism. These data suggest that TNF-
and IL-1 may
play a direct role in Helicobacter pylori-induced hypergastrinemia.
tumor necrosis factor; mitogen-activated protein kinase; protein kinase C; cytokines; signaling; gastric cells
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INTRODUCTION |
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THE
MICROAEROPHILIC ORGANISM Helicobacter pylori is an
important etiologic agent in the pathogenesis of chronic superficial gastritis and peptic ulcer disease (26). H. pylori
preferentially infects the gastric antrum, leading to an active
inflammatory state and increased production of gastrin at both the
peptide and mRNA levels (14, 18). In addition, there is a
marked increase in expression of multiple cytokines, including tumor
necrosis factor (TNF)- and interleukin (IL)-1, -6, -7, -8, and -10 (7, 8, 15, 27) in the infected stomach. Eradication of the organism leads to normalization of gastrin and a decrease in cytokine expression (7, 11, 17). These observations have suggested a possible link between the inflammatory response associated with the
organism, the altered expression of gastrin, and the observed abnormalities in circulating gastrin and elevated gastric acid secretion observed in H. pylori-positive duodenal ulcer
patients (20, 21). It has been suggested that altered
regulation of gastric acid secretion and the associated hormonal
factors may play an important role in the pathogenesis of H. pylori-related duodenal ulcers (7, 20, 21). Despite
this important association, the mechanism by which H. pylori-mediated gastric inflammation leads to altered regulation
of gastric secretion is unknown.
In an effort to further elucidate the mechanism by which H. pylori leads to dysregulation of gastric acid, we and others
(3, 12, 38) have demonstrated that constituents of
H. pylori and proinflammatory cytokines such as TNF-,
IL-1, and IL-8 can directly stimulate gastrin release from G cells.
Despite these observations, it is still unknown whether proinflammatory
cytokines directly modulate gastrin expression. Moreover, the mechanism
by which factors such as TNF-
and IL-1 may modulate gastric cells
remains unexplored.
The biological actions of proinflammatory cytokines are multiple,
extending from regulating cell growth to apoptosis. In the stomach, these multifunctional cytokines, which are released by monocytes and activated macrophages, also modulate several
physiological parameters, including gastric acid secretion (2,
28), somatostatin release (5), epithelial cell
growth (27), and gastric emptying (19, 32).
It is therefore reasonable to assume that gastric epithelial cells may
serve as a target for these chemical messengers. The aim of this study
was to examine whether TNF- and IL-1 could directly regulate gastrin
gene expression. In addition, we set out to explore the signal
transduction pathways mediating the effect of these cytokines on
gastric epithelial cells.
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METHODS |
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Cell culture and cell transfection. Canine G cells were prepared from freshly obtained canine antral mucosa as previously described (9, 31). Briefly, antral mucosa was separated from the submucosa and minced, and cells were dispersed by sequential incubation with collagenase and EDTA. Isolated cells were separated by centrifugal elutriation and then cultured on Matrigel-coated plates in Ham's F-12/DMEM containing 10% heat-inactivated dog serum, insulin (1 mg/ml), hydrocortisone (1 mg/ml), and gentamicin (100 mg/ml) for 40 h in a humidified atmosphere of 5% CO2-95% air at 37°C. The fraction used in these experiments consisted of 20-25% G cells based on immunohistochemical staining (9, 31).
The AGS cell line derived from a human gastric adenocarcinoma was cultured in DMEM supplemented with 10% fetal bovine serum (GIBCO-BRL, Grand Island, NY), 100 µg/ml penicillin, and 100 µg/ml streptomycin in a humidified atmosphere of 5% CO2-95% air. AGS cells were stably transfected as described previously (12). In brief, the 240 GasLuc AGS stable cell line was developed through stable transfection of AGS cells with the expression construct 240 GasLuc, which contains the 240 bp of the human gastrin promoter ligated upstream of the luciferase reporter gene in the pGL2B vector (Promega, Madison, WI). In some experiments, the mutant 240 GasLuc AGS stable cell line, which expresses a mutated epidermal growth factor (EGF)-responsive element (gERE) within the 240 GasLuc construct, was used for luciferase assays as previously described (12).Gastrin release and gastrin gene expression in canine G cells. After 40 h, enriched canine G cells were washed to remove dead and nonadherent cells and then incubated with ligands in Earle's balanced salt solution for 2 h. Radioimmunoassay was used to measure gastrin cell content and gastrin released into the media as previously described (9, 31).
For Northern blot analysis, cells were cultured as described above and exposed to TNF-TNF and IL-1 receptor expression in AGS cells by PCR.
To characterize the expression of the TNF and IL-1 receptors on AGS
cells, we extracted total RNA and reverse transcribed 5 µg according
to the SuperScript II preamplification system (GIBCO, Gaithersburg, MD)
protocol. The cDNA obtained from this reaction was mixed with PCR
buffer, MgCl2, dNTPs, Taq DNA
polymerase, and human TNF receptor or IL-1 receptor gene-specific
primers and amplified in an automated thermal cycler. Conditions for
the PCR reaction were as follows: initial denaturation 5 min at 94°C, annealing 1 min at 50°C, and extension 1 min at 72°C. The
subsequent cycles were denaturation 2 min at 94°C, annealing 2 min at
50°C, and extension 10 min at 72°C for 50 cycles. The TNF receptor
and IL-1 receptor human-specific primers were designed spanning the exon-exon junction; therefore, these primers are mRNA/cDNA specific and
nonreactive with genomic DNA. The TNF receptor-specific primers were
(forward) 5'-ATTTGCTGTACCAGGTGGCACAAAGGAACC-3' and (reverse) 5'-GTCGATTTCCCAACAATGGAGTAGAGC-3'. The IL-1 receptor-specific primers
were (forward) 5'-CTTGCCGCACGTCCTACACATACC-3' and (reverse) 5'-CGGGGAAGAAAATCAGAGCAGGAG-3'. The PCR products were
analyzed on a 1% agarose gel. The PCR products corresponding to the
TNF- and IL-1 receptors were 587 bp and 547 bp, respectively.
Luciferase assays. 240 GasLuc AGS cells were plated at a density of 0.5 × 106 cells/well, cultured for 24 h in DMEM, and then placed in serum-free media for 24 h before ligand treatment. In some experiments, the mitogen-activated protein kinase (MAPK) kinase inhibitor PD-98059 (New England Biolabs, Beverly, MA), p38 kinase inhibitor SB-202190 (Calbiochem-Novabiochem, San Diego, CA), protein kinase C (PKC) inhibitor bisindolylmaleimide I (GF-109203; Calbiochem-Novabiochem), myristoylated protein kinase A inhibitor (PKI; Calbiochem-Novabiochem), anti-TNF receptor antibody (R&D Systems, Minneapolis, MN), or IL-1 receptor antibody (IL-1ra) (Sigma, St. Louis, MO) were added 30 min before addition of cytokines. Luciferase assays were carried out using luciferin, ATP, and coenzyme A, in a Lumat LB9501 Luminometer (Lumat, Berthold, Germany) as described previously (12, 30). Luciferase assays were normalized to protein determined by the Bradford method (6).
Immune complex kinase assays.
AGS cells were lysed in 400 µl of lysis buffer [50 mM HEPES, 150 mM
NaCl, 10% glycerol, 1% Triton X-100, 1 mM EDTA, 1.5 mM MgCl2, 1 mM Na3VO4, 10 mM NaF, 10 mM
Na4P2O7 · 10H2O,
1 mM 4-(2-aminoethyl)-benzenesulfonylfluoride hydrochloride, 1 µg/ml
leupeptin, and 1 µg/ml aprotinin]. Lysate was clarified by
centrifugation at 16,000 g for 10 min at 4°C, and the
supernatant was used for the assay after protein normalization by the
Bradford method (6). The lysate samples were diluted with
lysis buffer (final volume of 600 µl and a final protein content of
300 µg) and incubated with either an anti-extracellular signal-regulated kinase (ERK)-2 or anti-p38 specific antibody (Santa
Cruz Biotechnology, Santa Cruz, CA) and mixed on a rotating platform
overnight at 4°C. Fifty percent protein A-Sepharose beads (50 µl;
Pharmacia Biotech, Piscataway, NJ) were added and rotated for 1 h,
then centrifuged for 2 min at 7,000 rpm at 4°C, and pellets were
washed once in 500 µl lysis buffer and twice in 500 µl kinase buffer (18 mM HEPES, 10 mM MgAc, 50 µM ATP). Kinase reactions were carried out by resuspending 20 µl kinase reaction buffer {18
mM HEPES, 10 mM Mg-Ac, 50 µM ATP, 2 µg/sample glutathione S-transferase-activating transcription factor 2 or myelin
basic protein (Sigma), and 2 µCi/sample [-32P]ATP
(Amersham)} and incubated for 30 min at 30°C. The reaction products
were electrophoresed on 10% acrylamide-SDS gels, stained, dried, and
autoradiographed. Phosphoprotein activity was quantitated by scanning densitometry.
Western blot analysis of PKC and measurement of PKC activity.
Cell membrane samples were prepared and analyzed as previously
described (37). Briefly, stimulated AGS cells were
suspended in 62.5 mM Tris · HCl (pH 7.4), 2 mM EDTA, and 2 mM
dithiothreitol and sonicated. Sonicates were centrifuged at 1,000 g for 5 min at 4°C. Supernatants were harvested and
centrifuged at 120,000 g for 25 min at 4°C and were
resuspended in 10 mM Tris · HCl (pH 7.4) containing 1 mM
dithiothreitol. Membrane samples (50 µg) were resolved by
electrophoresis on 10% acrylamide SDS gels. Proteins were transferred
to nitrocellulose blocked with 5% nonfat dry milk for 1 h. Blots
were incubated with the primary antibody [anti-PKC- or anti-PKC-
rabbit polyclonal antibody (Santa Cruz Biotechnology)] for 5 h.
After washing with Tris-buffered saline containing 0.25% dry milk,
blots were incubated with peroxidase-linked secondary antibody (goat
anti-rabbit horseradish peroxidase; Zymed) for 60 min. Immunoreactive
bands were visualized using the standardized EC-like
immunoblotting detection system (Amersham). PKC activity in AGS cell
membranes was measured by using an Amersham PKC assay kit according to
the manufacturer's instructions as previously described
(37).
Data analysis. Data are presented as means ± SE. Statistical analysis was performed using Student's t-test. P < 0.05 was considered significant.
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RESULTS |
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Effect of TNF- and IL-1 on gastrin release and mRNA in G cells.
We previously reported that treatment of G cells with TNF-
for
24 h led to a concentration-dependent increase in gastrin release
(5). In this study, we observed that IL-1
at
concentrations of 1 and 10 ng/ml stimulated gastrin release by 138 ± 12% (P < 0.05) and 192 ± 27%
(P < 0.05) of control, respectively (Fig. 1). Of note, the stimulatory effect of
IL-1 was lost at high ligand concentration. The reason for the loss in
stimulatory effect is not clear but may involve downregulation or
desensitization of the corresponding receptor. In identical cell
preparations, bombesin (10
9 M) stimulated gastrin release
by 331 ± 87% (P < 0.05). We also examined the
effect of these cytokines on gastrin mRNA in G cells. TNF-
and
IL-1
(10 ng/ml) significantly increased gastrin mRNA in canine G
cells to 181 ± 18% and 187 ± 28% of control levels, respectively, after 24 h of treatment (Fig.
2).
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TNF-- and IL-1
-mediated regulation of 240 GasLuc
activity in AGS cells.
In view of the limited number of G cells obtained in our canine
preparation, the heterogeneous population of cells, and the inherent
difficulty with manipulating primary cells, we chose to examine
cytokine-mediated gastrin regulation in the well-characterized AGS cell
line. We first confirmed by PCR that AGS cells expressed receptors for
IL-1 and TNF-
(data not shown). Next, we explored the effect of
TNF-
and IL-1
on gastrin promoter activity in AGS cells stably
transfected with the 240 GasLuc construct (Fig. 3). TNF-
and IL-1
dose-dependently
stimulated 240 GasLuc activity to maximal levels of 285 ± 12%
and 415 ± 26% of control, respectively. Stimulation of the
gastrin promoter was maximal 3 h after agonist treatment. After
3 h, the effect of cytokines on 240 GasLuc activity gradually
decreased. Monoclonal anti-human TNF receptor antibody was used to
examine the specificity of the observed response. Anti-TNF receptor
antibody inhibited the effect of TNF-
(10 ng/ml, 3 h) in a
dose-dependent manner with a half-maximal neutralization dose of ~1
µg/ml (Fig. 4A). In
contrast, the naturally occurring IL-1 antagonist IL-1ra (0.1-50
ng/ml) did not alter the stimulatory effect of TNF-
(data not
shown). IL-1ra dose-dependently inhibited the effect of IL-1
(10 ng/ml, 3 h) with an IC50 of ~9 ng/ml (Fig. 4B), whereas the anti-human TNF receptor antibody
(0.1-10 µg/ml) did not alter the stimulatory effect of IL-1
(data not shown).
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Effect of kinase inhibitors on TNF-- and IL-1-mediated activity
on 240 GasLuc activity.
We next examined the signal transduction pathways by which TNF-
(10 ng/ml) and IL-1
(10 ng/ml) regulate 240 GasLuc activity. For these
experiments, we used a series of well-characterized kinase inhibitors.
The stimulatory action of both cytokines on 240 GasLuc activity was
dose-dependently inhibited by PD-98059, SB-202190, and GF-109203 (data
not shown). These inhibitors blocked the action of both cytokines but
did not affect basal promoter activity. In contrast, PKI at
concentrations as high as 1 µM did not inhibit 240 GasLuc activity
stimulated by both cytokines. Cotreatment with PD-98059, SB-202190, and
GF-109203 led to an inhibitory effect, which was greater than that
observed with the individual antagonist (Fig.
5).
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Effect of TNF- and IL-1 on ERK and p38 kinase activity in AGS
cells.
There are inherent limitations associated with the interpretation of
data obtained by using pharmacological agents to inhibit kinase
pathways. Therefore, we determined whether the cytokines of interest
were capable of directly activating the pathways proposed to be
important in mediating their action in AGS cells. Both cytokines led to
a time-dependent increase in ERK and p38 kinase activity. Maximal
increase in activity (8- to 9-fold) for both kinases was achieved
within 15 min, with activity returning to basal after 60 min (data not
shown). As shown in Fig. 6, TNF-
and
IL-1
were potent activators of ERK activity. The effects of TNF-
and IL-1
were abolished by preincubation with PD-98059
(10
5 M) and also inhibited by the TNF receptor antibody
(10 µg/ml) and IL-1ra (50 ng/ml), respectively (Fig. 6). Both
cytokines activated p38 activity in a reversible manner (Fig.
7). SB-202190 (10
7 M)
inhibited the effect of both cytokines on p38 kinase activity. Anti-human TNF receptor antibody (10 µg/ml) and IL-1ra (50 ng/ml) inhibited TNF-
and IL-1
induction of p38 kinase activity,
respectively (Fig. 7). PD-98059 (10
5 M) and SB-202190
(10
7 M) did not alter basal ERK and p38 kinase activity.
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Effect of TNF- and IL-1
on PKC in the AGS cell.
In view of the inhibitory effect of GF-109203 on TNF-
- and
IL-1-mediated regulation of 240 GasLuc, we determined whether these
cytokines promote translocation of the conventional PKC isoforms (
and
) to AGS membranes. As shown in Fig.
8, AGS cells express both PKC isoforms,
and treatment with phorbol 12-myristate 13-acetate (TPA), TNF-
, and
IL-1
for 5 min promoted translocation of these into membranes. We
also examined the effects of TPA, TNF-
, and IL-1
on PKC activity
in AGS cells. As shown in Fig. 9, TNF-
(10 ng/ml), IL-1
(10 ng/ml), and TPA (10
6 M) led to an
increase in PKC activity in AGS cells.
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Effect of mutating the gERE on cytokine-mediated activation of
GasLuc.
We initiated characterization of the segment within the gastrin
promoter responsible for mediating the effect of TNF- and IL-1 on
gastrin gene transcription by examining the effect of both cytokines on
cells transfected with a construct mutated at the gERE. As shown in
Fig. 10, mutation of the gERE did not
inhibit the effect of either TNF-
(10 ng/ml) or IL-1
(10 ng/ml),
even though this mutation significantly inhibited luciferase induction by EGF (10
8 M; data not shown).
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DISCUSSION |
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Accumulating evidence indicates that gastrin secretion and gene
expression are directly regulated by a host of physiological factors,
including feeding, fasting, gastric acid, EGF, and somatostatin. Despite these observations, little is known regarding the pathways impacting gastrin regulation in pathological states such as during infection with the organism H. pylori. We attempted to
address this issue in the present study by examining the impact of only two of the factors thought to be involved in H. pylori-mediated pathogenesis, TNF- and IL-1, on gastrin gene
expression. Through the utilization of two cell models, primary canine
G cells and AGS cells, we demonstrated that both TNF-
and IL-1 can
directly activate gastrin gene expression. In addition, it appears that the MAPK and PKC pathways play a role in mediating the action of
TNF-
and IL-1 on gastrin regulation.
It has previously been demonstrated that TNF- can stimulate
gastrin release from primary cells (3, 38). Moreover, our work is consistent with the studies by Weigert and co-workers (38) demonstrating that IL-1 can lead to
gastrin release from isolated rabbit G cells. We extended these
observations by exploring the mechanism by which TNF-
and IL-1
impact gastrin regulation. Our work with G cells demonstrates that, in
addition to stimulating release of the peptide, both TNF-
and
IL-1
can increase gastrin mRNA, suggesting that these
proinflammatory factors may regulate gastrin expression at a
transcriptional level.
Elucidation of the mechanism by which the cytokines of interest mediate
transcription of the gastrin gene is virtually impossible in primary G
cells. We utilized AGS cells, a well-characterized gastric carcinoma
cell line that resembles gastric epithelial cells, as a model for
studying cytokine-mediated gastrin transcription. This model allowed us
to look at the effects of TNF- and IL-1 on transcriptional
regulation of the gastrin gene and provided a system in which to
explore cytokine-mediated signal transduction. Using this model, we
have successfully demonstrated that both TNF-
and IL-1 can directly
activate transcription of the gastrin gene through regulation of the
240-bp 5'-flanking region examined.
The promoter of the gastrin gene contains several regulatory sequences
including gERE, Sp1, and AP2 (23).
Previous studies have shown that the gERE element is regulated in a
positive manner by EGF, phorbol ester, and cAMP (23, 29).
These observations prompted us to examine whether TNF-- or
IL-1-mediated activity was also dependent on the gERE element. As shown
in our studies, mutation of the gERE element did not alter TNF-
- or
IL-1
-mediated 240 GasLuc activity, suggesting that the action of
both cytokines is independent of this promoter element. Elucidation of
the elements through which TNF-
and IL-1 regulate gastrin expression
is the focus of ongoing studies.
The mechanism by which TNF- or IL-1 regulates gastrin expression and
release is unknown. One may consider that the actions of both cytokines
are via an interdependent pathway. Specifically, TNF-
is a known
stimulant of IL-1 release from several cell systems. Our blocking
studies with anti-TNF-
antibody and IL-1ra confirm that each factor
leads to activation of 240 GasLuc via different receptors. An
additional consideration is that both cytokines are acting on a common
factor, which in turn is activating gastrin expression. One potential
factor is IL-8, which can be released from AGS cells in response to
both TNF-
and IL-1 (1, 4). We explored this possibility
by testing the effect of IL-8 on 240 GasLuc activity. Although not
shown here, IL-8 at concentrations as high as 10 nM failed to stimulate
240 GasLuc activity. Although this observation does not exclude a
modularity role of IL-8 on the regulation of gastrin gene expression,
it excludes this segment of the promoter as being an important target
for this chemokine.
Although much has been learned regarding the postreceptor events
leading to cytokine-mediated cell activation, the specific pathways by
which TNF- and IL-1 regulate many cell types remains unknown.
Moreover, it is apparent that gastrin gene transcription is regulated
by a host of signaling pathways, including tyrosine kinase, PKC, cAMP,
and MAPK (16, 23, 25, 29). Using a series of selective
pharmacological tools, we began to examine which pathways may be
mediating the action of TNF-
and IL-1 on gastrin expression. Our
antagonist studies support that PKC, ERK-2, and p38 kinase in part
mediate the action of both cytokines. Of interest, TNF-
and IL-1
appear to share similar mechanisms for regulation of 240 GasLuc
activity. Although both factors couple and activate independent cell
surface receptors, the postreceptor events for each appear to be quite
similar, an observation that has been made in other cell systems.
In view of the known limitations of pharmacological tools for the study
of cell signaling, we took our experiments one step further by
examining whether TNF- and IL-1 regulate the specific pathways of
interest (PKC, ERK-2, and p38). Consistent with the effect of TNF-
and IL-1 in other cell models (33, 34, 36), both cytokines
stimulated PKC activity in AGS cells. Moreover, both cytokines
stimulated translocation of two common PKC isoforms, PKC-
and -
,
lending further support for the role of PKC in cytokine-mediated 240 GasLuc activation. Both cytokines led to a time- and dose-dependent increase in ERK-2 and p38 kinase activity, findings consistent with
observations made in other systems (13, 24). Our data illustrating that the time frame and dose range needed for
cytokine-mediated GasLuc activity parallels those required for PKC,
ERK-2, and p38 activation supports that these events are linked.
The sequence of events leading to transcriptional activation of the
gastrin gene by TNF- and IL-1 remains unknown. An early event may
involve activation of PKC, which subsequently regulates ERK-2 and p38.
The fact that PKC inhibition does not abolish the effect of either
TNF-
or IL-1 on 240 GasLuc activity suggests that MAPK and PKC are
activated in a parallel and complementary fashion. Our studies
demonstrating that the different antagonists have added inhibitory
effects support this hypothesis. An additional upstream signaling
system involved in gastrin gene expression, which we did not explore,
includes the Raf-Ras signaling pathway (25).
In summary, we have demonstrated that both TNF- and IL-1 can
directly stimulate gastrin gene expression via a PKC- and
MAPK-dependent mechanism. Our findings support the hypothesis that
proinflammatory cytokines may play a direct role in H. pylori-associated hypergastrinemia.
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ACKNOWLEDGEMENTS |
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We are grateful to Pamela Glazer for typing this manuscript.
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FOOTNOTES |
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This work was supported by the Gastrointestinal Peptide Research Center and Gastrin Grant National Institute of Diabetes and Digestive and Kidney Diseases Grant P30-DK-34933.
Address for reprint requests and other correspondence: J. Del Valle, 6520 MSRBI, Box 0682, The Univ. of Michigan Medical School, Ann Arbor, MI 48109 (E-mail: jdelvall{at}umich.edu).
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 27 November 2000; accepted in final form 5 September 2001.
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