NF-κB信号通路在幽门螺杆菌致病机制中的作用的研究
摘要
目的:通过体外实验研究NF-κB信号通路在幽门螺杆菌引起慢性胃炎的机制中所起的作用,以及评价特异性调节NF-κB活性对于减轻幽门螺杆菌引起的慢性炎症反应的作用,为将来的动物及临床实验做好准备,为阻断慢性炎症向胃癌发展这一进程提供依据,从而为最终解决由幽门螺杆菌所引起的慢性胃炎等疾病提供有效的方案。
方法:分别培养幽门螺杆菌11637标准菌株以及人胃粘膜上皮细胞(GES-1),将GES-1细胞分为3组:空白组、GES-1+Hp组及GES-1+Hp+NF-κB抑制剂组,每组各做10例,在后两组中按细胞与细菌为1:50的量加入Hp11637菌株,共培养24小时后,提取上清液用ELISA法检测IL-8、TNF-α的含量,裂解细胞,用Western Blot法检测NF-κB的表达含量。以空白组为对照分别比较Hp及NF-κB抑制剂对于NF-κB信号通路的影响作用。
结果:1、成功培养Hp11637标准菌株及GES-1细胞。2、在GES-1细胞中加入Hp菌株后共培养24小时后提取上清液再次进行Hp培养,Hp培养成功。3、在GES-1细胞中按比例加入定量的Hp菌株,共培养24小时后检测上清液中的IL-8、TNF-α含量,较空白组明显升高(p<0.05),裂解细胞后检测裂解液中的NF-κB表达量较空白组升高(p<0.05)。4、在GES-1细胞中加入定量的Hp菌株以及特异性NF-κB信号通路抑制剂,共培养24小时后检测上清液中的IL-8、TNF-α含量,与仅加入Hp的干预组相比,表达量有所降低(p<0.05),裂解细胞后检测裂解液中的NF-κB表达量较干预组降低(p<0.05),但较空白组升高(p<0.05)。
结论:NF-κB信号通路在幽门螺杆菌引起慢性胃炎的发病机制中起到核心作用,采用特异性阻断NF-κB信号通路的方法可以有效减少幽门螺杆菌诱导的炎性因子的分泌。
Objective: Use in vitro experiment to study the function of NF-κB signal pathway in the pathogenic mechanism of chronic gastritis associated with helicobacter pylori infection to evaluate the effect of accommodation of NF-κB in abatement chronic inflammation associated with helicobacter pylori infection , to make up the basement of future animal or clinical experiment , so that we can stop the progress of chronic gastritis to gastric cancer and can support effect way to treat chronic gastritis associated with helicobacter pylori.
Methods: Helicobacter pylori standard strain(11637 strain) and gastric epithelial cell were cultured. The GES-1 were divided in to three groups:the blank group, the GES-1 and Hp group, the GES-1,Hp and inhibitor of NF-κB group. Each group contains 10 examples. The GES-1 and Hp were put together at the ratio of 1:50 in the last two groups. After the three groups were cultured for 24 hours, the supernatant liquid was separated to detect the contents of IL-8 and TNF-αby ELISA. Then the cells were splitted to detect the content of NF-κB by Western Blot. The datas were compared between three groups to evaluate the influence of Hp and NF-κB inhibitor to the NF-κB signal pathway.
Results: The Hp standard strain(11637 strain) and GES-1 were cultured successfully. 2.After GES-1 and Hp were cultured for 24 hours, the supernatant liquid was cultured in microaerobic atmosphere, then Hp can be cultured again. 3.After GES-1 and Hp were cultured together for 24 hours, the contents of IL-8 and TNF-αin the supernatant liquid were more than the blank group(p<0.05), and the content of NF-κB was more than the blank group(p<0.05). 4.After GES-1,Hp and NF-κB inhibitor were cultured for 24 hours, the contents of IL-8 and TNF-αin the supernatant liquid were less than the group of GES-1and Hp (p<0.05), the content of NF-κB was less than the group of GES-1 and Hp(p<0.05), but more than the blank group.
Conclusions: The NF-κB signal pathway plays an important role in the pathogenic mechanism of chronic gastritis associated with helicobacter pylori infection. We can block the NF-κB signal pathway to decrease the secretion of inflammatal factor induced by helicobacter pylori.
方法:分别培养幽门螺杆菌11637标准菌株以及人胃粘膜上皮细胞(GES-1),将GES-1细胞分为3组:空白组、GES-1+Hp组及GES-1+Hp+NF-κB抑制剂组,每组各做10例,在后两组中按细胞与细菌为1:50的量加入Hp11637菌株,共培养24小时后,提取上清液用ELISA法检测IL-8、TNF-α的含量,裂解细胞,用Western Blot法检测NF-κB的表达含量。以空白组为对照分别比较Hp及NF-κB抑制剂对于NF-κB信号通路的影响作用。
结果:1、成功培养Hp11637标准菌株及GES-1细胞。2、在GES-1细胞中加入Hp菌株后共培养24小时后提取上清液再次进行Hp培养,Hp培养成功。3、在GES-1细胞中按比例加入定量的Hp菌株,共培养24小时后检测上清液中的IL-8、TNF-α含量,较空白组明显升高(p<0.05),裂解细胞后检测裂解液中的NF-κB表达量较空白组升高(p<0.05)。4、在GES-1细胞中加入定量的Hp菌株以及特异性NF-κB信号通路抑制剂,共培养24小时后检测上清液中的IL-8、TNF-α含量,与仅加入Hp的干预组相比,表达量有所降低(p<0.05),裂解细胞后检测裂解液中的NF-κB表达量较干预组降低(p<0.05),但较空白组升高(p<0.05)。
结论:NF-κB信号通路在幽门螺杆菌引起慢性胃炎的发病机制中起到核心作用,采用特异性阻断NF-κB信号通路的方法可以有效减少幽门螺杆菌诱导的炎性因子的分泌。
Objective: Use in vitro experiment to study the function of NF-κB signal pathway in the pathogenic mechanism of chronic gastritis associated with helicobacter pylori infection to evaluate the effect of accommodation of NF-κB in abatement chronic inflammation associated with helicobacter pylori infection , to make up the basement of future animal or clinical experiment , so that we can stop the progress of chronic gastritis to gastric cancer and can support effect way to treat chronic gastritis associated with helicobacter pylori.
Methods: Helicobacter pylori standard strain(11637 strain) and gastric epithelial cell were cultured. The GES-1 were divided in to three groups:the blank group, the GES-1 and Hp group, the GES-1,Hp and inhibitor of NF-κB group. Each group contains 10 examples. The GES-1 and Hp were put together at the ratio of 1:50 in the last two groups. After the three groups were cultured for 24 hours, the supernatant liquid was separated to detect the contents of IL-8 and TNF-αby ELISA. Then the cells were splitted to detect the content of NF-κB by Western Blot. The datas were compared between three groups to evaluate the influence of Hp and NF-κB inhibitor to the NF-κB signal pathway.
Results: The Hp standard strain(11637 strain) and GES-1 were cultured successfully. 2.After GES-1 and Hp were cultured for 24 hours, the supernatant liquid was cultured in microaerobic atmosphere, then Hp can be cultured again. 3.After GES-1 and Hp were cultured together for 24 hours, the contents of IL-8 and TNF-αin the supernatant liquid were more than the blank group(p<0.05), and the content of NF-κB was more than the blank group(p<0.05). 4.After GES-1,Hp and NF-κB inhibitor were cultured for 24 hours, the contents of IL-8 and TNF-αin the supernatant liquid were less than the group of GES-1and Hp (p<0.05), the content of NF-κB was less than the group of GES-1 and Hp(p<0.05), but more than the blank group.
Conclusions: The NF-κB signal pathway plays an important role in the pathogenic mechanism of chronic gastritis associated with helicobacter pylori infection. We can block the NF-κB signal pathway to decrease the secretion of inflammatal factor induced by helicobacter pylori.
引文
1 Vandenplas Y. Helicobacter pylori infection. World J Gastroenterol 2000;6:20-31.
2 Xia Harry HX, Fan XG. Talley Nicholas J. Clarithromycin resistance in Helicobacrer pylori and its clinical relevance. World J Gastroenterol 1996;5:263-266.
3 Meyer JM, Silliman NP, Dixon CA. Siepman M, Sugg JE, Hopkins RJ.Helicobacter pylori and early duodenal ulcer status post-treatment:a review. Helicobacter 2006;6:84-92
4 Casella G, Buda CA, Maisano R, Schiavo M, Perego D, Baldini V. Complete regression of primary gastric MALT-lymphoma after double eradication Helicobacter pylori therapy: role and importance of endoscopic ultrasonography. Anticancer Res 2001;21:1499-1502.
5 Hiyama T, Haruma K, Kitadai Y, Masuda H, Miyamoto M, Ito M, Kamada T, Tanaka S, Uemura N, Yoshihara M, Sumii K, Shimamoto F, Chayama K. Clinicopathological featureas of gastric mucosa-asscciated lymphoid tissue lymphoma: a comparison with diffuse large B-cell lymphoma without a mucosa-asscociated lymphoid tissue lymphoma component. J Gastroenterol Hepatol 2001;16:734-739.
6 Delchier JC, Lamarque D, Levy M, Tkoub EM, Copie-Bergman C, Deforges L, Chaumette MT, Haioun C. Helicobacter pylori and gastric lymphoma: high seroprevance of CageA in diffuse large B-cell lymphoma but not in low-large lymphoma of mucosa-associated lymphoid tissue type. Am J Gastroenterol 2001;96:2324-2328.
7 Morgner A, Miehlke S, Fischbach W, Schmitt W, Muller-Hermelink H, Greiner A, Thiede C, Schetelig J, Neubauer A, Stolte M, Ehninger G, Bayerdorffer E. Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin Oncol 2001;19:2041-2048.
8 Suganuma M, Kurusu M, Okabe S, Sueoka N, Yoshida M, Wakatsuki Y, Fujiki H. Helicobacter pylori membrance protein 1: a new carcinogenic factor of Helicobacter pylori. Cancer Res 2001;61:6356-6359.
9 Sheng T, Zhang JZ. Current statua in study of Hp UreB. Shijie Huaren Xiaohua Zazhi 1999;7:881-884
10 Ishihara S, Rumi MA, Kadomaki Y, et al. J Immumol,2004;173:1406-416
11 Handa O, Naito Y, Takagi T, et al. J Pharmacol Exp Ther, 2004;309:670-676
12 Tak PP, Firestein GS. J Clin Invest, 2001;107:7-11
13 Moese S, Selbach M, Meyer TF, et al. Infect Immun, 2002;70:4687-4691
14 Innocenti M, Thoreson AC, Ferrero RL, et al. Infect Immun,2002;70:4581-4590
15 周小江,谢勇,吕农华,等. COX-2 和 NF-κB 在幽门螺杆菌感染及其相关疾病中的表达及意义. 中华消化内镜杂志 2005;22:397-399
16 Wada A, Ogushi K, Kimura T, et al. Helicobacter pylori-mediated transcriptional regulation of the human beta-defensin 2gene requries NF-kappaB. Cell Microbiol;2001,3:115-123
17 J. 萨姆布鲁克, D.W. 拉塞尔 著;黄培堂 等译.分子克隆实验指南.第三版.北京:科学出版社,2002.1716-1718.
18 Ghosh S, May MJ,Koop EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses.Annu Rev Immunol.1998; 16:225-60. (Review)
19 Grimm S, Baeuerle PA.The inducible transcription factor NF-kappaB: structure- function relationship of its protein subunits.Biochem J.1993; 290:297-308.
20 Macda S, Akanuma M, Mistsunoy et al. Distinct mechanism of Helicobacter pylori-mediated NF-KappaB activation between gastric cancer cells and monolytic cells. J Biol chem;2001.276:44856-44864
21 Yamaoka Y, Kodama T, Kita M, et al. Relation between cytokines and Helicobacter pylori in gastriccancer. Helicobacter,2001;6:116-124
22 Glocker E, Lange C, Covacci A , et al. Proteins encoded by the cag pathogenicity island of Helicobacter pylori are required for NF-KappaB activation. Infect Immun,2007;5:2346-2348
23 Isomoto H, Miyazaki M, Mizuta Y,et al. Expression of nuclear factor-kappa B in Helicobacter pylori-infected gastric histoche mucosa detected with southwester mistry. Scand J Gastroenterol,2000;3:247-254
24 Holck S, Norgaard A, Bennedsen M, et al. Gastric mucosal cytokine response in Helicobacter pylori-infected patients with gastrictis and peptic ulcers Association with inflamatory parameters and bacteria load. Immunol Med Microbiol,2003;36:175-180
25 农兵,梁增文,覃江.细胞外信号调节激酶在胃癌与癌旁组织中的表达及其临床意义.山东医药,2005, 45(27):33-34
26 Watanabe T, Higuchi K, Tominaga K, Fujiwara Y, Arakawa T. Acid regulates inflamatory response in a rat model of induction of gastric ulcer recurrence by interleukin 1 beta.Gut,2001;48:774-781
27 Watanabe T, Arakawa T, Fukuda T, Higuchi K, Kobayahi K. Role of neutrophils in a rat model gastric ulcer recurrence caused by interleukin-1 beta. Am J Pathol,1997;150:97-979
28 张尤历,刘厚任,周康,等.幽门螺杆菌VacA基因型及其表达产物与胃十二指肠疾病关系的研究.中华消化杂志,2000,20:89.
29 Paoluzi OA, Rossi P, Montesano C, et al. Discrepancy between polymerase chain reaction assay and wester blot analysis in the assessment of CagA status in dyspeptic patients. Helicobacter,2001;6:130-135
30 高泽立,江佛湖,等. 产细胞毒素幽门螺杆菌与胃癌发生关系的研究.中华消化内镜杂志,2004;21:395-396
31 Wada A, Ogushi K, Kimura T, et al. Helicobacter pylori-mediated transcriptional regulation of the human beta-defesin 2 gene requires NF-kappaB. Cell Microbiol,2001;3:115-123
32 Munzenmaier A, Lange C, Glocker E, et al. A secreted/shed product of Helicobacter pylori activates transcription factor nuclear factor-kappa B. J mmunol, 1997;159: 6140- 6147
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2 Xia Harry HX, Fan XG. Talley Nicholas J. Clarithromycin resistance in Helicobacrer pylori and its clinical relevance. World J Gastroenterol 1996;5:263-266.
3 Meyer JM, Silliman NP, Dixon CA. Siepman M, Sugg JE, Hopkins RJ.Helicobacter pylori and early duodenal ulcer status post-treatment:a review. Helicobacter 2006;6:84-92
4 Casella G, Buda CA, Maisano R, Schiavo M, Perego D, Baldini V. Complete regression of primary gastric MALT-lymphoma after double eradication Helicobacter pylori therapy: role and importance of endoscopic ultrasonography. Anticancer Res 2001;21:1499-1502.
5 Hiyama T, Haruma K, Kitadai Y, Masuda H, Miyamoto M, Ito M, Kamada T, Tanaka S, Uemura N, Yoshihara M, Sumii K, Shimamoto F, Chayama K. Clinicopathological featureas of gastric mucosa-asscciated lymphoid tissue lymphoma: a comparison with diffuse large B-cell lymphoma without a mucosa-asscociated lymphoid tissue lymphoma component. J Gastroenterol Hepatol 2001;16:734-739.
6 Delchier JC, Lamarque D, Levy M, Tkoub EM, Copie-Bergman C, Deforges L, Chaumette MT, Haioun C. Helicobacter pylori and gastric lymphoma: high seroprevance of CageA in diffuse large B-cell lymphoma but not in low-large lymphoma of mucosa-associated lymphoid tissue type. Am J Gastroenterol 2001;96:2324-2328.
7 Morgner A, Miehlke S, Fischbach W, Schmitt W, Muller-Hermelink H, Greiner A, Thiede C, Schetelig J, Neubauer A, Stolte M, Ehninger G, Bayerdorffer E. Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin Oncol 2001;19:2041-2048.
8 Suganuma M, Kurusu M, Okabe S, Sueoka N, Yoshida M, Wakatsuki Y, Fujiki H. Helicobacter pylori membrance protein 1: a new carcinogenic factor of Helicobacter pylori. Cancer Res 2001;61:6356-6359.
9 Sheng T, Zhang JZ. Current statua in study of Hp UreB. Shijie Huaren Xiaohua Zazhi 1999;7:881-884
10 Ishihara S, Rumi MA, Kadomaki Y, et al. J Immumol,2004;173:1406-416
11 Handa O, Naito Y, Takagi T, et al. J Pharmacol Exp Ther, 2004;309:670-676
12 Tak PP, Firestein GS. J Clin Invest, 2001;107:7-11
13 Moese S, Selbach M, Meyer TF, et al. Infect Immun, 2002;70:4687-4691
14 Innocenti M, Thoreson AC, Ferrero RL, et al. Infect Immun,2002;70:4581-4590
15 周小江,谢勇,吕农华,等. COX-2 和 NF-κB 在幽门螺杆菌感染及其相关疾病中的表达及意义. 中华消化内镜杂志 2005;22:397-399
16 Wada A, Ogushi K, Kimura T, et al. Helicobacter pylori-mediated transcriptional regulation of the human beta-defensin 2gene requries NF-kappaB. Cell Microbiol;2001,3:115-123
17 J. 萨姆布鲁克, D.W. 拉塞尔 著;黄培堂 等译.分子克隆实验指南.第三版.北京:科学出版社,2002.1716-1718.
18 Ghosh S, May MJ,Koop EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses.Annu Rev Immunol.1998; 16:225-60. (Review)
19 Grimm S, Baeuerle PA.The inducible transcription factor NF-kappaB: structure- function relationship of its protein subunits.Biochem J.1993; 290:297-308.
20 Macda S, Akanuma M, Mistsunoy et al. Distinct mechanism of Helicobacter pylori-mediated NF-KappaB activation between gastric cancer cells and monolytic cells. J Biol chem;2001.276:44856-44864
21 Yamaoka Y, Kodama T, Kita M, et al. Relation between cytokines and Helicobacter pylori in gastriccancer. Helicobacter,2001;6:116-124
22 Glocker E, Lange C, Covacci A , et al. Proteins encoded by the cag pathogenicity island of Helicobacter pylori are required for NF-KappaB activation. Infect Immun,2007;5:2346-2348
23 Isomoto H, Miyazaki M, Mizuta Y,et al. Expression of nuclear factor-kappa B in Helicobacter pylori-infected gastric histoche mucosa detected with southwester mistry. Scand J Gastroenterol,2000;3:247-254
24 Holck S, Norgaard A, Bennedsen M, et al. Gastric mucosal cytokine response in Helicobacter pylori-infected patients with gastrictis and peptic ulcers Association with inflamatory parameters and bacteria load. Immunol Med Microbiol,2003;36:175-180
25 农兵,梁增文,覃江.细胞外信号调节激酶在胃癌与癌旁组织中的表达及其临床意义.山东医药,2005, 45(27):33-34
26 Watanabe T, Higuchi K, Tominaga K, Fujiwara Y, Arakawa T. Acid regulates inflamatory response in a rat model of induction of gastric ulcer recurrence by interleukin 1 beta.Gut,2001;48:774-781
27 Watanabe T, Arakawa T, Fukuda T, Higuchi K, Kobayahi K. Role of neutrophils in a rat model gastric ulcer recurrence caused by interleukin-1 beta. Am J Pathol,1997;150:97-979
28 张尤历,刘厚任,周康,等.幽门螺杆菌VacA基因型及其表达产物与胃十二指肠疾病关系的研究.中华消化杂志,2000,20:89.
29 Paoluzi OA, Rossi P, Montesano C, et al. Discrepancy between polymerase chain reaction assay and wester blot analysis in the assessment of CagA status in dyspeptic patients. Helicobacter,2001;6:130-135
30 高泽立,江佛湖,等. 产细胞毒素幽门螺杆菌与胃癌发生关系的研究.中华消化内镜杂志,2004;21:395-396
31 Wada A, Ogushi K, Kimura T, et al. Helicobacter pylori-mediated transcriptional regulation of the human beta-defesin 2 gene requires NF-kappaB. Cell Microbiol,2001;3:115-123
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