Инфекция и иммунитет. 2019; 9: 253-261
Механизмы взаимодействия Helicobacter pylori c эпителием слизистой оболочки желудка. II. Реакция эпителия слизистой оболочки желудка в ответ на колонизацию и персистирование H. pylori
https://doi.org/10.15789/2220-7619-2019-2-253-261Аннотация
Распространенность рецидивирующих воспалительных заболеваний желудка и двенадцатиперстной кишки велика, однако роль микробов в развитии данной патологии оставалась неясной. Переломный момент в изучении этиологии воспалительных заболеваний верхних отделов пищеварительного тракта произошел после опубликования B.J. Marshall и J.R. Warren (1983) результатов выделения Helicobacter pylori со слизистой оболочки желудка больного, страдающего гастритом, и методах культивирования этих бактерий. Большинство бактерий вида H. pylori при колонизации организма находятся в свободном состоянии, но около 20% присоединяется к эпителиальным клеткам желудка. Были проанализированы последствия взаимодействия H. pylori с эпителием слизистой оболочки желудка и активации защитных механизмов, вызванных колонизацией и циркуляцией бактерий. Показано, что наряду с запуском провоспалительного ответа, индуцированного белками VacA и CagA, в котором последний способен вызывать комплекс ответных реакций, как в фосфорилированной, так и в нефосфорилированной форме, H. pylori повреждает межклеточные контакты, нарушает полярность и пролиферацию эпителия, активирует фосфатазы SHP-2, что приводит к развитию различных клеточных ответов. Рассмотрены механизмы запуска митоген-активируемого протеинкиназного каскада (MAPK). Обсуждены способность H. pylori регулировать процесс апоптоза, а именно его подавления, через экспрессию киназы ERK и белка MCL1, что облегчает его выживание на слизистой желудка, а также позитивное влияние циркуляции бактерий на выживание эпителиоцитов посредством индукции антиапоптотических факторов в клетках эпителия желудка. В значительной мере такие процессы, как активация транскрипционных факторов (NF-κB, NFAT, SRF, T-клеточный лимфоидный энхансерный фактор [TCF/LEF]), регуляция активности белка MCL1, который в свою очередь является одним из основных антиапоптотических факторов, и индукция синтеза фактора торможения миграции (MIF) обусловливают персистенцию H. pylori. Рассмотрено участие цитотоксина VacA в индукции апоптоза эпителиоцитов посредством запуска каскадных реакций, осуществляемых каспазами. Инфицирование H. pylori сопровождается секрецией комплекса провоспалительных цитокинов, причем данные подтверждаются как in vitro, так и in vivo. Основную роль в выработке данных цитокинов играет уреаза, которая активирует транскрипционный фактор NF-κB. Кроме того, сигнальные системы эпителия желудка могут быть активированы в результате связывания бактерий с рецептором на поверхности эпителиоцитов (взаимодействие с CD74 и молекулами II класса главного комплекса гистосовместимости). Рассмотрено участие различных субпопуляций CD4+ T-клеток, в частности Т-хелперов 17 (Th17), в формировании иммунного ответа к антигенам H. pylori в слизистой оболочке желудка.
Список литературы
1. Поздеев О.К., Поздеева А.О., Валеева Ю.В., Гуляев П.Е. Механизмы взаимодействия Helicobacter pylori c эпителием слизистой оболочки желудка. I. Факторы патогенности, способствующие успешной колонизации // Инфекция и иммунитет. 2018. Т. 8, № 3. С. 273–283. doi: 10.15789/2220-7619-2018-3-273-283
2. Al-Daccak R., Mooney N., Charron D. MHC class II signaling in antigen-presenting cells. Curr. Opin. Immunol., 2004, vol. 16, no. 1, pp. 108–113. doi: 10.1016/j.coi.2003.11.006
3. Amieva M.R., El-Omar E.M. Host-bacterial interactions in Helicobacter pylori infection. Gastroenterology, 2008, vol. 134, no. 1, pp. 306–323. doi: 10.1053/j.gastro.2007.11.009
4. Amieva M.R., Vogelmann R., Covacci A., Tompkins L.S., Nelson W.J., Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science, 2003, vol. 300, no. 5624, pp. 1430–1434. doi: 10.1126/science.1081919
5. Ashktorab H., Dashwood R.H., Dashwood M.M., Zaidi S.I., Hewitt S.M., Green W.R., Lee E.L., Daremipouran M., Nouraie M., Malekzadeh R., Smoot D.T. H. pylori-induced apoptosis in human gastric cancer cells mediated via the release of apoptosis-inducing factor from mitochondria. Helicobacter, 2008, vol. 13, no. 6, pp. 506–517. doi: 10.1111/j.1523-5378.2008.00646.x
6. Bagnoli F., Buti L., Tompkins L., Covacci A., Amieva M.R. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 45, pp. 16339–16344. doi: 10.1073/pnas.0502598102
7. Barrera C.A., Beswick E.J., Sierra J.C., Bland D., Espejo R., Mifflin R., Adegboyega P., Crowe S.E., Ernst P.B. Polarized expression of CD74 by gastric epithelial cells. J. Histochem. Cytochem., 2005, vol. 53, no. 12, pp. 1481–1489. doi: 10.1369/jhc.4A6552.2005
8. Beswick E.J., Bland D.A., Suarez G., Barrera C.A., Fan X.J., Reyes V.E. Helicobacter pylori binds to CD74 on gastric epithelial cells and stimulates interleukin-8 production. Infect. Immun., 2005, vol. 73, no. 5, pp. 2736–2743. doi: 10.1128/IAI.73.5.27362743.2005
9. Beswick E.J., Pinchuk I.V., Minch K., Suarez G., Sierra J.C., Yamaoka Y., Reyes V.E. The Helicobacter pylori urease B subunit binds to CD74 on gastric epithelial cells and induces NF-kappaB activation and interleukin-8 production. Infect. Immun., 2006, vol. 74, no. 2, pp. 1148–1155. doi: 10.1128/IAI.74.2.1148-1155.2006
10. Beswick E.J., Pinchuk I.V., Suarez G., Sierra J.C., Reyes V.E. Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events. J. Immunol., 2006, vol. 176, no. 11, pp. 6794–6801. doi: 10.4049/jimmunol.176.11.6794
11. Chang Y.J., Wu M.S., Lin J.T., Pestell R.G., Blaser M.J., Chen C.C. Mechanisms for Helicobacter pylori CagA-induced cyclin D1 expression that affect cell cycle. Cell. Microbiol., 2006, vol. 8, no. 11, pp. 1740–1752. doi: 10.1111/j.1462-5822.2006.00743.x
12. Churin Y., Al-Ghoul L., Kepp O., Meyer T.E., Birchmeier W., Naumann M. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J. Cell. Biol., 2003, vol. 161, no. 2, pp. 249–255. doi: 10.1083/jcb.200208039
13. Crabtree J.E., Farmery S.M., Lindley I.J., Figura N., Peichl P., Tompkins D.S. CagA/cytotoxic strains of Helicobacter pylori and interleukin-8 in gastric epithelial cell lines. J. Clin. Pathol., 1994, vol. 47, no. 10, pp. 945–950. doi: 10.1136/jcp.47.10.945
14. Crabtree J.E., Naumann M. Epithelial cell signaling in Helicobacter pylori infection. Curr. Signal Transd., 2006, vol. 1, no. 1, pp. 53–65. doi: 10.2174/157436206775269253
15. Crabtree J.E., Shallcross T.M., Heatley R.V., Wyatt J.I. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut, 1991, vol. 32 , no. 12, pp. 1473–1477. doi: 10.1136/gut.32.12.1473
16. Crabtree J.E., Wyatt J.I., Trejdosiewicz L.K., Peichl P., Nichols P.H., Ramsay N., Primrose J.N., Lindley I.J.D. Interleukin-8 expression in Helicobacter pylori infected, normal, and neoplastic gastroduodenal mucosa. J. Clin. Pathol., 1994, vol. 47, no. 1, pp. 61–66. doi: 10.1136/jcp.47.1.61
17. De Guzman B.B., Hisatsune J., Nakayama M., Yahiro K., Wada A., Yamasaki E., Nishi Y., Yamazaki S., Azuma T., Ito Y., Ohtani M., van der Wijk T., den Hertog J., Moss J., Hirayama T. Cytotoxicity and recognition of receptor-like protein tyrosine phosphatases, RPTPalpha and RPTPbeta, by Helicobacter pylori m2VacA. Cell. Microbiol., 2005, vol. 7, no. 9, pp. 1285–1293. doi: 10.1111/j.1462-5822.2005.00556.x
18. Fan X., Crowe S.E., Behar S., Gunasena H., Ye G., Haeberle H., Van Houten N., Gourley W.K., Ernst P.B., Reyes V.E. The effect of class II major histocompatibility complex expression on adherence of Helicobacter pylori and induction of apoptosis in gastric epithelial cells: a mechanism for T helper cell type 1-mediated damage. J. Exp. Med., 1998, vol. 187, no. 10, pp. 1659–1669. doi: 10.1084/jem.187.10.1659
19. Fan X., Gunasena H., Cheng Z., Espejo R., Crowe S.E., Ernst P.B., Reyes V.E. Helicobacter pylori urease binds to class II MHC on gastric epithelial cells and induces their apoptosis. J. Immunol., 2000, vol. 165, no. 4, pp. 1918–1924. doi: 10.4049/jimmunol.165.4.1918
20. Fischer W., Prassl S., Haas R. Virulence mechanisms and persistence strategies of the human gastric pathogen Helicobacter pylori. Curr. Top. Microbiol. Immunol., 2009, vol. 337, pp. 129–171. doi: 10.1007/978-3-642-01846-6_5
21. Higashi H., Tsutsumi R., Muto S., Sugiyama T., Azuma T., Asaka M., Hatakeyama M. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science, 2002, vol. 295, no. 5555, pp. 683–686. doi: 10.1126/science.1067147.
22. Ishiguro Y., Ohkawara T., Sakuraba H., Yamagata K., Hiraga H., Yamaguchi S., Fukuda S., Munakata A., Nakane A., Nishihira J. Macrophage migration inhibitory factor has a proinflammatory activity via the p38 pathway in glucocorticoid-resistant ulcerative colitis. Clin. Immunol., 2006, vol. 120, no. 3, pp. 335–341. doi: 10.1016/j.clim.2006.05.010
23. Iwai H., Kim M., Yoshikawa Y., Ashida H., Ogawa M., Fujita Y., Muller D., Kirikae T., Jackson P.K., Kotani S., Sasakawa C. A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling. Cell, 2007, vol. 130, no. 4, pp. 611–623. doi: 10.1016/j.cell.2007.06.043
24. Jung H.C., Kim J.M., Song I.S., Kim C.Y. Helicobacter pylori induces an array of pro-inflammatory cytokines in human gastric epithelial cells: quantification of mRNA for interleukin-8, -1 alpha/beta, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1 and tumour necrosis factor-alpha. J. Gastroenterol. Hepatol., 1997, vol. 12, no. 7, pp. 473– 480. doi: 10.1111/j.1440-1746.1997.tb00469.x
25. Kabir S. The role of interleukin-17 in the Helicobacter pylori induced infection and immunity. Helicobacter, 2011, vol. 16, no. 1, pp. 1–8. doi: 10.1111/j.1523-5378.2010.00812.x
26. Keates S., Keates A.C., Warny M., Peek R.M. Jr, Murray P.G., Kelly C.P. Differential activation on of mitogen-activated protein kinases in AGS gastric ati epithelial cells by cag+ and cag– Helicobacter pylori. J. Immunol., 1999, vol. 163, no. 10, pp. 5552–5559.
27. Lu H., Murata-Kamiya N., Saito Y., Hatakeyama M. Role of partitioning-defective 1/microtubule affinity-regulating kinases in the morphogenetic activity of Helicobacter pylori CagA. J. Biol. Chem., 2009, vol. 284, no. 34, pp. 23024–23036. doi: 10.1074/jbc.M109.001008
28. Lu H., Wu J.Y., Kudo T., Ohno T., Graham D.Y., Yamaoka Y. Regulation of interleukin-6 promoter activation in gastric epithelial cells infected with Helicobacter pylori. Mol. Biol. Cell, 2005, vol. 16, no. 10, pp. 4954–4966. doi: 10.1091/mbc.E05-05-0426
29. Matsushima K., Shiroo M., Kung H.F., Copeland T.D. Purification and characterization of a cytosolic 65-kilodalton phosphoprotein in human leukocytes whose phosphorylation is augmented by stimulation with interleukin 1. Biochemistry, 1988, vol. 27, no. 10, pp. 3765–3770. doi: 10.1021/bi00410a037
30. Mimuro H., Suzuki T., Nagai S., Rieder G., Suzuki M., Nagai T., Fujita Y., Nagamatsu K., Ishijima N., Koyasu S., Haas R., Sasakawa C. Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach. Cell Host Microbe, 2007, vol. 2, no. 4, pp. 250–263. doi: 10.1016/j.chom.2007.09.005
31. Mimuro H., Suzuki T., Tanaka J., Asahi M., Haas R., Sasakawa C. Grb2 is a key mediator of helicobacter pylori CagA protein activities. Mol. Cell, 2002, vol. 10, no. 4, pp. 745–755. doi: 10.1016/S1097-2765(02)00681-0
32. Mitchell R.A., Liao H., Chesney J., Fingerle-Rowson G., Baugh J., David J., Bucala R. Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc Natl. Acad. Sci. USA, 2002, vol. 99, no. 1, pp. 345–350. doi: 10.1073/pnas.012511599
33. Mizuno T., Ando T., Nobata K., Tsuzuki T., Maeda O., Watanabe O., Minami M., Ina K., Kusugami K., Peek R.M., Goto H. Interleukin-17 levels in Helicobacter pylori-infected gastric mucosa and pathologic sequelae of colonization. World J. Gastroenterol., 2005, vol. 11, no. 40, pp. 6305–6311. doi: 10.3748/wjg.v11.i40.6305
34. Murata-Kamiya N., Kurashima Y., Teishikata Y., Yamahashi Y., Saito Y., Higashi H., Aburatani H., Akiyama T., Peek R.M., Azuma T., Hatakeyama M. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene, 2007, vol. 26, no. 32, pp. 4617–4626. doi: 10.1038/sj.onc.1210251
35. Odenbreit S., Kavermann H., Püls J., Haas R. CagA tyrosine phosphorylation and interleukin-8 induction by Helicobacter pylori are independent from alpAB, HopZ and bab group outer membrane proteins. Int. J. Med. Microbiol., 2002, vol. 292, no. 3–4, pp. 257–266. doi: 10.1078/1438-4221-00205
36. Olivares D., Gisbert J.P., Pajares J.M. Helicobacter pylori infection and gastric mucosal epithelial cell apoptosis. Rev. Esp. Enferm. Dig., 2005, vol. 97, no. 7, pp. 505–520.
37. Oppenheim J.J., Zachariae C.O., Mukaida N., Matsushima K. Properties of the novel proinflammatory supergene “intercrine” cytokine family. Annu. Rev. Immunol., 1991, vol. 9, pp. 617–648. doi: 10.1146/annurev.iy.09.040191.003153
38. Parsons J.T. Focal adhesion kinase: the first ten years. J. Cell. Science, 2003, vol. 116, no. 8, pp. 1409–1416. doi: 10.1242/jcs.00373
39. Pinchuk I.V., Morris K.T., Nofchissey R.A., Earley R.B., Wu J.Y., Ma T.Y., Beswick E.J. Stromal cells induce Th17 during Helicobacter pylori infection and in the gastric tumor microenvironment. PLoS One, 2013, vol. 8, no. 1, pp. e53798. doi: 10.1371/journal.pone.0053798
40. Saadat I., Higashi H., Obuse C., Umeda M., Murata-Kamiya N., Saito Y., Lu H.S., Ohnishi N., Azuma T., Suzuki A., Ohno S., Hatakeyama M. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature, 2007, vol. 447, no. 7142, pp. 330–333. doi: 10.1038/nature05765
41. Saberi S., Douraghi M., Azadmanesh K., Shokrgozar M.A., Zeraati H., Hosseini M.E., Mohagheghi M.A., Parsaeian M., Mohammadi M. A potential association between Helicobacter pylori CagA EPIYA and multimerization motifs with cytokeratin 18 cleavage rate during early apoptosis. Helicobacter, 2012, vol. 17, no. 5, pp. 350–357. doi: 10.1111/j.1523-5378.2012.00954.x
42. Sebkova L., Pellicanò A., Monteleone G., Grazioli B., Guarnieri G., Imeneo M., Pallone F., Luzza F. Extracellular signal-regulated protein kinase mediates interleukin 17 (IL-17)-induced IL-8 secretion in Helicobacter pylori-infected human gastric epithelial cells. Infect. Immun., 2004, vol. 72, no. 9, pp. 5019–5026. doi: 10.1128/IAI.72.9.5019-5026.2004
43. Shi Y., Liu X.F., Zhuang Y., Zhang J.Y., Liu T., Yin Z., Wu C., Mao X.H., Jia K.R., Wang F.J., Guo H., Flavell R.A., Zhao Z., Liu K.Y., Xiao B., Guo Y., Zhang W.J., Zhou W.Y., Guo G., Zou Q.M. Helicobacter pylori-induced Th17 responses modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. J. Immunol., 2010, vol. 184, no. 9, pp. 5121–5129. doi: 10.4049/jimmunol.0901115
44. Tan S., Tompkins L.S., Amieva M.R. Helicobacter pylori usurps cell polarity to turn the cell surface into a replicative niche. PLoS Pathog., 2009, vol. 5, no. 5: e1000407. doi: 10.1371/journal.ppat.1000407
45. Tanahashi T., Kita M., Kodama T., Yamaoka Y., Sawai N., Ohno T., Mitsufuji S., Wei Y.P., Kashima K., Imanishi J. Cytokine expression and production by purified Helicobacter pylori urease in human gastric epithelial cells. Infect. Immun., 2000, vol. 68, no. 2, pp. 664–671. doi: 10.1128/IAI.68.2.664-671.2000
46. Wessler S., Backert S. Molecular mechanisms of epithelial-barrier disruption by Helicobacter pylori. Trends Microbiol., 2008, vol. 16, no. 8, pp. 397–405. doi: 10.1016/j.tim.2008.05.005
47. Wessler S., Höcker M., Fischer W., Wang T.C., Rosewicz S., Haas R., Wiedenmann B., Meyer T.F., Naumann M. Helicobacter pylori activates the histidine decarboxylase promoter through a mitogen-activated protein kinase pathway independent of pathogenicity island-encoded virulence factors. J. Biol. Chem., 2000, vol. 275, no. 5, pp. 3629–3636. doi: 10.1074/jbc.275.5.3629
48. Xia H.H., Talley N.J. Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis. Am. J. Gastroenterol., 2001, vol. 96, no. 1, pp. 16–26. doi: 10.1016/S0002-9270(00)02240-1
49. Xia Z., Dickens M., Raingeaud J., Davis R.J., Greenberg M.E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science, 1995, vol. 270, no. 5240, pp. 1326–1331. doi: 10.1126/science.270.5240.1326
50. Xiong S., Mu T., Wang G., Jiang X. Mitochondria-mediated apoptosis in mammals. Protein Cell., 2014, vol. 5, no. 10, pp. 737–749. doi: 10.1007/s13238-014-0089-1
51. Yokoyama K., Higashi H., Ishikawa S., Fujii Y., Kondo S., Kato H., Azuma T., Wada A., Hirayama T., Aburatani H., Hatakeyama M. Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 27, pp. 9661–9666. doi: 10.1073/pnas.0502529102
Russian Journal of Infection and Immunity. 2019; 9: 253-261
Mechanisms of interacting Helicobacter pylori with gastric mucosal epithelium. II. A reaction of gastric epithelium on Helicobacter pylori colonization and persistence
https://doi.org/10.15789/2220-7619-2019-2-253-261Abstract
Gastric and duodenal recurrent inflammatory diseases have a high prevalence, but the role played by microbes in its development remained unclear. However, the data published in 1983 by Marshall and Warren about isolating Helicobacter pylori from the stomach mucosa of the patient with gastritis and proposing relevant cultivation methods was the turning point in investigating etiology of the upper digestive tract inflammatory disorders. Moreover, it was shown that the majority of H. pylori spp. are found within the gastric lumen upon colonization, whereas around 20% of them are attached to the epithelial cells in the stomach. In addition, effects of interacting H. pylori with gastric epithelium and activation of some defense mechanisms due to bacterial colonization and spreading were analyzed. It was found that along with triggering pro-inflammatory response induced by proteins VacA as well as phosphorylated/unphosphorylated CagA, wherein the latter is able to induce a set of protective reactions H. pylori disrupts intercellular contacts, affects epithelial cell polarity and proliferation, and activates SHP-2 phosphatase resulting in emerging diverse types of cellular responses. The activation mechanisms for the mitogen-activated protein kinase (MAPK) pathway were discussed. The ability of H. pylori to regulate apoptosis, particularly via its suppression, by expressing ERK kinase and protein MCL1 facilitating bacterial survival in the gastric mucosa as well as beneficial effects related to bacterial circulation on gastric epithelial cell survival elicited by anti-apoptotic factors were also examined. Of note, persistence of H. pylori are mainly determined by activating transcriptional factors including NF-κB, NFAT, SRF, T-cell lymphoid enhancing factor (TCF/LEF), regulating activity of MCL1 protein, in turn, being one of the main anti-apoptotic factors, as well as induced production of the migration inhibitory factor (MIF). The role of VacA cytotoxin in triggering epithelial cell apoptosis via caspase-mediated pathways was also considered. Infection with H. pylori is accompanied by release of proinflammatory cytokine cocktail detected both in vitro and in vivo. In particular, bacterial urease activating transcriptional factor NF-κB was shown to play a crucial role in inducing cytokine production. Moreover, such signaling pathways may be activated after H. pylori is attached to the cognate receptor in the gastric epithelial surface by interacting with CD74 and MHC class II molecules. Finally, a role for various CD4+ T cell subsets, particularly type 17 T helper cells (Th17) in inducing immune response against H. pylori antigens in gastric mucosa was revealed were also discussed.
References
1. Pozdeev O.K., Pozdeeva A.O., Valeeva Yu.V., Gulyaev P.E. Mekhanizmy vzaimodeistviya Helicobacter pylori c epiteliem slizistoi obolochki zheludka. I. Faktory patogennosti, sposobstvuyushchie uspeshnoi kolonizatsii // Infektsiya i immunitet. 2018. T. 8, № 3. S. 273–283. doi: 10.15789/2220-7619-2018-3-273-283
2. Al-Daccak R., Mooney N., Charron D. MHC class II signaling in antigen-presenting cells. Curr. Opin. Immunol., 2004, vol. 16, no. 1, pp. 108–113. doi: 10.1016/j.coi.2003.11.006
3. Amieva M.R., El-Omar E.M. Host-bacterial interactions in Helicobacter pylori infection. Gastroenterology, 2008, vol. 134, no. 1, pp. 306–323. doi: 10.1053/j.gastro.2007.11.009
4. Amieva M.R., Vogelmann R., Covacci A., Tompkins L.S., Nelson W.J., Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science, 2003, vol. 300, no. 5624, pp. 1430–1434. doi: 10.1126/science.1081919
5. Ashktorab H., Dashwood R.H., Dashwood M.M., Zaidi S.I., Hewitt S.M., Green W.R., Lee E.L., Daremipouran M., Nouraie M., Malekzadeh R., Smoot D.T. H. pylori-induced apoptosis in human gastric cancer cells mediated via the release of apoptosis-inducing factor from mitochondria. Helicobacter, 2008, vol. 13, no. 6, pp. 506–517. doi: 10.1111/j.1523-5378.2008.00646.x
6. Bagnoli F., Buti L., Tompkins L., Covacci A., Amieva M.R. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 45, pp. 16339–16344. doi: 10.1073/pnas.0502598102
7. Barrera C.A., Beswick E.J., Sierra J.C., Bland D., Espejo R., Mifflin R., Adegboyega P., Crowe S.E., Ernst P.B. Polarized expression of CD74 by gastric epithelial cells. J. Histochem. Cytochem., 2005, vol. 53, no. 12, pp. 1481–1489. doi: 10.1369/jhc.4A6552.2005
8. Beswick E.J., Bland D.A., Suarez G., Barrera C.A., Fan X.J., Reyes V.E. Helicobacter pylori binds to CD74 on gastric epithelial cells and stimulates interleukin-8 production. Infect. Immun., 2005, vol. 73, no. 5, pp. 2736–2743. doi: 10.1128/IAI.73.5.27362743.2005
9. Beswick E.J., Pinchuk I.V., Minch K., Suarez G., Sierra J.C., Yamaoka Y., Reyes V.E. The Helicobacter pylori urease B subunit binds to CD74 on gastric epithelial cells and induces NF-kappaB activation and interleukin-8 production. Infect. Immun., 2006, vol. 74, no. 2, pp. 1148–1155. doi: 10.1128/IAI.74.2.1148-1155.2006
10. Beswick E.J., Pinchuk I.V., Suarez G., Sierra J.C., Reyes V.E. Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events. J. Immunol., 2006, vol. 176, no. 11, pp. 6794–6801. doi: 10.4049/jimmunol.176.11.6794
11. Chang Y.J., Wu M.S., Lin J.T., Pestell R.G., Blaser M.J., Chen C.C. Mechanisms for Helicobacter pylori CagA-induced cyclin D1 expression that affect cell cycle. Cell. Microbiol., 2006, vol. 8, no. 11, pp. 1740–1752. doi: 10.1111/j.1462-5822.2006.00743.x
12. Churin Y., Al-Ghoul L., Kepp O., Meyer T.E., Birchmeier W., Naumann M. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J. Cell. Biol., 2003, vol. 161, no. 2, pp. 249–255. doi: 10.1083/jcb.200208039
13. Crabtree J.E., Farmery S.M., Lindley I.J., Figura N., Peichl P., Tompkins D.S. CagA/cytotoxic strains of Helicobacter pylori and interleukin-8 in gastric epithelial cell lines. J. Clin. Pathol., 1994, vol. 47, no. 10, pp. 945–950. doi: 10.1136/jcp.47.10.945
14. Crabtree J.E., Naumann M. Epithelial cell signaling in Helicobacter pylori infection. Curr. Signal Transd., 2006, vol. 1, no. 1, pp. 53–65. doi: 10.2174/157436206775269253
15. Crabtree J.E., Shallcross T.M., Heatley R.V., Wyatt J.I. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut, 1991, vol. 32 , no. 12, pp. 1473–1477. doi: 10.1136/gut.32.12.1473
16. Crabtree J.E., Wyatt J.I., Trejdosiewicz L.K., Peichl P., Nichols P.H., Ramsay N., Primrose J.N., Lindley I.J.D. Interleukin-8 expression in Helicobacter pylori infected, normal, and neoplastic gastroduodenal mucosa. J. Clin. Pathol., 1994, vol. 47, no. 1, pp. 61–66. doi: 10.1136/jcp.47.1.61
17. De Guzman B.B., Hisatsune J., Nakayama M., Yahiro K., Wada A., Yamasaki E., Nishi Y., Yamazaki S., Azuma T., Ito Y., Ohtani M., van der Wijk T., den Hertog J., Moss J., Hirayama T. Cytotoxicity and recognition of receptor-like protein tyrosine phosphatases, RPTPalpha and RPTPbeta, by Helicobacter pylori m2VacA. Cell. Microbiol., 2005, vol. 7, no. 9, pp. 1285–1293. doi: 10.1111/j.1462-5822.2005.00556.x
18. Fan X., Crowe S.E., Behar S., Gunasena H., Ye G., Haeberle H., Van Houten N., Gourley W.K., Ernst P.B., Reyes V.E. The effect of class II major histocompatibility complex expression on adherence of Helicobacter pylori and induction of apoptosis in gastric epithelial cells: a mechanism for T helper cell type 1-mediated damage. J. Exp. Med., 1998, vol. 187, no. 10, pp. 1659–1669. doi: 10.1084/jem.187.10.1659
19. Fan X., Gunasena H., Cheng Z., Espejo R., Crowe S.E., Ernst P.B., Reyes V.E. Helicobacter pylori urease binds to class II MHC on gastric epithelial cells and induces their apoptosis. J. Immunol., 2000, vol. 165, no. 4, pp. 1918–1924. doi: 10.4049/jimmunol.165.4.1918
20. Fischer W., Prassl S., Haas R. Virulence mechanisms and persistence strategies of the human gastric pathogen Helicobacter pylori. Curr. Top. Microbiol. Immunol., 2009, vol. 337, pp. 129–171. doi: 10.1007/978-3-642-01846-6_5
21. Higashi H., Tsutsumi R., Muto S., Sugiyama T., Azuma T., Asaka M., Hatakeyama M. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science, 2002, vol. 295, no. 5555, pp. 683–686. doi: 10.1126/science.1067147.
22. Ishiguro Y., Ohkawara T., Sakuraba H., Yamagata K., Hiraga H., Yamaguchi S., Fukuda S., Munakata A., Nakane A., Nishihira J. Macrophage migration inhibitory factor has a proinflammatory activity via the p38 pathway in glucocorticoid-resistant ulcerative colitis. Clin. Immunol., 2006, vol. 120, no. 3, pp. 335–341. doi: 10.1016/j.clim.2006.05.010
23. Iwai H., Kim M., Yoshikawa Y., Ashida H., Ogawa M., Fujita Y., Muller D., Kirikae T., Jackson P.K., Kotani S., Sasakawa C. A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling. Cell, 2007, vol. 130, no. 4, pp. 611–623. doi: 10.1016/j.cell.2007.06.043
24. Jung H.C., Kim J.M., Song I.S., Kim C.Y. Helicobacter pylori induces an array of pro-inflammatory cytokines in human gastric epithelial cells: quantification of mRNA for interleukin-8, -1 alpha/beta, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1 and tumour necrosis factor-alpha. J. Gastroenterol. Hepatol., 1997, vol. 12, no. 7, pp. 473– 480. doi: 10.1111/j.1440-1746.1997.tb00469.x
25. Kabir S. The role of interleukin-17 in the Helicobacter pylori induced infection and immunity. Helicobacter, 2011, vol. 16, no. 1, pp. 1–8. doi: 10.1111/j.1523-5378.2010.00812.x
26. Keates S., Keates A.C., Warny M., Peek R.M. Jr, Murray P.G., Kelly C.P. Differential activation on of mitogen-activated protein kinases in AGS gastric ati epithelial cells by cag+ and cag– Helicobacter pylori. J. Immunol., 1999, vol. 163, no. 10, pp. 5552–5559.
27. Lu H., Murata-Kamiya N., Saito Y., Hatakeyama M. Role of partitioning-defective 1/microtubule affinity-regulating kinases in the morphogenetic activity of Helicobacter pylori CagA. J. Biol. Chem., 2009, vol. 284, no. 34, pp. 23024–23036. doi: 10.1074/jbc.M109.001008
28. Lu H., Wu J.Y., Kudo T., Ohno T., Graham D.Y., Yamaoka Y. Regulation of interleukin-6 promoter activation in gastric epithelial cells infected with Helicobacter pylori. Mol. Biol. Cell, 2005, vol. 16, no. 10, pp. 4954–4966. doi: 10.1091/mbc.E05-05-0426
29. Matsushima K., Shiroo M., Kung H.F., Copeland T.D. Purification and characterization of a cytosolic 65-kilodalton phosphoprotein in human leukocytes whose phosphorylation is augmented by stimulation with interleukin 1. Biochemistry, 1988, vol. 27, no. 10, pp. 3765–3770. doi: 10.1021/bi00410a037
30. Mimuro H., Suzuki T., Nagai S., Rieder G., Suzuki M., Nagai T., Fujita Y., Nagamatsu K., Ishijima N., Koyasu S., Haas R., Sasakawa C. Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach. Cell Host Microbe, 2007, vol. 2, no. 4, pp. 250–263. doi: 10.1016/j.chom.2007.09.005
31. Mimuro H., Suzuki T., Tanaka J., Asahi M., Haas R., Sasakawa C. Grb2 is a key mediator of helicobacter pylori CagA protein activities. Mol. Cell, 2002, vol. 10, no. 4, pp. 745–755. doi: 10.1016/S1097-2765(02)00681-0
32. Mitchell R.A., Liao H., Chesney J., Fingerle-Rowson G., Baugh J., David J., Bucala R. Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc Natl. Acad. Sci. USA, 2002, vol. 99, no. 1, pp. 345–350. doi: 10.1073/pnas.012511599
33. Mizuno T., Ando T., Nobata K., Tsuzuki T., Maeda O., Watanabe O., Minami M., Ina K., Kusugami K., Peek R.M., Goto H. Interleukin-17 levels in Helicobacter pylori-infected gastric mucosa and pathologic sequelae of colonization. World J. Gastroenterol., 2005, vol. 11, no. 40, pp. 6305–6311. doi: 10.3748/wjg.v11.i40.6305
34. Murata-Kamiya N., Kurashima Y., Teishikata Y., Yamahashi Y., Saito Y., Higashi H., Aburatani H., Akiyama T., Peek R.M., Azuma T., Hatakeyama M. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene, 2007, vol. 26, no. 32, pp. 4617–4626. doi: 10.1038/sj.onc.1210251
35. Odenbreit S., Kavermann H., Püls J., Haas R. CagA tyrosine phosphorylation and interleukin-8 induction by Helicobacter pylori are independent from alpAB, HopZ and bab group outer membrane proteins. Int. J. Med. Microbiol., 2002, vol. 292, no. 3–4, pp. 257–266. doi: 10.1078/1438-4221-00205
36. Olivares D., Gisbert J.P., Pajares J.M. Helicobacter pylori infection and gastric mucosal epithelial cell apoptosis. Rev. Esp. Enferm. Dig., 2005, vol. 97, no. 7, pp. 505–520.
37. Oppenheim J.J., Zachariae C.O., Mukaida N., Matsushima K. Properties of the novel proinflammatory supergene “intercrine” cytokine family. Annu. Rev. Immunol., 1991, vol. 9, pp. 617–648. doi: 10.1146/annurev.iy.09.040191.003153
38. Parsons J.T. Focal adhesion kinase: the first ten years. J. Cell. Science, 2003, vol. 116, no. 8, pp. 1409–1416. doi: 10.1242/jcs.00373
39. Pinchuk I.V., Morris K.T., Nofchissey R.A., Earley R.B., Wu J.Y., Ma T.Y., Beswick E.J. Stromal cells induce Th17 during Helicobacter pylori infection and in the gastric tumor microenvironment. PLoS One, 2013, vol. 8, no. 1, pp. e53798. doi: 10.1371/journal.pone.0053798
40. Saadat I., Higashi H., Obuse C., Umeda M., Murata-Kamiya N., Saito Y., Lu H.S., Ohnishi N., Azuma T., Suzuki A., Ohno S., Hatakeyama M. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature, 2007, vol. 447, no. 7142, pp. 330–333. doi: 10.1038/nature05765
41. Saberi S., Douraghi M., Azadmanesh K., Shokrgozar M.A., Zeraati H., Hosseini M.E., Mohagheghi M.A., Parsaeian M., Mohammadi M. A potential association between Helicobacter pylori CagA EPIYA and multimerization motifs with cytokeratin 18 cleavage rate during early apoptosis. Helicobacter, 2012, vol. 17, no. 5, pp. 350–357. doi: 10.1111/j.1523-5378.2012.00954.x
42. Sebkova L., Pellicanò A., Monteleone G., Grazioli B., Guarnieri G., Imeneo M., Pallone F., Luzza F. Extracellular signal-regulated protein kinase mediates interleukin 17 (IL-17)-induced IL-8 secretion in Helicobacter pylori-infected human gastric epithelial cells. Infect. Immun., 2004, vol. 72, no. 9, pp. 5019–5026. doi: 10.1128/IAI.72.9.5019-5026.2004
43. Shi Y., Liu X.F., Zhuang Y., Zhang J.Y., Liu T., Yin Z., Wu C., Mao X.H., Jia K.R., Wang F.J., Guo H., Flavell R.A., Zhao Z., Liu K.Y., Xiao B., Guo Y., Zhang W.J., Zhou W.Y., Guo G., Zou Q.M. Helicobacter pylori-induced Th17 responses modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. J. Immunol., 2010, vol. 184, no. 9, pp. 5121–5129. doi: 10.4049/jimmunol.0901115
44. Tan S., Tompkins L.S., Amieva M.R. Helicobacter pylori usurps cell polarity to turn the cell surface into a replicative niche. PLoS Pathog., 2009, vol. 5, no. 5: e1000407. doi: 10.1371/journal.ppat.1000407
45. Tanahashi T., Kita M., Kodama T., Yamaoka Y., Sawai N., Ohno T., Mitsufuji S., Wei Y.P., Kashima K., Imanishi J. Cytokine expression and production by purified Helicobacter pylori urease in human gastric epithelial cells. Infect. Immun., 2000, vol. 68, no. 2, pp. 664–671. doi: 10.1128/IAI.68.2.664-671.2000
46. Wessler S., Backert S. Molecular mechanisms of epithelial-barrier disruption by Helicobacter pylori. Trends Microbiol., 2008, vol. 16, no. 8, pp. 397–405. doi: 10.1016/j.tim.2008.05.005
47. Wessler S., Höcker M., Fischer W., Wang T.C., Rosewicz S., Haas R., Wiedenmann B., Meyer T.F., Naumann M. Helicobacter pylori activates the histidine decarboxylase promoter through a mitogen-activated protein kinase pathway independent of pathogenicity island-encoded virulence factors. J. Biol. Chem., 2000, vol. 275, no. 5, pp. 3629–3636. doi: 10.1074/jbc.275.5.3629
48. Xia H.H., Talley N.J. Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis. Am. J. Gastroenterol., 2001, vol. 96, no. 1, pp. 16–26. doi: 10.1016/S0002-9270(00)02240-1
49. Xia Z., Dickens M., Raingeaud J., Davis R.J., Greenberg M.E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science, 1995, vol. 270, no. 5240, pp. 1326–1331. doi: 10.1126/science.270.5240.1326
50. Xiong S., Mu T., Wang G., Jiang X. Mitochondria-mediated apoptosis in mammals. Protein Cell., 2014, vol. 5, no. 10, pp. 737–749. doi: 10.1007/s13238-014-0089-1
51. Yokoyama K., Higashi H., Ishikawa S., Fujii Y., Kondo S., Kato H., Azuma T., Wada A., Hirayama T., Aburatani H., Hatakeyama M. Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 27, pp. 9661–9666. doi: 10.1073/pnas.0502529102
