Int J Med Sci 2016; 13(4):298-303. doi:10.7150/ijms.14239
Helicobacter pylori Infection Synergistic with IL-1β Gene Polymorphisms Potentially Contributes to the Carcinogenesis of Gastric Cancer
1. Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
2. Department of Respiratory Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
* Contributed equally
Hong JB, Zuo W, Wang AJ, Lu NH. Helicobacter pylori Infection Synergistic with IL-1β Gene Polymorphisms Potentially Contributes to the Carcinogenesis of Gastric Cancer. Int J Med Sci 2016; 13(4):298-303. doi:10.7150/ijms.14239. Available from http://www.medsci.org/v13p0298.htm
Helicobacter pylori (H. pylori) infection is the most common chronic bacterial infection in the world and the etiological agent for most gastric cancer (GC). Interleukin-1β (IL-1β) is a potent proinflammatory cytokine, and its deregulation is closely associated with the tumorigenesis of several cancers. Recent studies have revealed that the IL-1β-31 and -511T alleles are closely associated with gastric carcinogenesis due to their roles in the induction of gastric precancerous lesions and hypochlorhydria. Furthermore, H. pylori infection has a synergistic effect on the development of GC with IL-1β gene polymorphisms, and the highest prevalence of severe gastric abnormalities are found in patients with both host and bacterial high-risk genotypes (cagA(+)/vacAs1(+)/IL-1β-511T). Therefore, these recent advances demonstrate that H. pylori synergistic with IL-1β gene polymorphisms contribute to the gastric carcinogenesis by their involvement in precancerous gastric lesions and low gastric acid secretion.
Keywords: gastric cancer, IL-1β, gene polymorphism, precancerous lesion
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide [1, 2]. The intestinal type of GC develops through a cascade of well-defined and recognizable processes: inflammation, atrophy, intestinal metaplasia, dysplasia, and carcinogenesis . The annual incidence of GC patients with atrophic gastritis, intestinal metaplasia, mild-to-moderate dysplasia, and severe dysplasia are 0.1%, 0.25%, 0.6%, and 6.0%, respectively . GC is closely associated with the environment, diet and gene mutations [5-8]. Helicobacter pylori (H. pylori) infection is the aetiological agent for most GC , and its related host gene polymorphisms are associated with the susceptibility to gastric carcinogenesis . Interleukin-1β (IL-1β) is a potent proinflammatory cytokine that contributes to gastric carcinogenesis mainly through its gene polymorphisms [11, 12]. However, the underlying mechanisms by which H. pylori promote the tumorigenesis of GC and the synergistic effects with IL-1β gene polymorphisms remain to be determined. Here, we review the recent advances concerning synergistic role of H. pylori with IL-1β gene polymorphisms in gastric carcinogenesis and the associated potential mechanisms.
H. pylori infection promotes carcinogenesis of GC
GC is one of many cancers associated with inflammation, which is induced by H. pylori infection [13, 14]. Furthermore, GC develops merely in persons with H. pylori infection, and is more prone to occur in patients with histologic findings of severe gastric atrophy, corpus-predominant gastritis, or intestinal metaplasia [15, 16]. On the other hand, H. pylori eradication may reduce the prevalence of precancerous gastric lesions and prevent the development of gastric cancer, even in those patients without precancerous lesions and in healthy asymptomatic infected Asian individuals [17-21]. In addition, metachronous gastric carcinoma can be prevented by H. pylori eradication in patients who received endoscopic resection of early GC . These studies demonstrate that H. pylori infection is closely associated with gastric carcinogenesis.
IL-1β gene polymorphisms promote carcinogenesis of GC
IL-1β gene polymorphisms are closely associated with GC
IL-1β is involved in a variety of cellular activities including inflammatory response and secretion of gastric acid [23, 24]. Deregulation of IL-1β has been found in several cancers. IL-1β gene polymorphisms including IL-1β-31 (T > C) and IL-1β-511 (C > T) have been shown to be closely related to gastric tumorigenesis [25-28]. The IL-1β-31C/T and IL-1β-511C/T genotypes (CT carriers) are found to more frequently occur in patients with GC and have been considered as risk factors for GC in Chinese population [29, 30]. CT carriers have a higher risk of sporadic, early, diffuse or noncardia GC . Meanwhile, the IL-1β-511 T allele is significantly associated with an increased risk of GC [32, 33], especially in patients with IL-1β-511TT [12, 34, 35]. Interestingly, healthy volunteers from the high prevalence region have a higher frequency of the IL-1β-511T/T genotype compared to those from the low prevalence region of GC . These facts clearly demonstrate that the IL-1β-31 and -511T alleles are closely correlated to GC.
Furthermore, IL-1β polymorphisms may be associated with the histological type of GC [12, 36]. Intestinal type of GC, but not the diffuse or mixed-type of GC, more frequently occur in patients with IL-1β-511T genotype [12, 37-39]. The most common histological type of GC is poorly differentiated in patients with TT genotype .
In addition, IL-1β gene polymorphisms have been demonstrated to be associated with GC progression. The proportion of patients with IL-1β-31TT (or IL-1β-511CC) increases with advancing stages. In particular, the prevalence of either IL-1β-31TT or IL-1β-511CC genotype is double in patients with stage IV cancer compared to those with stage I cancer . Interestingly, the IL-1β-31CC genotype carrier may have a protective effect against GC progression, as GC patients who have both the IL-1β-31CC and IL-1β-511TT genotypes are associated with a better prognosis .
Thus, IL-1β gene polymorphisms play multiple roles in the tumorigenesis of GC; however, the underlying mechanism is largely unknown. Current available data suggest that IL-1β gene polymorphisms may promote GC by its involvement in precancerous gastric lesions and low gastric acid secretion.
IL-1β gene polymorphisms are closely associated with precancerous gastric lesions
Atrophic gastritis, intestinal metaplasia, and dysplasia are putative precancerous gastric lesions . Patients with intestinal metaplasia are at an increased risk for GC [15, 43]. An intestinal metaplasia patient has 10.9 times higher probability of developing GC than a subject without intestinal metaplasia . High-grade dysplasia is clinically more ominous and susceptible to coexist with or progress to adenocarcinoma . Therefore, in order to elucidate the roles of IL-1β gene polymorphisms in gastric carcinogenesis, it is of vital importance to study its correlation to precancerous gastric lesions.
A previous study indicates that differences in IL-1β gene expression due to the high frequency of a single nucleotide polymorphism may have significant biological impacts in the population . The IL-1β-31 polymorphism is found to be closely associated with the degree of mononuclear cell infiltration and atrophy in the antrum . The highest atrophy and gastritis scores frequently occur in patients with the IL-1β-511 T/T genotype . These results verify the association between IL-1β polymorphisms and both of gastric inflammation and atrophy . Intriguingly, all Mozambican subjects with intestinal metaplsia are IL-1β-511 T carriers . Furthermore, the prevalence of dysplasia is significantly higher in patient with IL-1β-511 TT genotype . These studies demonstrated that the IL-1β T alleles are associated with premalignant gastric lesions.
IL-1β gene polymorphisms are correlated to low gastric acid levels
The rate of adenocarcinoma significantly increases in Mongolian gerbils infected with H. pylori after a long-term administration of a proton pump inhibitor by promoting the progression of atrophic corpus gastritis . Moreover, progressive hyperplasia as well as mucocystic and incomplete intestinal metaplasia develop in aged mice with chronic achlorhydria because of lacking the gastric H/K-ATPase . These data suggest that the use of acid-suppressive drugs is associated with an increased risk of GC through inhibition of gastric acid secretion . In support of this hypothesis, the prevalence of body atrophy and intestinal metaplasia increases in patients with hypochlorhydria , and those with a low acid output have a relatively high risk to develop GC .
IL-1β potentially inhibits acid secretion by downregulating H+/K+ATPase expression and repressing gastrin expression [57, 58], which subsequently suppresses expression of Sonic Hedgehog, ultimately leading to gastric atrophy .
IL-1β-511 TT and C noncarriers have higher levels of IL-1β than CT and C carriers, respectively . Similarly, when compared to cells transfected with a plasmid expressing IL-1β-31C, up to a 3-fold increase of IL-1β expression occurs in gastric carcinoma cells transfected with IL-1β-31T expression plasmid . IL-1β gene polymorphisms may enhance the production of IL-1β variants, leading to repression of gastric acid secretion, which is associated with the grade of gastric atrophy in patients with H. pylori infection [11, 24, 61].
Recently, a study discloses that the IL-1β-511 T allele stimulates the expression of IL-1β but does not decrease gastric acid output, suggesting that there are alternative mechanisms by which IL-1β polymorphisms enhance GC development . Similarly, as previously mentioned, patients with H. pylori infection and IL-1β polymorphisms with increased production of IL-1β are susceptible to GC through the CpG island methylation . Meanwhile, IL-1β has been found to increase the invasion of carcinoma cells through activation of NF-kappa B, hence enhancing the expression of matrix metalloproteinase-9 . Moreover, IL-1β has been reported to stimulate IL-8 expression through mitogen-activated protein kinase and reactive oxygen species signaling, both of which are directly correlated with the vascularization of GC .
H. pylori infection is associated with IL-1β expression
H. pylori infection induces IL-1β and suppresses acid secretion, while the expression of IL-1β decreases after H. pylori eradication, followed by an increase in gastric acidity [65, 66]. It is discovered that mucosal levels of IL-1β increases prior to the development of GC in an experimental mouse model with H. pylori infection . In addition, gastric concentrations of IL-1β in children with H. pylori infection are significantly higher than those without H. pylori infection . Furthermore, higher mucosal IL-1β levels are observed in H. pylori-infected GC patients with IL-1β-31TT compared to those with IL-1β-31CT and IL-1β-31CC . On the other hand, population with IL-1β-31 CT and TT genotypes in Asia and Latin America are more susceptible to infection by H. pylori, compared to those with IL-1β-31 CC . Overall, these studies indicate that H. pylori infection has an interactive relationship with IL-1β, especially in patients with IL-1β-31TT.
H. pylori has a synergistic role with IL-1β polymorphisms in gastric carcinogenesis
H. pylori infection has a synergistic effect with IL-1β gene polymorphisms on the development of GC . IL-1β-511 T allele is more frequently observed in H. pylori-positive patients than in H. pylori-negative patients with noncardia GC . Interestingly, though H. pylori infection alone has only a modest effect on GC development, the risk for GC is significantly increased when combined with the IL-1β-511T/T genotype . Similarly, patients with the IL-1β-511TT genotype with active infection of H. pylori have higher risk for developing GC [27, 34]. In particular, patients with both bacterial and host high-risk genotypes (vacuolating cytotoxin gene A s1 region (vacAs1)/IL-1β-511*T carrier, vacAm1/IL-1β-511*T carrier, and cytotoxin-associated gene A (cagA)-positive/IL-1β-511*T carrier) present the highest risk .
Children with IL-1β-511TT/-31CC have an increased risk of developing relatively severe gastric mucosal histological changes in South China, where H. pylori infection is prevalent . Likewise, an increased prevalence of intestinal metaplasia and atrophic gastritis is found in patients with IL-1β-511T/-31C [74, 75]. In addition, H. pylori-related atrophic gastritis has been shown to be the more malignant phenotype compared to H. pylori-negative atrophic gastritis in patients with IL-1β-31CC/-511TT genotypes . A modestly higher prevalence of intestinal metaplasia is observed in patients with H. pylori infection, especially in those infected with vacA m1 strain . Furthermore, patients with both host and bacterial high-risk genotypes (cagA(+)/vacAs1(+)/IL-1β-511T) have the highest prevalence of severe gastric abnormalities (severe lymphocytic and granulocytic infiltration, atrophic gastritis and intestinal metaplasia) .
Mechanistically, H. pylori infection induces the expression of IL-1β, which in turn promotes gastric carcinogenesis by affecting both inflammatory and epithelial cells . In addition, hypochlorhydria and atrophic gastritis can be induced by IL-1β polymorphisms, which depends on H. pylori infection . These results demonstrate that H. pylori infection synergistic with IL-1β polymorphisms results in gastric precancerous lesions and hypochlorhydria, which contribute to the gastric carcinogenesis.
Challenges and a look to the future
The positive correlation of IL-1β gene polymorphisms to GC and its precursors has been observed in numerous studies. However, this conclusion still awaits confirmation by further investigation. It has been reported that IL-1β polymorphisms have no effect on the degree of gastric neutrophil and mononuclear cell infiltration, or gastric atrophy . In addition, no evidence of an association of haplotypes of IL-1β with an increased risk of developing either chronic gastritis or intestinal metaplasia has been observed [80, 81]. Furthermore, in atrophic body gastritis patients, IL-1β-511 polymorphisms are not associated with the development of gastric neoplastic lesions after long-term follow up . In some populations, no significant correlation is found between IL-1β gene polymorphisms and GC [83-87], and IL-1β has no predictive value for the development of GC . Similarly, no association has been found between IL-1β polymorphisms and diffuse or intestinal GC . Finally, IL-1β-511C/T and the T carrier have been reported to have a decreased risk for gastric carcinoma in Japanese individuals . These inconsistent findings may result from a range of factors such as heterogeneity of cancer subtypes, limited sample size, gene-environment interactions , and ethnic differences .
Thus, multi-centered, large sample scale, multi-racial, perspective, randomized, and controlled studies are needed to verify the association of IL-1β gene polymorphisms with GC. Meanwhile, the underlying mechanisms of the synergistic effect of H. pylori infection and IL-1β gene polymorphisms in gastric carcinogenesis are still elusive. Furthermore, it remains to be determined if there are any other related gene polymorphisms, in coordination with IL-1β, that play a synergistic role in the development of GC.
H. pylori infection synergistic with IL-1β gene polymorphisms may promote gastric carcinogenesis by their involvement in precancerous gastric lesions and hypochlorhydria. Further investigation is needed to verify these findings in different populations and subtypes of GC, and to disclose alternative underlying mechanisms.
This work was supported by the Natural Science Foundation of Jiangxi Province, China (No. 20122BAB215010).
The authors have declared that no competing interest exists.
1. Danaei G, Vander Hoorn S. et al. Comparative Risk Assessment collaborating g. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet. 2005;366:1784-93
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29
3. Correa P, Haenszel W, Cuello C. et al. A model for gastric cancer epidemiology. Lancet. 1975:58-60
4. de Vries AC, van Grieken NC, Looman CW. et al. Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands. Gastroenterology. 2008;134:945-52
5. Cokkinides VE, Bandi P, Siegel RL. et al. Cancer-related risk factors and preventive measures in US Hispanics/Latinos. CA Cancer J Clin. 2012;62:353-63
6. Correa P. Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol. 1995;19(Suppl 1):S37-43
7. Herrera V, Parsonnet J. Helicobacter pylori and gastric adenocarcinoma. Clin Microbiol Infect. 2009;15:971-6
8. Wen YY, Pan XF, Loh M. et al. Association of the IL-1B +3954 C/T polymorphism with the risk of gastric cancer in a population in Western China. Eur J Cancer Prev. 2014;23:35-42
9. Hunt RH, Camilleri M, Crowe SE. et al. The stomach in health and disease. Gut. 2015;64:1650-68
10. He C, Tu H, Sun L. et al. Helicobacter pylori-related host gene polymorphisms associated with susceptibility of gastric carcinogenesis: a two-stage case-control study in Chinese. Carcinogenesis. 2013;34:1450-7
11. El-Omar EM, Carrington M, Chow WH. et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398-402
12. Yu J, Zeng Z, Wang S. et al. IL-1B-511 polymorphism is associated with increased risk of certain subtypes of gastric cancer in Chinese: a case-control study. Am J Gastroenterol. 2010;105:557-64
13. de Martel C, Ferlay J, Franceschi S. et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13:607-15
14. Graham DY. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits. Gastroenterology. 2015;148:719-31 e3
15. Uemura N, Okamoto S, Yamamoto S. et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784-9
16. Hsu PI, Lai KH, Hsu PN. et al. Helicobacter pylori infection and the risk of gastric malignancy. Am J Gastroenterol. 2007;102:725-30
17. You WC, Brown LM, Zhang L. et al. Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J Natl Cancer Inst. 2006;98:974-83
18. Lee YC, Chen TH, Chiu HM. et al. The benefit of mass eradication of Helicobacter pylori infection: a community-based study of gastric cancer prevention. Gut. 2013;62:676-82
19. Leung WK, Lin SR, Ching JY. et al. Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut. 2004;53:1244-9
20. Wong BC, Lam SK, Wong WM. et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA. 2004;291:187-94
21. Ford AC, Forman D, Hunt RH. et al. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. BMJ. 2014;348:g3174
22. Fukase K, Kato M, Kikuchi S. et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet. 2008;372:392-7
23. Jayaraman P, Sada-Ovalle I, Nishimura T. et al. IL-1beta promotes antimicrobial immunity in macrophages by regulating TNFR signaling and caspase-3 activation. J Immunol. 2013;190:4196-204
24. Waghray M, Zavros Y, Saqui-Salces M. et al. Interleukin-1beta promotes gastric atrophy through suppression of Sonic Hedgehog. Gastroenterology. 2010;138:562-72 72 e1-2
25. El-Omar EM, Rabkin CS, Gammon MD. et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 2003;124:1193-201
26. Garza-Gonzalez E, Bosques-Padilla FJ, El-Omar E. et al. Role of the polymorphic IL-1B, IL-1RN and TNF-A genes in distal gastric cancer in Mexico. Int J Cancer. 2005;114:237-41
27. Kumar S, Kumar A, Dixit VK. Evidences showing association of interleukin-1B polymorphisms with increased risk of gastric cancer in an Indian population. Biochem Biophys Res Commun. 2009;387:456-60
28. Zeng ZR, Hu PJ, Hu S. et al. Association of interleukin 1B gene polymorphism and gastric cancers in high and low prevalence regions in China. Gut. 2003;52:1684-9
29. He BS, Pan YQ, Xu YF. et al. Polymorphisms in interleukin-1B (IL-1B) and interleukin 1 receptor antagonist (IL-1RN) genes associate with gastric cancer risk in the Chinese population. Dig Dis Sci. 2011;56:2017-23
30. Yang J, Hu Z, Xu Y. et al. Interleukin-1B gene promoter variants are associated with an increased risk of gastric cancer in a Chinese population. Cancer Lett. 2004;215:191-8
31. Starzynska T, Ferenc K, Wex T. et al. The association between the interleukin-1 polymorphisms and gastric cancer risk depends on the family history of gastric carcinoma in the study population. Am J Gastroenterol. 2006;101:248-54
32. Vincenzi B, Patti G, Galluzzo S. et al. Interleukin 1beta-511T gene (IL1beta) polymorphism is correlated with gastric cancer in the Caucasian population: results from a meta-analysis. Oncol Rep. 2008;20:1213-20
33. Xue H, Lin B, Ni P. et al. Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: a meta-analysis. J Gastroenterol Hepatol. 2010;25:1604-17
34. Chan AO, Chu KM, Huang C. et al. Association between Helicobacter pylori infection and interleukin 1beta polymorphism predispose to CpG island methylation in gastric cancer. Gut. 2007;56:595-7
35. Martinez T, Hernandez-Suarez G, Bravo MM. et al. Association of interleukin-1 genetic polymorphism and CagA positive Helicobacter pylori with gastric cancer in Colombia. Rev Med Chil. 2011;139:1313-21
36. Lee KA, Ki CS, Kim HJ. et al. Novel interleukin 1beta polymorphism increased the risk of gastric cancer in a Korean population. J Gastroenterol. 2004;39:429-33
37. Kamangar F, Cheng C, Abnet CC. et al. Interleukin-1B polymorphisms and gastric cancer risk-a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006;15:1920-8
38. Ruzzo A, Graziano F, Pizzagalli F. et al. Interleukin 1B gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in Helicobacter pylori-negative gastric cancer of intestinal and diffuse histotype. Ann Oncol. 2005;16:887-92
39. Wang P, Xia HH, Zhang JY. et al. Association of interleukin-1 gene polymorphisms with gastric cancer: a meta-analysis. Int J Cancer. 2007;120:552-62
40. Ikehara SK, Ikehara Y, Matsuo K. et al. A polymorphism of C-to-T substitution at -31 IL1B is associated with the risk of advanced gastric adenocarcinoma in a Japanese population. J Hum Genet. 2006;51:927-33
41. Tahara T, Shibata T, Nakamura M. et al. Effect of IL-1beta and TNF-alpha polymorphisms on the prognosis and survival of gastric cancer patients. Clin Exp Med. 2011;11:211-7
42. Dinis-Ribeiro M, Areia M, de Vries AC. et al. Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy. 2012;44:74-94
43. Naylor GM, Gotoda T, Dixon M. et al. Why does Japan have a high incidence of gastric cancer? Comparison of gastritis between UK and Japanese patients. Gut. 2006;55:1545-52
44. Kim N, Park RY, Cho SI. et al. Helicobacter pylori infection and development of gastric cancer in Korea: long-term follow-up. J Clin Gastroenterol. 2008;42:448-54
45. Clouston AD. Timely topic: Premalignant lesions associated with adenocarcinoma of the upper gastrointestinal tract. Pathology. 2001;33:271-7
46. Lind H, Haugen A, Zienolddiny S. Differential binding of proteins to the IL1B -31 T/C polymorphism in lung epithelial cells. Cytokine. 2007;38:43-8
47. Tahara T, Shibata T, Yamashita H. et al. Synergistic effect of IL-1beta and TNF-alpha polymorphisms on the H. pylori-related gastric pre-malignant condition. Hepatogastroenterology. 2012;59:2416-20
48. Furuta T, El-Omar EM, Xiao F. et al. Interleukin 1beta polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology. 2002;123:92-105
49. Hwang IR, Kodama T, Kikuchi S. et al. Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection. Gastroenterology. 2002;123:1793-803
50. Peleteiro B, Lunet N, Carrilho C. et al. Association between cytokine gene polymorphisms and gastric precancerous lesions: systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2010;19:762-76
51. Marcos-Pinto R, Dinis-Ribeiro M, Carneiro F. et al. First-degree relatives of early-onset gastric cancer patients show a high risk for gastric cancer: phenotype and genotype profile. Virchows Arch. 2013;463:391-9
52. Hagiwara T, Mukaisho K, Nakayama T. et al. Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori. Gut. 2011;60:624-30
53. Judd LM, Andringa A, Rubio CA. et al. Gastric achlorhydria in H/K-ATPase-deficient (Atp4a(-/-)) mice causes severe hyperplasia, mucocystic metaplasia and upregulation of growth factors. J Gastroenterol Hepatol. 2005;20:1266-78
54. Ahn JS, Eom CS, Jeon CY. et al. Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies. World J Gastroenterol. 2013;19:2560-8
55. El-Omar EM, Oien K, El-Nujumi A. et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology. 1997;113:15-24
56. Vieth M, Stolte M. Elevated risk for gastric adenocarcinoma can be predicted from histomorphology. World J Gastroenterol. 2006;12:6109-14
57. Guo T, Qian JM, Zhao YQ. et al. Effects of IL-1beta on the proliferation and apoptosis of gastric epithelial cells and acid secretion from isolated rabbit parietal cells. Mol Med Rep. 2013;7:299-305
58. Datta De D, Bhattacharjya S, Maitra M. et al. IL1B induced Smad 7 negatively regulates gastrin expression. PLoS One. 2011;6:e14775
59. Chourasia D, Achyut BR, Tripathi S. et al. Genotypic and functional roles of IL-1B and IL-1RN on the risk of gastroesophageal reflux disease: the presence of IL-1B-511*T/IL-1RN*1 (T1) haplotype may protect against the disease. Am J Gastroenterol. 2009;104:2704-13
60. Chakravorty M, Datta De D, Choudhury A. et al. IL1B promoter polymorphism regulates the expression of gastric acid stimulating hormone gastrin. Int J Biochem Cell Biol. 2009;41:1502-10
61. Takagi A, Deguchi R, Kobayashi K. et al. Cytokine expressions and H. pylori-associated gastric mucosal lesion. Keio J Med. 2002:51-2
62. Hu S, Song QB, Yao PF. et al. No relationship between IL-1B gene polymorphism and gastric acid secretion in younger healthy volunteers. World J Gastroenterol. 2005;11:6549-53
63. Yamanaka N, Morisaki T, Nakashima H. et al. Interleukin 1beta enhances invasive ability of gastric carcinoma through nuclear factor-kappaB activation. Clin Cancer Res. 2004;10:1853-9
64. Hwang YS, Jeong M, Park JS. et al. Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells. Oncogene. 2004;23:6603-11
65. Takashima M, Furuta T, Hanai H. et al. Effects of Helicobacter pylori infection on gastric acid secretion and serum gastrin levels in Mongolian gerbils. Gut. 2001;48:765-73
66. Wang M, Furuta T, Takashima M. et al. Relation between interleukin-1beta messenger RNA in gastric fundic mucosa and gastric juice pH in patients infected with Helicobacter pylori. J Gastroenterol. 1999;34(Suppl 11):10-7
67. Fox JG, Wang TC, Rogers AB. et al. Host and microbial constituents influence Helicobacter pylori-induced cancer in a murine model of hypergastrinemia. Gastroenterology. 2003;124:1879-90
68. Queiroz DM, Rocha AM, Melo FF. et al. Increased gastric IL-1beta concentration and iron deficiency parameters in H. pylori infected children. PLoS One. 2013;8:e57420
69. Chang YW, Jang JY, Kim NH. et al. Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1beta cytokine in Korean patients with gastric cancer. Int J Cancer. 2005;114:465-71
70. Sun X, Xu Y, Zhang F. et al. Association between the IL1B -31C > T polymorphism and Helicobacter pylori infection in Asian and Latin American population: A meta-analysis. Microb Pathog. 2015;86:45-52
71. Li C, Xia HH, Xie W. et al. Association between interleukin-1 gene polymorphisms and Helicobacter pylori infection in gastric carcinogenesis in a Chinese population. J Gastroenterol Hepatol. 2007;22:234-9
72. Figueiredo C, Machado JC, Pharoah P. et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst. 2002;94:1680-7
73. Li J, Wang F, Zhou Q. et al. IL-1 polymorphisms in children with peptic symptoms in South China. Helicobacter. 2011;16:246-51
74. Rad R, Dossumbekova A, Neu B. et al. Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut. 2004;53:1082-9
75. Rad R, Prinz C, Neu B. et al. Synergistic effect of Helicobacter pylori virulence factors and interleukin-1 polymorphisms for the development of severe histological changes in the gastric mucosa. J Infect Dis. 2003;188:272-81
76. Wang SY, Shen XY, Wu CY. et al. Analysis of whole genomic expression profiles of Helicobacter pylori related chronic atrophic gastritis with IL-1B-31CC/-511TT genotypes. J Dig Dis. 2009;10:99-106
77. Leung WK, Chan MC, To KF. et al. H. pylori genotypes and cytokine gene polymorphisms influence the development of gastric intestinal metaplasia in a Chinese population. Am J Gastroenterol. 2006;101:714-20
78. Shigematsu Y, Niwa T, Rehnberg E. et al. Interleukin-1beta induced by Helicobacter pylori infection enhances mouse gastric carcinogenesis. Cancer Lett. 2013;340:141-7
79. Xuan J, Deguchi R, Watanabe S. et al. Relationship between IL-1beta gene polymorphism and gastric mucosal IL-1beta levels in patients with Helicobacter pylori infection. J Gastroenterol. 2005;40:796-801
80. Murphy G, Thornton J, McManus R. et al. Association of gastric disease with polymorphisms in the inflammatory-related genes IL-1B, IL-1RN, IL-10, TNF and TLR4. Eur J Gastroenterol Hepatol. 2009;21:630-5
81. Kupcinskas L, Wex T, Kupcinskas J. et al. Interleukin-1B and interleukin-1 receptor antagonist gene polymorphisms are not associated with premalignant gastric conditions: a combined haplotype analysis. Eur J Gastroenterol Hepatol. 2010;22:1189-95
82. Lahner E, Corleto VD, D'Ambra G. et al. Is interleukin-1 genotyping useful for the clinical management of patients with atrophic body gastritis?. Aliment Pharmacol Ther. 2008;27:355-65
83. Al-Moundhri MS, Al-Nabhani M, Al-Bahrani B. et al. Interleukin-1beta gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms and gastric cancer risk in an Omani Arab population. Gastric Cancer. 2006;9:284-90
84. Camargo MC, Mera R, Correa P. et al. Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms and gastric cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006;15:1674-87
85. Kamangar F, Abnet CC, Hutchinson AA. et al. Polymorphisms in inflammation-related genes and risk of gastric cancer (Finland). Cancer Causes Control. 2006;17:117-25
86. Kim N, Cho SI, Yim JY. et al. The effects of genetic polymorphisms of IL-1 and TNF-A on Helicobacter pylori-induced gastroduodenal diseases in Korea. Helicobacter. 2006;11:105-12
87. Wong HL, Rabkin CS, Shu XO. et al. Systemic cytokine levels and subsequent risk of gastric cancer in Chinese Women. Cancer Sci. 2011;102:1911-5
88. Gatti LL, Burbano RR, de Assumpcao PP. et al. Interleukin-1beta polymorphisms, Helicobacter pylori infection in individuals from Northern Brazil with gastric adenocarcinoma. Clin Exp Med. 2004;4:93-8
89. Ito H, Kaneko K, Makino R. et al. Interleukin-1beta gene in esophageal, gastric and colorectal carcinomas. Oncol Rep. 2007;18:473-81
90. Zhang Y, Liu C, Peng H. et al. IL1 receptor antagonist gene IL1-RN variable number of tandem repeats polymorphism and cancer risk: a literature review and meta-analysis. PLoS One. 2012;7:e46017
Corresponding author: Professor Nong-hua Lu, Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China. Email: lunonghuacom