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B in the Antrum of the Human Stomach
Departments of
*
Experimental Internal Medicine,
Pathology, and
Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B as a mediator of mucosal inflammation.
Experiments in vitro show that NF-B activation may be a critical
event in the production of proinflammatory molecules in
Helicobacter pylori-associated gastritis. This study
examines the expression and activity of NF-B in situ in antral
biopsies of 69 consecutive patients with immunohistochemical
techniques. In the uninflamed stomach, NF-B was highly expressed and
active in a subset of epithelial cells, which were identified as
predominantly G cells. In accordance with this activity, G cells were
shown to express high levels of the NF-B target cytokine TNF-
, a
well-documented stimulator of gastrin production. In patients with
H. pylori-associated gastritis, NF-B activity was
markedly enhanced. Activation occurred preferentially in the epithelial
cells. The number of cells showing activated NF-B correlated with
the activity of gastritis, a measure of neutrophil influx, whereas no
correlation was found with the chronicity of inflammation, a measure of
the presence of mononuclear inflammatory cells. This correlation is
direct evidence of the importance of NF-B-dependent signal
transduction for neutrophil influx in H.
pylori-associated gastritis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One of the sentinel transcriptional modulators in the host response to
bacterial invasion is the NF-B family of proteins
(2, 3, 4, 5). This transcription factor mediates both acute and
chronic inflammation through the regulation of many proinflammatory
proteins (2). NF-B is present in the cell as a hetero-
or homodimer and remains inactive by binding to an inhibitory protein,
I-B, within the cytoplasm (3). Subunits that can form
these dimers are NF-B1 and NF-B2 (expressed as precursors p105
and p100, processed to p50 and p52, respectively), RelA (p65), RelB,
and c-Rel (4, 5). The dimer, typically composed of a p50
and a p65 subunit, is translocated to the nucleus after degradation of
the inhibitory I-B in response to a wide variety of stimuli
(4, 5). Although it is generally assumed that NF-B is
ubiquitously expressed by all cell types, exact expression patterns
remain to be studied for most human tissues.
A unique model system to study the induction of the innate immune
response by a single pathogenic bacterial species exists in the human
stomach. Here, colonization of the mucous layer overlaying the gastric
epithelial cells by the Gram-negative bacterium Helicobacter
pylori results in an acute host response, mostly followed by
persistence of the bacterium and chronic gastric inflammation (6, 7). The presence of H. pylori is associated with
peptic ulcer disease (8), atrophic gastritis, gastric
adenocarcinoma (9, 10), and gastric mucosa-associated
lymphoid tissue lymphoma (11). NF-B plays an important
role in the inflammatory response in the intestine (12),
and accordingly, H. pylori activates this transcription
factor (13, 14, 15). This activation may in turn cause
gastritis via the induction of proinflammatory cytokines such as IL-1
and TNF- and chemokines like IL-8 (15, 16). We examined
in this study the expression and activation of NF-B in the antrum of
the human stomach in both the histologically uninflamed mucosa and
H. pylori-associated gastritis. We also investigated a
possible correlation of the activity of NF-B with the commonly used
histopathological classification of the severity of gastritis, the
Sidney score. Our findings show that in the antrum of the stomach,
activation of NF-B correlated with the activity of gastritis, a
measure of neutrophil influx, whereas this did not correlate with the
chronicity of gastritis, a measure of the presence of mononuclear
inflammatory cells. Furthermore, we found that expression and
activation of NF-B are associated with the epithelial cells,
especially G cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Gastroduodenoscopy was performed on 69 consecutive patients
referred to the endoscopy unit of the Academic Medical Center in
Amsterdam for upper abdominal complaints. These patients were enrolled
in a prospective study investigating the prevalence of H.
pylori in patients with upper abdominal complaints in the general
practitioner’s setting; the study was approved by the Ethics Committee
of the Academic Medical Center. Biopsies were taken from the antrum of
the stomach as part of these investigations. Specimens were fixed in
PBS-buffered paraformaldehyde for 30 min and embedded in paraffin with
the use of standard methods. H. pylori status was determined
by serology, by culturing the bacteria, and by routine histology
(hematoxylin and eosin stain) by an independent pathologist. A patient
was considered H. pylori positive if the bacterium was
cultured or if both serology and pathology were positive. The
histological grade of gastritis was scored according to the Sydney
classification (17), by a pathologist blinded to the
NF-B activation score (see below).
Antibodies
Antisera to different NF-B subunits, anti-p65 rabbit
polyclonal IgG Ab C-20, anti-p65 mouse monoclonal IgG1 Ab F-6,
anti-p50 rabbit polyclonal IgG Ab H-119, anti-p52 rabbit
polyclonal IgG Ab K-27, anti-RelB rabbit polyclonal IgG Ab C-19,
and anti-TRAF2 rabbit polyclonal IgG Ab M-19, were purchased from
Santa Cruz Biotechnology (Santa Cruz, CA). A mouse monoclonal IgG3 Ab
(Boehringer Mannheim, Mannheim, Germany), raised against the p65
nuclear localization signal, was used to detect activated NF-B. This
Ab binds to the p65 unit only after release from the inhibitory I-B
subunit and thus specifically recognizes activated p65, allowing
assessment of NF-B activation in situ (14, 18, 32). For
detection of chromogranin A and gastrin, we used anti-chromogranin
A mouse mAb clone DAK-A3 and anti-gastrin rabbit polyclonal Ab A568
(DAKO, Glostrup, Denmark). A mouse monoclonal IgM Ab against TNF-,
clone 4C6-H6, was purchased from Instruchemie (Hilversum, The
Netherlands). For H. pylori visualization, the rabbit
polyclonal Ab B0471 (DAKO) was used.
Immunohistochemistry
Paraffin sections (4 µm) were dewaxed and rehydrated in graded
alcohols. Endogenous peroxidase activity was quenched with 1.5%
H2O2 in PBS for 30 min at
room temperature. Nonspecific staining was blocked with 10 mM Tris, 5
mM EDTA, 0.15 M NaCl, 0.25% gelatin, 0.05% (v/v) Tween 20, pH 8.0,
for 30 min at room temperature. After a washing with PBS, one of the
following primary Abs was applied: anti-p65 polyclonal (1:500);
anti-p65 monoclonal (1:50); anti-p50 (1:50); anti-p52
(1:10); anti-RelB (1:20); anti-TRAF2 (1:50); anti-active
p65 (1:500 of 1 µg/ml stock); anti-chromogranin A (1:50);
anti-gastrin (1:200) anti-TNF (1:50) in PBS containing 1% BSA.
For double staining, combinations of monoclonal and polyclonal Abs were
used. Sections were stored overnight at 4°C. The following day, for
single staining, sections were washed in PBS and incubated with a
secondary biotinylated goat anti-rabbit Ig (DAKO, 1:500) or
anti-mouse Ig Ab (DAKO, 1:200) for 1 h at room temperature and
washed with PBS. Hereafter, sections were incubated with AB complex
(DAKO) as described in the manufacturer’s instructions for 1 h at
room temperature. Peroxidase activity was detected with
diaminobenzidine
(DAB,2 Sigma, St.
Louis, MO) (5 mg DAB and 10 µl
H2O2 in 10 ml 0.05 M Tris,
pH 7.8), resulting in the formation of a brown reaction product.
Sections were briefly counterstained with hematoxylin, dehydrated in
graded alcohols, and mounted. For double staining experiments,
secondary Abs used were combinations of alkaline phosphatase-conjugated
goat anti-rabbit (1:100) with goat anti-mouse biotin, or
alkaline phosphatase-conjugated goat anti-mouse (1:100) with goat
anti-rabbit biotin. Sections were then incubated with streptavidin
ß-galactosidase (1:40, Boehringer Mannheim) at room temperature for
30 min. The streptavidin ß-gal was detected with 1% X-gal (DAKO) in
iron phosphate buffer (0.02%
MgCl2·6H2O, 0.099%
potassium ferricyanide, 0.127% potassium ferrocyanide) at 37°C for
15 min, resulting in a blue color. After washing in Tris-buffered
saline, the alkaline phosphatase was detected in purple by the Fast Red
detection method (DAKO). Double-stained sections were mounted in
Ultramount (DAKO), an aqueous mounting medium. Controls consisted of
omitting the primary and secondary Ab and use of an appropriate Ig
control. Single staining in adjacent sections always preceded double
staining experiments.
NF-B activation score
To assess the activity of NF-B in situ in the human stomach,
specimens from all patients were stained for active NF-B. Two
pictures of each section were taken at x200 magnification (0.0325
mm2/picture), and positive cells were counted,
blind to the clinical diagnosis, in each microscope field with the use
of an image analysis program (EFM Software, Rotterdam, The
Netherlands). The mean of the two fields was taken as a relative
measure of NF-B activity. To be able to compare the results between
patients, it was ensured that all sections visualized the entire axis
from the superficial epithelium to the muscularis mucosa.
Statistical analysis
Data are presented as mean ± SEM. Comparisons between groups of data were made using a one-way ANOVA followed by a Tukey post hoc test. p values < 0.05 were considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the expression of NF-B in situ in human tissue
and to assess the site and extent of activation of this transcription
factor, in response to colonization by a pathogenic bacterium, we
collected biopsies of 69 consecutive patients with upper abdominal
complaints (Table I
). Of these, 26
patients were H. pylori positive, 6 after an unsuccessful
attempt at eradication. Of the 43 H. pylori-negative
patients, 8 were recently successfully eradicated. The histological
grade of gastritis was scored according to the Sydney classification
(Table II).
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B in the H. pylori-negative
stomach
It is now clear that H. pylori activates the
transcription factor NF-B and that this event plays a central role
in the induction of the inflammatory reaction often associated with
colonization with this bacterium. However, the expression of NF-B in
the antral mucosa, the main site of colonization, has thus far not been
studied. To study the expression of different NF-B subunits in the
normal gastric mucosa, we examined their expression in histologically
normal gastric biopsy specimens (no activity and no chronicity of
inflammation as assessed by the Sidney classification (Table II
)) with
the use of immunohistochemical techniques. In the antrum of the normal
stomach (n = 26 patients), low but detectable
expression of the p65 NF-B subunit was found in the cytoplasm of the
superficial gastric pit cells (Fig. 1A). Deeper in the gastric
glands, however, many cells were found with a very high p65 content
(Fig. 1, A, B, and H). In some of these cells,
NF-B was detected not only in large amounts in the cytoplasm but
also in the nucleus, suggesting activation of NF-B in these cells in
the absence of overt signs of inflammation. The expression pattern of
the p50 subunit (n = 15 patients; not shown), and RelB
subunit (n = 15 patients; not shown) was similar to
that of the p65 protein. The expression of the p52 subunit
(n = 15 patients) was clearly different; it showed a
staining pattern reminiscent of the p65, p50, and RelB subunits in
gastric epithelial cells, but in addition and in contrast to the other
subunits a relatively high expression in clusters of inflammatory cells
(Fig. 1C). We concluded that NF-B subunits are highly
expressed in a specific subpopulation of cells in the uninflamed
stomach.
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B expression in the endocrine cell region
The immunohistochemical determination of NF-B protein
expression showed that high levels of NF-B subunits are expressed in
a subset of epithelial cells deeper in the gastric glands. The
morphology and localization of the NF-B-expressing cells suggested
that NF-B expression in the stomach corresponded to the endocrine
cell population. To investigate this, sections were double-stained with
a monoclonal anti-chromogranin A Ab, a marker for enteroendocrine
cells, and a polyclonal -NF-B p65 Ab. We observed that the
NF-B-expressing region in the stomach indeed corresponded to the
chromogranin A-positive cells and those cells immediately adjacent to
the chromogranin A-positive cells (n = 69 patients;
Fig. 1D). An almost complete correlation was observed in
double staining experiments in which sections were stained with a
polyclonal Ab against gastrin and an anti-NF-B p65 mAb
(n = 10 patients; Fig. 1, E and
F). Apparently, many of the highly NF-B-expressing cells
are G cells. These results were further confirmed by single staining
experiments of adjacent sections (not shown). We concluded that
expression of NF-B in the uninflamed stomach is associated with the
G cells.
Activity of NF-B in the uninflamed stomach
The nuclear localization of NF-B found staining with an Ab that
recognizes total p65 protein suggested that this transcription factor
may be active in the uninflamed mucosa. The possible activation of
NF-B was further investigated using an Ab directed against the
nuclear localization sequence of the p65 subunit (14, 18, 32). Because this epitope is exposed only after degradation of
the inhibitory protein I-B, this Ab recognizes activated p65. In
adjacent sections, this Ab (Fig. 1H) identified the same
cells that displayed nuclear localization of the protein when stained
with the polyclonal anti-total p65 Ab (Fig. 1, G and
H). For further proof of activation, we also examined
whether these cells showed expression of TRAF2, a transcriptional
target of NF-B (28). Staining for TRAF2 revealed high
expression of this protein in the same cells that contain activated
NF-B (n = 12 patients; Fig. 1, H and
I). Furthermore, double staining for activated p65 and
gastrin in the uninflamed, H. pylori-negative stomach
(n = 26 patients) revealed that activation of NF-B
occurs preferentially in the endocrine cell region of the stomach,
mostly in the G cells (Fig. 3, B, E, and F). We
concluded that the uninflamed stomach shows constitutive activation of
NF-B, in the same cells that maintain high NF-B expression, and
that these cells are mainly endocrine G cells.
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in the uninflamed mucosa
Because active NF-B was found predominantly in the G cells, we
were interested to see whether these cells would express the cytokine
TNF-, because the production of this cytokine is stimulated by
NF-B. Therefore, we stained for TNF- and gastrin in adjacent
sections (n = 20 patients; Fig. 2, A and B) and
double staining experiments (n = 10 patients; Fig. 2, C and D). As shown in Fig. 2, these stainings
showed that the G cells are the main site of production of TNF- in
the histologically uninflamed stomach. Thus, in accordance with the
observed activity of NF-B, G cells produce the proinflammatory
cytokine TNF-.
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B activation in the H. pylori-infected stomach
The activation of NF-B in the gastric mucosa in response to
colonization by a pathogenic bacterium was studied in patients with
H. pylori infection. To this end, a double stain of active
NF-B and gastrin was performed for all 69 patients studied. The
number of cells with activity of NF-B in the H.
pylori-colonized stomach was markedly enhanced, as compared with
uninflamed tissue (Fig. 3, A
and B). Whereas p65 NF-B was found in all cell types
(Fig. 3C), the active NF-B was mainly detected in the
epithelial cells. Remarkably, whereas some isolated inflammatory cells
scattered throughout the mucosa often also stained with the
anti-active p65 Ab, the large infiltrates of neutrophils did not
(Fig. 3D). Double staining of active NF-B and H.
pylori showed that many of the NF-B-positive cells were not in
direct contact with the bacteria (Fig. 3B). Active NF-B
was primarily detected in the cells deeper in the gastric glands, many
of them G cells (Fig. 3, E--H). Thus, we found
markedly enhanced activity of NF-B in H. pylori-infected
patients, predominantly in the epithelial cells deeper in the gastric
glands.
Active NF-B and the histopathological severity of
gastritis
Because NF-B seems to play a pivotal role in the
induction of inflammation in the gastric mucosa, we compared a measure
of the activity of this transcription factor with the severity of
gastritis scored according to the Sidney criteria. To obtain a
quantitative measure of NF-B activity in the stomach biopsies, the
active NF-B-positive cells were counted, blind to the
clinical diagnosis. As depicted in Fig. 4A, H. pylori
infection results in a marked increase in active NF-B-positive cells
(uninflamed (870 cells/mm2) vs inflamed (2430
cells/mm2); p << 0.01). Separate
analysis of the patients who received treatment (Fig. 4B)
revealed that in patients successful eradication of the bacterium
restored the mean active NF-B score to normal whereas in those
patients in whom treatment was unsuccessful this score remained high.
To investigate the relation of the number of active NF-B-positive
cells to the severity of gastritis, we examined a possible correlation
between the active NF-B score and the histopathological score based
on the Sydney classification system. The number of active
NF-B-positive cells correlated well with the activity of gastritis,
a measure of neutrophil influx (Fig. 5A). Interestingly, however,
no such correlation was found between the activity of NF-B and the
chronicity of inflammation, a score of the number of mononuclear
inflammatory cells (Fig. 5B). As shown in Fig. 5B, H. pylori-negative patients with chronic
gastritis (n = 17 patients, with moderate to severe
chronicity of gastritis (Table II)) did not show enhanced activation of
NF-B compared with patients without chronic gastritis
(n = 26). The significantly higher NF-B activity in
patients with severely chronic gastritis is most likely explained by
the fact that 9 of 10 of these patients have a marked to severe
activity of disease (see Table II). We concluded that activation of
NF-B correlates the activity of gastritis and thus with neutrophil
influx in the gastric mucosa in response to colonization with H.
pylori.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B
in the uninflamed and inflamed stomach. NF-B was differentially
expressed in the antrum of the human stomach. Although most cell types
expressed some NF-B, the G cells displayed particularly high levels
of this transcription factor. We found activity of p65 NF-B in the G
cells in the histologically uninflamed gastric mucosa. Activation was
judged by four different criteria: nuclear localization of
the protein; staining with an Ab against active NF-B; and
high expression of the NF-B target genes, TRAF2 and TNF-. The
activity was markedly enhanced activation in H.
pylori-infected patients in these cells.
NF-B is a key regulator of the innate immune response and its high
expression and activity in the G cells, which are not known to be
involved in the immune response, is a surprising finding. However, G
cells stimulate release of acid into the stomach via the production of
gastrin (19, 20), and therefore these cells may help
combat bacterial infection of the stomach by increasing their gastrin
secretion and subsequent bactericidal acidification of the stomach.
Indeed, the production of gastric acid provides an essential
nonimmunological first line of defense against colonization by
enteropathogenic bacteria (21). Exogenous bacteria are
usually rapidly destroyed at a pH up to 4.0, and impaired gastric acid
production caused by use of antacids, stomach resections, and
especially chronic autoimmune gastritis with parietal cell destruction
and pernicious anemia is associated with colonization of the stomach
and small intestine with fecal type bacteria and increased risk of
disease during cholera epidemics (21). The notion that G
cells are capable of reacting to bacterial infection is further
supported by the hypergastrinemia observed in H.
pylori-infected patients (22). Indeed, three reports
describe enhanced production of gastrin after exposure of isolated
antral G cells to live H. pylori or H. pylori
extracts (23, 24, 25). Thus, the expression and activity of
NF-B in the G cells may be a bona fide reflection of a role of these
cells in innate immunity.
In accordance, we show that these cells are the main site of production
of the NF-B-regulated cytokine TNF- (4) in the
uninflamed stomach. Addition of exogenous TNF- to isolated G cells
stimulates the production of gastrin in vitro (23, 25, 26, 27).
Our finding that G cells produce TNF- and respond to H.
pylori with enhanced NF-B activation may suggest that
colonization by this bacterium increases expression of TNF- in the G
cells through activation of NF-B and causes increased gastrin
production in an autocrine manner. Thus, the high levels of NF-B and
TNF- expression in the G cells may couple the innate immune response
to the production of bactericidal gastric acid.
Additionally, NF-B may play a specific role in the cell fate and/or
differentiation of these cells. Because NF-B plays an important role
in the protection of cells from apoptosis via stimulation of the
production of anti-apoptotic proteins (4, 28), such as
TRAF2 (28, 29), the activity of this transcription factor
is likely to play a role herein. Indeed, whereas the superficial
gastric epithelial cells undergo enhanced apoptosis in H.
pylori-infected patients, G cells may be protected from this
process by their high expression of NF-B, and increased G cell mass
has been reported in these patients (30, 31).
H. pylori infection greatly increased the number of cells
containing active NF-B, activation occurred predominantly in the
epithelial cells, and little activation was detected in neutrophils.
This is in agreement with findings by Rogler et al. (32)
in patients with inflammatory bowel disease, who showed that NF-B
was mainly activated in epithelial cells and macrophages. These authors
also demonstrated a correlation between the activity of NF-B and an
endoscopic score of inflammation. In our study, the increase in NF-B
activity correlated well with the activity of gastritis, a measure of
neutrophil influx, as scored according to the Sydney classification
system. Together, these studies support an important role for
epithelial NF-B activation in the production of neutrophil
chemoattractants like IL-8.
No correlation was found with the chronicity of inflammation, a measure
of the number of mononuclear inflammatory cells in the mucosa, given
that H. pylori-negative patients with chronic inflammation
did not have a higher NF-B activity score than those without. This
lack of correlation is further supported by our finding that the
NF-B activity score was restored to normal values in patients
recently treated successfully whereas it is well known that the chronic
component of gastritis may last for up to 1 year after successful
treatment.
Double staining for H. pylori and active p65 NF-B showed
that most of the epithelial cells exhibiting activation of NF-B were
not in direct contact with the bacteria. The activation occurred
preferentially deeper in the gastric glands, in the endocrine cell
region, where no H. pylori are found because the bacterium
resides in the superficial mucus layer. Therefore, NF-B activation
in the stomach does not seem to require direct contact with bacteria
and may thus be dependent on a secreted factor. Accordingly, H.
pylori virulence and induction of epithelial IL-8 expression are
strongly associated with a group of 31 bacterial genes, the
pathogenicity island (33, 34), which encodes a type
IV toxin secretion system (35).
In conclusion, our findings show that in the uninflamed antrum of the
stomach high NF-B expression and activity are associated with the G
cells, which produce TNF-, a well-documented stimulator of gastrin
release. This suggests an autocrine mechanism of gastrin production by
TNF- that may be enhanced on colonization by pathogenic bacteria.
Our data also show a strong correlation between epithelial NF-B
activation and neutrophil influx in H. pylori-associated
gastritis, a clear illustration of the importance of NF-B activation
in chemokine production.
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Acknowledgments |
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Footnotes |
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2 Abbreviation used in this paper: DAB, diaminobenzidine.
Received for publication October 12, 1999. Accepted for publication January 4, 2000.
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References |
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|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B, a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336:1066.B- NF-B structures: at the interface of inflammation control. Cell 95:729.[Medline]
B and Rel proteins: evolutionary conserved mediators of immune responses. Annu. Rev. Immunol. 16:225.[Medline]
B/Rel transcription factors.. 1998. J. Exp. Med. 187:143.B in immune and inflammatory responses in the gut. Gut 43:856.B. J. Immunol. 159:6140.[Abstract]
B in gastric epithelial cells. Gastroenterology 113:1099.[Medline]
B in gastric epithelial cells. J. Immunol. 160:2401., interleukin 1ß and interleukin-8 production in patients with Helicobacter pylori infection. Scand. J. Gastroenterol. 29:425.[Medline]
B by a monoclonal antibody. Biol. Chem. Hoppe-Seyler 376:9.[Medline]
increase gastrin release from human gastric antral fragments. Eur. J. Gastroenterol. Hepatol. 9:773.[Medline]
B antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:1680.B pathways. J. Exp. Med. 188:1381.B is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115:357.[Medline]
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