期刊
EUROPEAN JOURNAL OF CANCER
卷 49, 期 12, 页码 2760-2770出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2013.03.031
关键词
Helicobacter pylori; Interleukin-1 beta; E-cadherin; Nitric oxide; Gastric cancer; Inflammation; DNA methylation
类别
Helicobacter pylori infection induced interleukin-1 beta (IL-1 beta) production and is associated with aberrant DNA methylation and gastric diseases. Here, we investigated the role of IL-1 beta in H. pylori-induced gastric inflammation and DNA methylation using IL-1 receptor type 1 knockout (IL-1R1(-/-)) mice, and compared the therapeutic efficacy of antimicrobial therapy with IL-1 receptor antagonist (IL-1ra). IL-1R1(-/-) and wild-type (WT) mice were infected with H. pylori for 16, 24 and 32 weeks. Infected WT mice at 24 weeks were given either antimicrobial therapy or IL-1ra. Comparing to the IL-1R1(-/-) mice, infected WT mice with functional IL-1 beta signaling had higher gastritis scores, higher IL-1 beta and iNOS mRNA expression, higher nitric oxide (NO) production and increased frequency of E-cadherin (E-ad) methylation at all the time points analyzed. IL-1 beta release was significantly elevated in infected WT mice than normal controls at 16 weeks post-infection (p < 0.005). Treatment of infected mice with antimicrobial therapy and IL-1ra significantly reduced the degree of gastritis (p < 0.005; p < 0.05, respectively), iNOS expression (p < 0.0001; p < 0.01, respectively) and NO production (both p < 0.001) compared with untreated controls. Mice receiving antimicrobial therapy had significantly lower IL-1 beta expression than untreated controls (p < 0.0001). Both treatments reduced the incidence of E-cad methylation in infected mice compared with controls, however, no statistical significance was observed. There was no significant alteration of total DNA methyltransferase (DNMT) activity. These results demonstrated that IL-1 beta played a crucial role in H. pylori-induced gastric inflammation and DNA methylation. H. pylori eradication and IL-1ra administration could ameliorate inflammatory stress. (C) 2013 Elsevier Ltd. All rights reserved.
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