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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2011  |  Volume : 54  |  Issue : 1  |  Page : 103-106
Proinflammatory cytokines and thrombomodulin in patients with peptic ulcer disease and gastric cancer, infected with Helicobacter pylori


1 Department of Pathology and Gastroenterology, Research Center for Gastroenterology and Liver Disease, Shaheed Beheshti University, M.C., Tehran, Iran
2 Department of Pathology, Iran University of Medical Sciences, Tehran, Iran

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Date of Web Publication7-Mar-2011
 

   Abstract 

Backgrounds: Helicobacter pylori infect more than half of the global population. It is suggested to be related with gastritis, peptic ulcer disease (PUD), and gastric cancer. Aims: The aim of this present study was to evaluate proinflammatory cytokines including interleukin 1, 6, 8, 10, and thrombomodulin in H. pylori-infected patients with PUD and gastric cancer. Patients: This cross-sectional study was conducted in Taleghani Hospital on 111 patients with H. pylori infection. Materials and Methods: Patients were divided into three groups of PUD, cancer, and control (normal on endoscopy), according to the results of endoscopy. The serum levels of interleukins 1, 6, 8, and 10 and thrombomodulin was determined using enzyme-linked immunosorbent assay (ELISA) technique. H. pylori infection was diagnosed by histological examination of the endoscopic biopsy. Results: One hundred eleven patients were included in the study; 30 as PUD group, 30 as gastric cancer group, and 51 as controls. There was no significant difference between the means of IL-1 and IL-10 levels among the three groups (P = 0.744 and 0.383, respectively). IL-6, IL-8, and thrombomodulin levels were found to be statically different among the three groups (P < 0.05). The level of IL-6, IL-8, and thrombomodulin in cancer group was significantly higher than PUD and control groups (P < 0.05). Conclusion: There is a significant association between H. pylori infection and serum IL-6, IL-8, and thrombomodulin but such relation is not present between H. pylori and IL-1 and IL-10. Immunity response (IL-6, IL-8 and thrombomodulin) is more severe in cancer patient than PUD.

Keywords: Cytokine, Helicobacter pylori, interleukin, peptic ulcer disease

How to cite this article:
Haghazali M, Molaei M, Mashayekhi R, Zojaji H, Pourhoseingholi MA, Shooshtarizadeh T, Mirsattari D, Zali MR. Proinflammatory cytokines and thrombomodulin in patients with peptic ulcer disease and gastric cancer, infected with Helicobacter pylori. Indian J Pathol Microbiol 2011;54:103-6

How to cite this URL:
Haghazali M, Molaei M, Mashayekhi R, Zojaji H, Pourhoseingholi MA, Shooshtarizadeh T, Mirsattari D, Zali MR. Proinflammatory cytokines and thrombomodulin in patients with peptic ulcer disease and gastric cancer, infected with Helicobacter pylori. Indian J Pathol Microbiol [serial online] 2011 [cited 2019 Dec 10];54:103-6. Available from: http://www.ijpmonline.org/text.asp?2011/54/1/103/77343



   Introduction Top


Helicobacter pylori is a gram-negative bacterium that persistently colonizes more than half of the global human population. [1],[2] It is probably the most prevalent human pathogen worldwide. [3] Since H. pylori was initially suggested in 1983 by Marshall and Warren to be implicated in gastritis and peptic ulcer disease. [4] H. pylori has also been found associated with gastric carcinoma and was classified as a class I carcinogen. [5] Most H. pylori infections are acquired early in life and may persist for the life of the individual. [6] While infected individuals mount an inflammatory response that becomes chronic, along with a detectable adaptive immune response, these responses are ineffective in clearing the infection. [7] H. pylori has unique features that allow it to reside within the harsh conditions of the gastric environment, and also to evade the host immune response. [1] In order to successfully colonize the human stomach, H. pylori must initially overcome multiple innate host defenses. Remarkably, H. pylori can persistently colonize the stomach for decades or an entire lifetime despite development of an acquired immune response. [1]

Recent evidence suggests that persistence of infection is achieved through initial interactions between H. pylori adhesions and cellular receptors, after which H. pylori must avoid clearance by immune system. This is accomplished by avoiding host recognition, by producing specific bacterial factors that stimulate selective expression of host genes, and by inducing an ineffective T-cell response. [8] Understanding the mechanisms of colonization, persistence and virulence factors of the bacterium as well as the innate and adaptive immune responses of the host are critically important for the development of new strategies to prevent the development of H. pylori-induced gastroduodenal diseases. [9]

The IgG subclass response is determined by the type of bacteria producing the infection as well as genetic factors of the host. Patients with a H. pylori infection develop a specific immune response that is mainly of the IgA and IgG subclasses. [10]

Endothelial membrane bound thrombomodulin is a high-affinity receptor for thrombin to inhibit coagulation. Thrombomodulin has an important function in thrombosis, inflammation, and atherosclerosis. [11] The role of thrombomodulin is also searched in association with different diseases such as unstable angina and gastric disorders specifically when there is an infection with H. pylori.[12],[13]

Our literature review showed that some cytokines, especially IL-7 and IL-8, play some roles in H. pylori-associated gastritis. [14] There is also a connection between H. pylori-associated gastritis and other interleukins including IL-1 and IL-10. [15],[16] Recombinant attenuated  Salmonella More Details typhimurium DNA vaccine expressing UreB protein and IL-2 protein with immunogenicity can be constructed, which can protect mice against H. pylori infection, which may help the development of a human-use H. pylori DNA vaccine. [17] Another study believes that macrophages may be a major source of IL-6 in the gastric mucosa upon H. pylori infection. [18] Host factors including intracellular pathogen receptors and IL-8 production play an important role in H. pylori-induced gastric mucosal damage. [19]

However, there are controversies about the increasing cytokines levels in H. pylori-positive patients compared to H. pylori-negative subjects. Therefore, we designed the present study to evaluate the host immunologic response in patients with dyspepsia, peptic ulcer disease (PUD), and gastric cancer.


   Materials and Methods Top


An analytic cross-sectional study evaluating the host immunologic response in patients with dyspepsia, PUD, and gastric cancer, infected with H. Pylori, was designed. Subjects were selected randomly from the patients referred to Taleghani hospital of Tehran for upper gastrointestinal (GI) endoscopy between September 2006 and December2007. They were divided into three groups of PUD, cancer, and control, according to the results of endoscopic evaluation. A blood sample was obtained from each individual to determine the serum levels of interleukins 1, 6, 8, and 10 and thrombomodulin, using enzyme-linked immunosorbent assay (ELIZA) technique. Normal ranges of these items are listed in [Table 1]. H. pylori infection was diagnosed according to the histological study of endoscopic specimen.
Table 1: Normal ranges of immunologic factors

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Descriptive statistical indices such as frequency, mean, median, mode, standard deviation, and standard error were calculated. One way analysis of variance (ANOVA) was used in combination with post-hoc tests Bonferroni and LSD, to analyze the data. A difference with P < 0.05 was interpreted as statistically significant.


   Results Top


We included 111 patients in our study; 30 as PUD group, 30 as gastric cancer group, and 51 as controls. [Table 2] lists the demographic features of the participants in each arm of the study.
Table 2: Demographic characteristics of subjects in each arm of the study

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There was no significant difference between the means of IL-1 and IL-10 levels among the three groups of the study (P = 0.744 and 0.383, respectively). IL-6 levels were found to be statically different among the three groups (P = 0.001). Post-hoc analysis indicated that IL-6 level was higher in cancer group compared with control group (P < 0.001, mean difference = 14.80) and PUD group (P = 0.002, mean difference = 15.00). Similarly, IL-8 levels were statistically dissimilar in the three arms of the study (P = 0.008), which could be attributed to the higher levels of this marker in cancer group weighed against control group (P = 0.007, mean difference = 80.53) and PUD group (P = 0.005, mean difference = 95.81).

The three groups showed statistically different values of thrombomodulin (P < 0.001); this marker was present in higher levels in cancer group compared with control group (P < 0.001, mean difference = 3.57) and PUD group (P = 0.003, mean difference = 2.74).


   Discussion Top


Immunoglobulins have been shown to be a diagnostic value in gastric diseases. In a study performed on 83 symptomatic patients undergoing endoscopic examination, H. pylori-specific IgG, IgG1, IgG2, IgG3, and IgG4 subclasses were measured using ELISA technique. The results of histological examination and IgG serology showed significantly higher levels of IgG2 antibodies found in patients with duodenal ulcer as compared with patients with functional dyspepsia (P < 0.01). The results of this study suggest that the IgG subclass response in subjects infected with H. pylori may be a marker of DU disease as well as increased levels of inflammation. [20] In another study, specific serum IgG subclass antibodies against H. pylori antigens and recombinant CagA were analyzed in 75 symptomatic children with histologically confirmed H. pylori infection. Total CagA IgG titers were higher in children with active and more severe chronic antral inflammation. [21]

However, the diagnostic value of other immunologic markers in gastric disease is not as clear as for immunoglobulins. A previous study used real-time polymerase chain reaction (RT-PCR) technique to measure the expression levels of different interleukins in patients with H. pylori-positive peptic ulcer disease. [22] The interleukin levels after ulcer healing in H. pylori-positive patients were not significantly different from the levels at the time of ulcer diagnosis. After eradication of H. pylori, a significant and persisting increase in IL-4 level was observed while IL-10 expression was markedly reduced. In another study, Obonyo et al.[23] assessed the role of H. pylori infection in the expression of IL-10 and IL-12 in vitro. They found out that level of IL-12 was inversely correlated with an increase in the number of H. pylori organisms and IL-10 levels were significantly increased (P < 0.01) at the higher multiplicity of infection, indicating the cells were viable. [10] In our study, we did not detect any significant difference in IL-10 serum level between ulcer group and control group (P > 0.05).

A previous study on 61 subjects with dyspepsia showed that H. pylori infection was associated with lower levels of thrombomodulin in the antrum mucosa. [24] In our study, we showed that thrombomodulin serum level had no significant difference in PUD group in comparison with control group, but it is significantly higher in cancer group (P < 0.05).

Rokka et al.[25] showed that in a cellular level, H. pylori infection induces expression of IL-6 in gastric cells. In the present study, we concluded that IL-6 level is not significantly higher in PUD group but it is elevated in cancer group significantly (P < 0.05).

Oderda et al.[3] performed a research on 48 children, 32 of whom had H. pylori-positive gastritis and they measured the amount of INF, IL-1β, and IL-10 with RT-PCR. They demonstrated that IL-1β expression was similar in infected children and control subjects (P < 0.05). In this study, we also showed that IL-1 level is not significantly different in three groups (P < 0.05).

Although we detected an association between H. pylori infection and IL-6, IL-8, and thrombomodulin serum levels, but we did not find any relation between H. pylori and IL-1 and IL-10 level. It seems that our findings need further investigations with large sample size and more precise methods for measuring the serum level of interleukins. The significant high level of IL-6, IL-8, and thrombomodulin in cancer group also needs more detailed researches.


   Acknowledgements Top


This study was supported by Research Center of Gastrointestinal and Liver Disease (RCGLD) Taleghani hospital Tehran, Iran. We also thank Farzan Institute for Research and Technology for technical assistance.

 
   References Top

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Correspondence Address:
Mahsa Molaei
Department of Pathology, Research Center for Gastroenterology and Liver Disease, Shaheed Beheshti University, M.C., Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.77343

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  [Table 1], [Table 2]

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