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CagA strains of H.pylori (Hp) are known to be associated with gastroduodenal diseases. Polymorphisms in inflammation related genes, such as cytokines and their receptors, were thought to partly determine the outcome of Hp infection and the progression of gastritis. It is supposed that interleukin 23 receptor (IL23R), a basic cytokine receptor in the inflammatory IL-17/IL-23 axis, may be related to gastritis. In the present study, we evaluated the association of IL23R +2199 rs10889677 polymorphism and cagA positivity with chronic gastritis. In addition, we studied the infiltration of polymorphonuclear (PMN) and mononuclear (MN) Leukocytes into surrounding tissues of corpus. Biopsies taken from the corpus of the patients were classified as two groups: Hp-infected and Hpuninfected. The severity of gastritis was graded from normal to severe, chronic gastritis and chronic active gastritis. Virulence factor, cagA, was evaluated using PCR and the polymorphism in IL23R was investigated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). AA and AC carriers of IL23R +2199 polymorphism, but not CC genotype in Hp-uninfected patients, were not associated with cellular infiltration and gastritis in both groups (p > 0.05). CagA positivity was significantly associated with increased risk of PMN (P= 0.013), but not with MN infiltration (P= 0.069). Also gastritis was found to be associated with cagA positivity (P= 0.044). Our results show decreased Hp infection probability in patients with CC genotype of 2199 +IL23R. According to the clinical and pathological features in Hp-infected group, IL23R polymorphism doesn't influence chronic gastritis and chronic active gastritis.
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Life Science Journal 2014;11(2s) http://www.lifesciencesite.com
40
Evaluation of H.pylori Infection and IL23R Gene Polymorphism in Dyspeptic Subjects
Farid Zandi1, Hedayatollah Shirzad2, Nader Bagheri3, Ghorbanali Rahimian4, Loghman Salimzadeh2, Fateme
Azadegan 5, Kambiz yousefzadeh Eshkevari5, Fateme Fatahi5, Abbas Ahmadi6, Alireza Gharib6, Sara Gholami7,
Behnam Zamanzad2 *
1Department of Microbiology and Immunology, Kurdistan University of Medical Sciences, Sanandaj, Iran
2Department of Microbiology and Immunology, Shahrekord University of Medical Sciences, Shahrekord, Iran
3Department of Microbiology and Immunology, Tehran University of Medical Sciences, Tehran, Iran
4Department of Internal Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
5Cellular & Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
6Deputy of Research and Technology, Kurdistan University of Medical Sciences, Sanandaj, Iran
7Department of medical genetics, Mashhad University of Medical Sciences, Mashhad, Iran
* Corresponding Author: Behnamzamanzad5@gmail.com
Abstract: CagA strains of H.pylori (Hp) are known to be associated with gastroduodenal diseases. Polymorphisms
in inflammation related genes, such as cytokines and their receptors, were thought to partly determine the outcome
of Hp infection and the progression of gastritis. It is supposed that interleukin 23 receptor (IL23R), a basic cytokine
receptor in the inflammatory IL-17/IL-23 axis, may be related to gastritis. In the present study, we evaluated the
association of IL23R +2199 rs10889677 polymorphism and cagA positivity with chronic gastritis. In addition, we
studied the infiltration of polymorphonuclear (PMN) and mononuclear (MN) Leukocytes into surrounding tissues of
corpus. Biopsies taken from the corpus of the patients were classified as two groups: Hp-infected and Hp-
uninfected. The severity of gastritis was graded from normal to severe, chronic gastritis and chronic active gastritis.
Virulence factor, cagA, was evaluated using PCR and the polymorphism in IL23R was investigated by polymerase
chain reaction-restriction fragment length polymorphism (PCR-RFLP). AA and AC carriers of IL23R +2199
polymorphism, but not CC genotype in Hp-uninfected patients, were not associated with cellular infiltration and
gastritis in both groups (p > 0.05). CagA positivity was significantly associated with increased risk of PMN (P=
0.013), but not with MN infiltration (P= 0.069). Also gastritis was found to be associated with cagA positivity (P=
0.044). Our results show decreased Hp infection probability in patients with CC genotype of 2199 +IL23R.
According to the clinical and pathological features in Hp-infected group, IL23R polymorphism doesn't influence
chronic gastritis and chronic active gastritis.
[Farid Zandi, Hedayatollah Shirzad, Nader Bagheri, Ghorbanali Rahimian, Loghman Salimzadeh, Fateme
Azadegan, Kambiz yousefzadeh Eshkevari, Fateme Fatahi, Abbas Ahmadi, Alireza Gharib, Sara Gholami, Behnam
Zamanzad. Evaluation of H. pylori Infection and IL23R Gene Polymorphism in Dyspeptic Subjects. Life Sci J
2014;11(2s):40-46]. (ISSN:1097-8135). http://www.lifesciencesite.com. 9
Keywords: IL23R, polymorphism, Helicobacter pylori, gastritis
Introduction
Hp is a spiral-shaped Gram negative flagellate
bacterium that colonizes the gastric mucosa of
approximately 50 % of the world's population (1, 2).
Hp infection induces inflammation in gastric mucosa
that involved in chronic gastritis (3, 4). Hp-associated
inflammatory response is defined by an immense
mucosal infiltration of macrophages, PMNs, T cells,
and plasma cells (5, 6).Gastritis may progress to
other steps Such as, gastric atrophy, intestinal
metaplasia, and gastric cancer (7-9). It may also lead
to precancerous lesions looking like monoclonal
lymphocytic proliferation, lymphoid follicle (LF)
development and later primary gastric lymphoma
(PGL) which develop only in a portion of individual
with gastritis because of multifactorial effects of host
virulence and bacterial factors that vary among
different racial and social groups (10). Among
bacterial factors, studies in developed countries
mention that cagA-Positive strains of Hp are more
often associated to gastroduodenal diseases than
cagA-negative strains (11-14); however this has not
been proven in developing countries with a high
widespread of Hp infection. Among host factors
several inflammatory proteins including cytokines,
growth factors, and chemokines have been known to
control adaptive immune response in contrast to Hp
infection (15, 16). Firstly, El-Omar was reported an
association between gastric cancer risk and
interleukin 1 gene cluster polymorphisms (17).
Studies from the western world show roles of anti-
and pro- inflammatory cytokine genes such as
Interleukin-1 beta (IL-1β), Interleukin 1 receptor
antagonist (IL-1RN), Interleukin-10 (IL-10), and
tumor necrosis factor alpha (TNF-α) gene
polymorphisms affect risk in gastritis (18) and
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41
precursors (17, 19). However Asian studies did not
find any such association (20-22). IL-23 is a
heterodimeric cytokine composed of the p40 and p19
in which p40 is the common subunit shared with
Interleukin-12 (IL-12) and p19 is the special subunit
with a higher affinity to IL-23R (23).The locus of
IL23R gene is on chromosome 1p31 and encodes a
subunit of the IL-23 R. The heterodimeric IL-23R
compound composed of IL-23R subunit associate
with the IL-12Rβ1 subunit shared with the IL-12R
complex. One of the most studied polymorphism in
IL23R gene is R381Q (rs11209026) is located in the
coding sequence of the IL23R and interchange
arginine to glutamine in codon 381 (24). Recently, an
inflammation pathway of IL-23/IL-17 axis reported
to play fundamental role in inflammatory and
autoimmune diseases(25), such as psoriasis (26),
lupus nephritis(27), and intestinal inflammation (28).
The new delineated pathway IL-23/IL-17 has proved
to be included in the etiology of several chronic
inflammatory diseases such as inflammatory bowel
disease (IBD) (29), and ankylosing spondylitis. In
addition, there is high level experssion of IL-23 in
Hp-infected gastric mucosa (30). IL-23R, as the key
component to IL-23R, was shown to play an
influential role in the launching, supporting and
accelerating of IL-23/IL-17 inflammatory signal
transduction pathway (30). In 2006, Duerr et al.
indicated a strong relation between Crohn’s disease
and polymorphisms of the IL23R gene (29). Different
genotypes of IL23R gene have been evaluated for
association with chronic inflammatory disorders (31).
From then, IL23R gene was shown to be an
influential gene in many other
autoimmune/inflammatory diseases. Among the
recognized polymorphisms of IL23R, the functional
SNP of +2199A/C (rs10889677) located in the 3´-
untranslated region (UTR) has been repeatedly
shown to be related to different
autoimmune/inflammatory diseases. However, the
results are in debate in different diseases. In a study
from Hungary, the AA genotype of rs10889677
reported as a risk factor for rheumatoid arthritis (32)
However, researchers concluded A allele has a
protective role for ankylosing spondylitis (33).
Contradictory, some studies indicated that wild type
C allele increases the risk to Graves’ ophthalmopathy
(34) and idiopathic dilated cardiomayopathy (35).
Unfortunately, there is no study on this issue from
Iran. In the present study we therefore aimed to
evaluate an association of IL23R +2199A/C
polymorphism with gastritis, using a case-control
approach. We also evaluated the association of cagA
positivity, IL23R +2199A/C polymorphism, and their
interactions with cellular infiltrations and
precancerous stages using a case-only approach in a
population from central area of Iran.
Material and Methods
A total of 435 patients with nonulcer dyspepsia
(NUD) who were undergoing upper gastrointestinal
endoscopy were tested for Hp infection using in-
house RUT. Hp infected and uninfected patients were
determined by the rapid urease test, PCR 16srRNA,
urea and histological examination of biopsies taken
from the corpus. Patients were classified as Hp-
infected only if the three tests were positive and Hp-
uninfected if the three tests were negative,
respectively. Demographic and clinical data were
obtained through interview using a standard clinical
pro forma. Exclusion criteria included history of
gastric neoplasm or surgery, liver disease, and
previous treatment with non-steroidal anti-
inflammatory drugs, proton pump inhibitors,
antibiotics, or bismuth salts. Informed consents for
participation were signed by all the study subjects.
The study protocol was approved by the Clinical
Research Ethics Committee of the Shahrekord
University of Medical Sciences.
Histological examination
Sections of biopsy specimens were embedded
10 % buffered formalin and stained with
Hematoxylin and Eosin to examine gastritis and with
Giemsa to detect Hp. The histological severity of
gastritis was blindly graded from normal to severe
based on the grade of PMN and MN infiltration,
chronic gastritis and chronic active gastritis
according to the Updated Sydney System (36) on a
four-point scale: 0, no; 1, mild; 2, moderate; and 3,
severe changes.
DNA isolation
Genomic DNA was extracted from biopsies
taken from the corpus using Biospin Tissue Genomic
DNA Extraction Kit (Bio Flux, Japan). All extracted
DNA was resuspended in UltraPure RNAse/DNAse-
Free Distilled water.
Genotyping for IL23R +2199A/C (rs10889677)
polymorphism
Genotyping analysis IL23R genotyping was
performed by PCR-RFLP as reported by Chen et al
(24). Primer sequences for +2199A/C variation of
IL23R gene are as follows: sense -
AGGGGATTGCTGGGCCATAT-3´, anti-sense 5´-
TGTGCCTGTATGTGTGACCA-3´. The PCR
amplification was performed in a total volume of 25
uL mixture containing: 100 ng genomic DNA, 1.0
mM of each primer, 200 mM of each dNTP, 2.0 mM
of MgCl2 and 1.0 U Taq DNA polymerase and 10 X
Taq buffer (Fermentas) using the Biometra Tgradient
96 (Biometra, Germany). PCR conditions were as
follows: denaturation at 95 °C for 5 min, followed by
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38 cycles of 95 °C for 30 s, 60 °C for 45 s, and 72 °C
for 60 s. A final extension was carried out at 72 °C
for 10 min and cooling down to 4 °C. The PCR
products were digested by restriction endonuclease
MnLI (Fermentas), according to the manufacturer’s
instructions, at 37°C overnight and then separated by
10% polyacrylamide gel electrophoresis. Gel analysis
was performed after staining with ethidium bromide.
PCR products were shown to be digested into three
types of fragments (Fig. 1). To confirm the
genotyping results, selected PCR samples in both
groups including samples of each genotype were re-
genotyped by other laboratory personnel. There was
no difference after re-genotyped the randomly
selected samples.
Fig 1: PCR-RFLP polyacrylamide gel electrophoresis
of the IL23R +2199A/C (rs10889677) polymorphism
indicating the No.1 (CC = 154, 61 bp), 2,3,4,5 (AC =
215, 154, 61 bp), 6,7( AA= 215 bp) genotypes.
Determination of cagA ( +/- ) in Hp-infected
subjects
Amplification for cagA was performed by
polymerase chain reaction as reported by Bagheri et
al (1).Primer sequences for cagA gene are as follows:
sense ATGACTAACGAAACTATTGATC-3´,
anti-sense 5´ CAGGATTTTTGATCGCTTTATT-3´.
For cagA evaluation, the PCR program comprised 35
cycles of denaturation (at 94 °C for 30 s), annealing
(at 56 °C for 30 s, extension at 72 °C for 30 s), and
one final extension (at 72 °C for 5 min).
Statistical analysis
Data were analyzed using SPSS 16.0 (SPSS
Inc., Chicago, IL). Hardy–Weinberg equilibrium in
all subjects was analyzed with the x2 goodness-of-fit
test before the ensuing analyses. The confounding
effects of age and gender were adjusted using
conditional logistic regression. Logistic regression
analyses were used to calculate odds ratios (ORs) and
95% confidence intervals (CIs) for gastritis in
association with genotypes. Also Statistical analysis
was performed by Mann-Whitney Rank Sum test or
non paired t test depending on the data set. Values of
p <0.05 were considered as significant.
Results
Demographic and clinical characteristics
Genomic DNA was obtained among the193
(44.4%) Hp-infected and 242(55.6%) Hp-uninfected
gastritits then the DNA all subjects were genotyped.
The demographic data of all subjects were
demonstrated in Table 1. There was no significant
difference between the two groups with respect to the
age and gender distribution (p > 0.05)
Table 1: Demographic data of study subjects.
Variable Hp-infected
(%)
Hp-
Uninfected
(%)
P
value
Overall
193(44.4%) 242(55.6%)
Gender
Male
Female
78(41.9%)
115(46.2%)
108(58.1%)
134(53.8%) 0.377
Age
Mean±SD
(year)
47.24 ±17.28 48.29 ±19.49 0.556
IL23R +2199CC genotype and Hp infection
susceptibility
The frequencies of the polymorphism in cases
and controls are shown in Table 2. Frequencies of
IL23R +2199 genotypes in Hp-infected (CC, 16.8%;
CA, 37.4% and AA, 45.8%) were different from
those in Hp-uninfected (CC, 24.8%; CA, 29.2% and
AA, 46.0%). Compared with AA genotype and CA
genotype, the CC genotype significantly decreased
Hp infection risk with ORs of 1.634 (95% CI: 0.985-
2.710).
IL23R +2199A/C polymorphisms and gastritis
In our study population, IL23R +2199A/C
(rs10889677) variants (AA, AC, CC) evaluated in
Hp-infected and Hp-uninfected population (p > 0.05).
Carriers of IL23R +2199A/C were not associated
with chronic active gastritis and chronic gastritis in
both groups. Also allele C (AC/CC) was not
associated with risk for gastritis development in both
group (Table 3 and 4).
IL23R +2199A/C polymorphisms and cellular
infiltration
IL23R+2199A/C genotypes evaluated with
grade of mononuclear and polymorphonuclear
infiltration on Hp-infected and Hp-uninfected groups.
The results are compared in Table 5 and Table 6.
There was no significant association in both groups
(p > 0.05).
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Table 2. Adjusted Odds Ratios (ORs) and 95% confidence intervals (CIs) for Hp-infected in relation to IL23R
+2199 genotypes
Genotype
Hp
-
infected (%)
Hp
-
P
value
OR
#
(95% CI)
IL23R +2199
AA
82(45.8%)
93(46.0%)
0.523
1.009(0.674
-
1.511)
AC
67(37.4%)
59(29.2%)
0.056
0.690(0.449
-
1.059)
CC
30(16.8%)
50(24.8%)
0.037
1.634(0.985
-
2.710)
# Adjusted for age and gender
Table 3: Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for gastritis in relation to IL23R +2199 genotypes
in Hp-infected subjects
IL23R +I2199 Hp-infected (%) Chronic active Gastritis(%) Chronic Gastritis(%)
P
value
OR
#
(95% CI)
AA 61(48.8%) 28(42.4%) 33(55.9%) 0.131 0.581(0.286-1.179)
AC 43(34.4%) 25(37.9%) 18(30.5%) 0.387 1.389(0.660-2.925)
CC 21(16.8%) 13(19.7%) 8(13.6%) 0.360 1.564(0.598-4.088)
AC/CC** 64(51.2%) 38(57.6%) 26(44.1%) 0.131 1.723(0.848-3.500)
# Adjusted for age and gender.
**C allele, common between homozygote (CC) and heterozygote (AC) situation of IL23R +I2199 polymorphism
Table 4:Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for gastritis in relation to IL23R +2199 genotypes
in Hp-uninfected subjects
L23R +I2199 Hp-Uninfected (%) Chronic active Gastritis(%) Chronic Gastritis(%)
P
value OR
#
(95% CI)
AA 28(40.6%) 10(50.0%) 18(36.7%) 0.309 1.722(0.602-4.929)
AC 24(34.8%) 6(30.0%) 18(36.7%) 0.594 0.738(0.241-2.260)
CC 17(24.6%) 4(20.0%) 13(26.5%) 0.571 0.692(0.195-2.455)
AC/CC** 41(59.4%) 10(50.0%) 31(63.3%) 0.309 0.581(0.203-1.662)
# Adjusted for age and gender.
**C allele, common between homozygote (CC) and heterozygote (AC) situation of IL23R +I2199 polymorphism
Table 5: Association of IL23R +2199 genotypes with
cellular infiltrations in Hp-infected subjects
Genotype No. Mononuclear
infiltration*
Polymorphonuclear
infiltration*
IL-23R
AA
AC
CC
66
46
22
1.33 ±0.664(0-3)
1.38 ±0.733(0-3)
1.32 ±0.646 (0-
3)
0.47 ±0.561(0-3)
0.57 ±0.544(0-3)
0.55 ±0.510 (0-3)
P
value 0.949 0.556
*The histopathological parameters were scored as: 0,
none; 1, mild; 2, moderate; 3, severe
HP cagA positivity, cellular infiltration and
gastritis
CagA positivity was comparable among Hp-
infected subjects with PMN and MN infiltration
(Table 7). Patients with PMN infiltration were
associated with cagA positivity than were those with
cagA negativity (p=0.013). However, MN infiltration
was not associated with cagA positivity among Hp-
infected subjects (p=0.069). Gastritis was significantly
higher in patients with cagA-positive compared to
those observed in cagA-negative patients (Table 8),
then cagA positivity imparted risk for gastritis (p =
0.044, OR = 2.128, 95% CI = 1.014–4.470).
Table 6:Association of IL23R +2199 genotypes with
cellular infiltrations in Hp-uninfected subjects
Genotype No. Mononuclearin
filtration*
Polymorphonuclear
infiltration*
IL-23R
AA
AC
CC
40
26
22
1.02 ±0.832 (0-
3)
1.27 ±0.667 (0-
3)
1.18 ±0.853 (0-
3)
0.28 ±0.506 (0-3)
0.23 ±0.430 (0-3)
0.23 ±0.528 (0-3)
P
value 0.388 0.858
*The histopathological parameters were scored as: 0,
none; 1, mild; 2, moderate; 3, severe
Table 7:Association of cagA (+/- ) with cellular
infiltration in Hp-infected subjects
Genotype No Mononuclear
infiltration*
Polymorphonuclear
infiltration*
cagA (+)
96
1.43 ± 0.645 (0-3)
0.60 ± 0.535 (0-3)
cagA (-)
51
1.22 ±0.757 (0-3)
0.37 ±0.528 (0-3)
P value
0.069
0.013
*The histopathological parameters were scored as: 0,
none; 1, mild; 2, moderate; 3, severe
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Table 8: Association of cagA ( +/-) with gastritis in
Hp-infected subjects
Genotype No. (%) Chronic active
Gastritis(%)
Chronic
Gastritis(%)
cagA (+) 93(68.9%) 55 (76.4%) 38 (60.3%)
cagA (-) 42(31.1%) 17 (23.6%) 25 (39.7%)
P
value 0.044
OR
#
(95%
CI) 2.128 (1.014-
4.470)
# Adjusted for age and gender.
Discussion
In the present study we found that frequencies of
IL23R+2199A/C genotypes and alleles, except for
genotype CC, were not comparable in infected
patients and uninfected Hp subjects. IL23R+2199CC
genotype decreases susceptibility to Hp that may
indicate Hp infection is associated with pathway of
IL-23/IL-17 axis. Also, we found that variants of
IL23R gene, IL23R +2199 CA, IL23R +2199 AA,
IL23R +2199 CC, were not associated with gastritis in
Hp-uninfected and Hp-infected patients. These
findings suggest that IL23R polymorphisms may
independent of the presence or absence of Hp has no
effect on chronic active gastritis and chronic gastritis.
Whereas, one study suggest IL23R +2199CC,
genotype significantly decreased gastric cancer risk
and some of IL23R+2199A/C genotypes associated
with increased risk of certain subtypes of gastric
cancer, but not with all of them (24). This may
indicate that the effect of IL23R polymorphism on
inflammatory processes varied with inflammatory
Steps. This result is consistent with the different
mechanisms of inflammation so that in precancerous
and gastritis stages some of cytokines are dominant
and have specific role in start of inflammation process
but as stage Progress, another cytokines participate,
therefore, we observe many cytokines affection in the
latter stages. As there is no enough biological report
that revealed the function of IL23R +2199
polymorphism, especially in precancerous, it is
difficult to fully elucidate this phenomenon about our
study. IL23R+2199A/C allele carrier genotypes were
not found to be associated with neutrophil and
lymphocyte infiltration in HP-infected and HP-
uninfected which is consistent with the above. Our
results may corroborate those of Horvath et al (37).,
who studies indicate that IL-23 makes a contribution
to both Th1 and Th17 responses during Hp infection
especially during the chronic stage of infection (37).
We suggest that may be an induced inflammatory
response by Hp that caused by Th1 but not with Th17,
So IL23R polymorphisms does not affect the
inflammatory response in our study. Another study
suggests the presence of CagA contributes to
regulation of cytokine production in DCsco-cultured
with Hp in the mouse model of infection, this data
suggests that IL-23 makes a minor contribution to the
development of chronic gastritis in this model of Hp
infection (37). Contradictory, a study from Iran
reported a higher levels of IL-23 in Hp-infected
patients (including DU and AS groups) than in the Hp
negative control group (38). Also studies revealed that
the inflamed gastric mucosa of Hp-positive patients
could secrete IL-23 (39). However another study
reported no significant difference in mucosal IL-17
and IL-23 mRNA expression between Hp-infected and
uninfected patients (1) that accordance with our study.
Gastric mucosa of patients with both duodenal and
gastric ulcers was equally potent for secretion of IL-23
compared with patients with chronic active gastritis
with no signs of peptic ulcer disease. The release of
IL-23 was greater by Hp-infected gastric mucosa than
by gastric mucosa not infected by Hp mainly for
patients with chronic gastritis and only after
stimulation with LPS. Similar findings have been
published elsewhere (30, 40). Nevertheless, LPS of
Hp has also been described to behave in a different
manner (41). CagA positivity was more frequently
associated with neutrophil infiltration but we don’t
found association between cagA positivity and
lymphocyte infiltration. Also cagA positivity
correlated with gastritis that shows cagA virulence
factor may have initiated role in precancerous stages
especially in chronic active gastritis and chronic
gastritis. The results of one study also showed that the
serum levels of IL-23 were not influenced by the cagA
status of Hp. These results indicate that bacterial
factors other than cagA may act as inducers of IL-23
(38).
In this study in particular, we have demonstrated
that polymorphism of IL 23R doesn’t play a role in
control of Hp-induced gastritis. Whether IL23R is an
independent mediator in the pathogenesis of gastritis
or not cannot be excluded with safety from the
presented findings. Further investigation is necessary
to elucidate fully the exact role of IL23R in the
pathogenesis of gastritis. Our results highlight the
importance of cagA virulence factors in explaining
differential outcomes after infection with Hp.
However, the importance of host genetic factors rather
than Hp virulence in explaining variations in
outcomes after infection in different Asian countries
has been reported (42).
Acknowledgements
We thank the Cellular & Molecular Research
Center, Shahrekord University of Medical Sciences.
Corresponding Author Address:
Dr Behnam Zamanzad, MD, PhD, Departement of
Microbiology and Immunology, Shahrekord
Life Science Journal 2014;11(2s) http://www.lifesciencesite.com
45
University of Medical Sciences, Shahrekord, Iran.
Fax: +98-381-333491,
E-mail: Behnamzamanzad5@gmail.com
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1/16/2014
... T helper 17 cells (Th17) are IL-17 producing Th cells 11,12 . Recent studies revealed an inflammatory pathway of IL-23/IL-17 axis play the pivotal role in inflammatory and autoimmune diseases such as long-lasting autoimmune disease, inflammation of the kidney and intestinal inflammation 13 . The IL-23 is responsible for stimulating of Th17 in this inflammatory pathway 13 . ...
... Recent studies revealed an inflammatory pathway of IL-23/IL-17 axis play the pivotal role in inflammatory and autoimmune diseases such as long-lasting autoimmune disease, inflammation of the kidney and intestinal inflammation 13 . The IL-23 is responsible for stimulating of Th17 in this inflammatory pathway 13 . ...
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OBJECTIVES: %Helicobacter pylori is an identified carcinogen for gastric cancer, however, the underlying mechanisms remain to be defined. In this review, we sought to elucidate the role of apoptosis in gastric carcinogenesis, to determine the influence of H. pylori infection on apoptosis, and finally to provide insights into the mechanisms by which H. pylori may lead to gastric carcinogenesis.METHODS:A broad-based MEDLINE and Current Contents literature search was performed to identify relevant publications between 1966 and March 2000 addressing H. pylori infection, apoptosis, cell proliferation, gastric carcinoma, oncogenes, and tumor suppressor genes, as well as the products of these genes. Abstracts from recent major conferences that provided adequate additional data were also included.RESULTS:Apoptotic cells are rare in the glandular neck region (the generative cell zone) of normal gastric mucosa. With progression of atrophic gastritis, the generative cell zone shifts downward and a relatively large number of apoptotic cells occur. In intestinalized glands, both apoptotic cells and proliferative cells are present in deeper portions of the glands, corresponding to the generative zone. A higher frequency of apoptosis has been observed in gastric dysplasia than in coexisting gastric carcinomas, whereas the number of proliferative cells is significantly higher in gastric carcinoma than in dysplasia. Upregulation of oncogene bcl-2 in premalignant lesions and “downregulation” of the gene after malignant change is probably a common event. Accumulation of p53 protein is first detected in dysplasia, although mutation of the p53 gene may occur in intestinal metaplasia. H. pylori infection induces apoptosis in gastric epithelial cells, which returns to normal after eradication of the infection. Numerous molecules produced by H. pylori including cytotoxin (VacA), lipopolysaccharide, monochloramine, and nitric oxide may directly induce apoptosis. Moreover, H. pylori–stimulated host inflammatory/immune responses lead to release of a large amount of cytokines. Cytokines produced by type 1 T helper cells, such as TNF-α and IFN-γ, markedly potentiate apoptosis. Gastric cell proliferation is significantly higher in patients with H. pylori infection than in normal controls, and eradication of the infection leads to a reduction in cell proliferation. Apoptosis and cell proliferation are also increased in precancerous lesions such as gastric atrophy, intestinal metaplasia, and dysplasia in the presence of H. pylori infection. However, H. pylori–induced apoptosis may no longer be cell cycle–dependent in these lesions because of the occurrence of alterations and mutations of apoptosis-regulating genes, resulting in a loss of balance between apoptosis and cell proliferation.CONCLUSIONS:It is hypothesized that H. pylori–induced apoptosis may play a key role in gastric carcinogenesis by increasing cell proliferation and/or resulting in gastric atrophy.