IL-1基因多态性对胃粘膜TNF-α、NF-κB的表达和活性的影响

Enhenced NF-κB Activity and TNF-α Transcript in h.pylori (+) Individuals Are Associated with IL-1b Gene Polymorphisms

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±0.17vs.0.87±0.18和0.94±0.16;1.10±0.16vs0.90±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±0.12vs0.89±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-κBmRNA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。

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- α and activation of NF-κB may be involved in IL-IB-511 T allele associated gastric cancerogenesis. Methods One hundred and five healthy samples from the regions with 10w incidence of gastric cancer were genotyped for IL-I Beta 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-κB. 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 signa ling play crucial role in the relationship between IL-1B gene polymorphism and gastric cancerogenesis.