Enhenced NF-κB Activity and TNF-α Transcript in h.pylori (+) Individuals Are Associated with IL-1b Gene Polymorphisms
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摘要: 目的 探讨IL-1的基因多态性影响H.pylori感染后胃癌发生的机制。方法 通过多态性分析和血清H.pylori抗体测定，收集105例癌低发区的学生作为研究对象，其中IL-1-511T/T 基因型32名（13名H.pylori+），C/C基因型36名（15名H.pylori+），C/T基因型37名（14名H.pylori+）。结果 在胃体组织，H.pylori阴性个体TNF-α和NF-κB表达量极少，而且IL-1B-511各基因型间也无显著差异。在H.pylori阳性个体，胃体部TNF-α和NF-κB mRNA有较为明显的表达，IL-1B-511T/T基因型个体比C/T和C/C基因型明显增加，分别为1.20±0.17 vs. 0.87±0.18和0.94±0.16；1.10±0.16 vs 0.90±0.15和0.97±0.17，F=33.4和12.9，P=0.0001和0.001。H.pylori阴性的NF-κB mRNA活性很低。在H.pylori阳性个体，NF-κB 活性显著增加。而且IL-1B-511T/T基因型个体比C/T和C/C基因型明显增加，分别为0.99±0.12vs 0.89±0.15和0.90±0.14，F=5.6，P=0.005。结论 H.pylori感染促进TNF-α和NF-κB mRNA表达，上调NF-κB活性，在IL-1B-511T/T基因型个体更明显。提示H.pylori感染后，存在IL-1B基因多态性→IL-1β↑→炎症细胞因子↑→胃癌发生的完整通路。Abstract: Objective IL-1β gene polymorphisms affect the expression of of IL-1β. The induction of IL-1β by H.pylori strongly inhibited acid secretion,which has been supposed to contribute to a high incidence of gastric cancer. However, IL-1B-511 T allele has no influence in gastric acid output according to our recent study. We hypothesized that the expression of proinflammatory cytokine such as IL-1B and TNF-a and activation of NF-κB may be involved in IL-1B-511 T allele associated gastric cancerogenesis. Methods One hundred and five healthy samples from the regions with low incidence of gastric cancer were genotyped for IL-1Beta 511 polymorphisms by PCR-RFLP. The expression of IL-1β, NF-κB and TNF-α were measured using RT-PCR, and NF-κB activity were detected by EMSA. Results In gastric corpus of H.pylori(-) Individuals, the expression of NF-κB and TNF-α were similar and remarkably lower than H.pylori(+) group.In addition, T/T genotype of IL-1B-511 among the H.pylori infected individuals, expressed higher level of NF-κB and TNF-α(1.20±0.17 vs. 0.87±0.18 and 0.94±0.16；1.10±0.16 vs. 0.90±0.15 and 0.97±0.17，F=33.4 and 12.9，P=0.0001 and 0.001,respectively) and induced the strongest NF-κB activity (0.99±0.12 vs. 0.89±0.15 and 0.90±0.14，F=5.6，P=0.005) than that of other two genotypes. Whereas,H.pylor(-) Individuals showed attenuated activity of NF-kB. Conclusion Chronic H.pylori infection induced expression of IL-1β, TNF-α and activate NF-κB activity, which predisposed individuals with IL-1B-511T/T genotype. Our findings suggested TNF-α and NF-κB signaling play crucial role in the relationship between IL-1B gene polymorphism and gastric cancerogenesis.
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Key words:
- Gastric cancer /
- IL-1B /
- Polymorphism /
- TNF-α /
- NF-κB /
- Inflammatory
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