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Helicobacter pylori secreted peptidyl prolyl cis, trans-isomerase drives Th17 inflammation in gastric adenocarcinoma

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Abstract

Helicobacter pylori infection is characterized by an inflammatory infiltrate, consisting mainly of neutrophils and T cells. This study was undertaken to evaluate the type of gastric T cell response elicited by the secreted peptidyl prolyl cis, trans-isomerase of H. pylori (HP0175) in patients with distal gastric adenocarcinoma. The cytokine profile and the effector functions of gastric tumor-infiltrating lymphocytes (TILs) specific for HP0175 was investigated in 20 patients with distal gastric adenocarcinoma and H. pylori infection. The helper function of HP0175-specific TILs for monocyte MMP-2, MMP-9, and VEGF production was also investigated. TILs cells from H. pylori infected patients with distal gastric adenocarcinoma produced Interleukin (IL)-17 and IL-21 in response to HP0175. HP0175-specific TILs showed poor cytolytic activity while expressing helper activity for monocyte MMP-2, MMP-9 and VEGF production. These findings indicate that HP0175 is able to drive gastric Th17 response. Thus, HP0175, by promoting pro-inflammatory low cytotoxic TIL response, matrix degradation and pro-angiogenic pathways, may provide a link between H. pylori and gastric cancer.

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References

  1. Warren JR, Marshall BJ (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulcer ulceration. Lancet 1:1311–1315

    PubMed  Google Scholar 

  2. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH et al (1991) Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 325:1127–1131

    Article  CAS  PubMed  Google Scholar 

  3. Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A et al (1993) Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342:575–577

    Article  CAS  PubMed  Google Scholar 

  4. D’Elios MM, Appelmelk BJ, Amedei A, Bergman MP, Del Prete G (2004) Gastric autoimmunity: the role of Helicobacter pylori and molecular mimicry. Trends Mol Med 10:316–323

    Article  PubMed  Google Scholar 

  5. Fox JG, Wang TC (2007) Inflammation, atrophy, and gastric cancer. J Clin Invest 117:60–69

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1994) Schistosomes, liver flukes and Helicobacter pylori. Lyon, 7–14 June 1994. IARC Monogr Eval Carcinog Risks Hum 61:1–241

    Google Scholar 

  7. D’Elios MM, Manghetti M, De Carli M, Costa F, Baldari CT et al (1997) Th1 effector cells specific for Helicobacter pylori in the gastric antrum of patients with peptic ulcer disease. J Immunol 158:962–967

    PubMed  Google Scholar 

  8. Kaparakis M, Philpott DJ, Ferrero RL (2007) Mammalian NLR proteins; discriminating foe from friend. Immunol Cell Biol 85:495–502

    Article  CAS  PubMed  Google Scholar 

  9. Amedei A, Cappon A, Codolo G, Cabrelle A, Polenghi A et al (2006) The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses. J Clin Invest 116:1092–1101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Luzza F, Parrello T, Monteleone G, Sebkova L, Romano M et al (2000) Up-regulation of IL-17 is associated with bioactive IL-8 expression in Helicobacter pylori-infected human gastric mucosa. J Immunol 165:5332–5337

    CAS  PubMed  Google Scholar 

  11. Shi Y, Liu XF, Zhuang Y, Zhang JY, Liu T et al (2010) Helicobacter pylori-induced Th17 response modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. J Immunol 184:5121–5129

    Article  CAS  PubMed  Google Scholar 

  12. Caruso R, Fina D, Peluso I, Fantini MC, Tosti C et al (2007) IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis. J Immunol 178:5957–5965

    CAS  PubMed  Google Scholar 

  13. Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P et al (2008) Critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nat Immunol 9:650–657

    Article  CAS  PubMed  Google Scholar 

  14. Korn T, Bettelli E, Oukkaì M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517

    Article  CAS  PubMed  Google Scholar 

  15. Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N et al (1994) Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 269:6271–6274

    CAS  PubMed  Google Scholar 

  16. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    Article  CAS  PubMed  Google Scholar 

  17. Folkman J (2006) Angiogenesis. Annu Rev Med 57:1–18

    Article  CAS  PubMed  Google Scholar 

  18. Miossec P, Korn T, Kuchroo VK (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med 361:888–898

    Article  CAS  PubMed  Google Scholar 

  19. Cone RE, Chattopadhyay S, Sharafieh R, Lemire Y, O’Rourke J et al (2009) T cell sensitivity to TGF-β is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber. Int Immunol 21:567–574

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Sebkova L, Pellicanò A, Monteleone G, Grazioli B, Guarnieri G et al (2004) Extracellular signal-regulated protein kinase mediates interleukin 17 (IL-17)-induced IL-8 secretion in Helicobacter pylori-infected human gastric epithelial cells. Infect Immun 72:5019–5026

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25:9–34

    Article  CAS  PubMed  Google Scholar 

  22. Zhang B, Rong G, Wei H, Zhang M, Bi J et al (2008) The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun 374:533–537

    Article  CAS  PubMed  Google Scholar 

  23. Codolo G, Amedei A, Steere AC, Papinutto E, Cappon A et al (2008) Borrelia burgdorferi-NapA driven Th17 cell inflammation in Lyme arthritis. Arthritis Rheum 58:3609–3617

    Article  CAS  PubMed  Google Scholar 

  24. Pathak SK, Basu S, Bhattacharyya A, Pathak S, Banerjee A et al (2006) TLR4-dependent NF-kappaB activation and mitogen- and stress-activated protein kinase 1-triggered phosphorylation events are central to Helicobacter pylori peptidyl prolyl cis-, trans-isomerase (HP0175)-mediated induction of IL-6 release from macrophages. J Immunol 177:7950–7958

    CAS  PubMed  Google Scholar 

  25. Basu S, Pathak SK, Chatterjee G, Pathak S, Basu J et al (2008) Helicobacter pylori protein HP0175 transactivates epidermal growth factor receptor through TLR4 in gastric epithelial cells. J Biol Chem 283:32369–32376

    Article  CAS  PubMed  Google Scholar 

  26. Basak C, Pathak SK, Bhattacharyya A, Pathak S, Basu J et al (2005) The secreted peptidyl prolyl cis, trans-isomerase HP0175 of Helicobacter pylori induces apoptosis of gastric epithelial cells in a TLR4- and apoptosis signal-regulating kinase 1-dependent manner. J Immunol 174:5672–5680

    CAS  PubMed  Google Scholar 

  27. Amedei A, Niccolai E, Della Bella C, Cianchi F, Trallori G et al (2009) Characterization of tumor antigen peptide-specific T cells isolated from the neoplastic tissue of patients with gastric adenocarcinoma. Cancer Immunol Immunother 58:1819–1830

    Article  CAS  PubMed  Google Scholar 

  28. D’Elios MM, Bergman MP, Azzurri A, Amedei A, Benagiano M et al (2001) H(+), K(+)-ATPase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis. Gastroenterology 120:377–386

    Article  PubMed  Google Scholar 

  29. D’Elios MM, Amedei A, Benagiano M, Azzurri A, Del Prete G (2005) Helicobacter pylori, T cells and cytokines: the “dangerous liaisons”. FEMS Immunol Med Microbiol 44:113–119

    Article  PubMed  Google Scholar 

  30. Fox JG, Beck P, Dangler CA, Whary MT, Wang TC et al (2000) Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy. Nat Med 6:536–542

    Article  CAS  PubMed  Google Scholar 

  31. D’Elios MM, Manghetti M, Almerigogna F, Amedei A, Costa F et al (1997) Different cytokine profile and antigen-specificity repertoire in Helicobacter pylori-specific T cell clones from the antrum of chronic gastritis patients with or without peptic ulcer. Eur J Immunol 27:1751–1755

    Article  PubMed  Google Scholar 

  32. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH et al (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398–402

    Article  CAS  PubMed  Google Scholar 

  33. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH et al (2001) The role of interleukin-1 polymorphisms in the pathogenesis of gastric cancer. Nature 412:99–103

    Article  CAS  PubMed  Google Scholar 

  34. Caruso R, Fina D, Paoluz OA, Del Vecchio Blanco G, Stolfi C et al (2008) IL-23-mediated regulation of IL-17 production in Helicobacter pylori-infected gastric mucosa. Eur J Immunol 38:470–478

    Article  CAS  PubMed  Google Scholar 

  35. Zhang JY, Liu T, Guo H, Liu XF, Zhuang Y et al (2011) Induction of a Th17 cell response by Helicobacter pylori urease subunit B. J Immunol 216:803–810

    CAS  Google Scholar 

  36. D’Elios MM, Andersen LP (2009) Inflammation, immunity, and vaccines for H. pylori. Helicobacter 14(S1):21–28

    Google Scholar 

  37. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X et al (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15:1016–1022

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T et al (2006) IL-23 promotes tumour incidence and growth. Nature 442:461–465

    Article  CAS  PubMed  Google Scholar 

  39. Meulmeester E, Ten Dijke P (2011) The dynamic roles of TGF-β in cancer. J Pathol 223:205–218

    Article  CAS  PubMed  Google Scholar 

  40. Tuccillo C, Cuomo A, Rocco A, Martinelli E, Staibano S et al (2005) Vascular endothelial growth factor and neo-angiogenesis in H. pylori gastritis in humans. J Pathol 207:277–284

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Italian Ministry of University and Research Grant 2008C33HRL_003, the Italian Ministry of Health and the Istituto Superiore di Sanità (to M.M.D.E.), the Indian Council of Medical Research, Government of India (to M.K.) and Progetto di Eccellenza Fondazione Cassa di Risparmio di Padova e Rovigo and Associazione Italiana per la Ricerca sul Cancro Grant Regionale 2008 (to M.d.B.).

Conflict of interest

The authors have no financial conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy

    Amedeo Amedei, Chiara Della Bella, Elena Niccolai, Marisa Benagiano & Mario Milco D’Elios

  2. Patologia Medica, AOU Careggi Firenze, viale Morgagni 85, 50134, Florence, Italy

    Amedeo Amedei, Giacomo Emmi & Mario Milco D’Elios

  3. VIMM Padua, via Orus 2, 35129, Padua, Italy

    Fabio Munari, Giuseppe Zanotti & Marina de Bernard

  4. Division of General and Oncologic Surgery, AOU Careggi, Florence, Italy

    Lapo Bencini & Marco Farsi

  5. Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy

    Fabio Cianchi

  6. Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata, 700009, India

    Manikuntala Kundu

Authors
  1. Amedeo Amedei
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  2. Fabio Munari
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  3. Chiara Della Bella
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  10. Giuseppe Zanotti
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  11. Marina de Bernard
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  12. Manikuntala Kundu
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  13. Mario Milco D’Elios
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Corresponding author

Correspondence to Mario Milco D’Elios.

Additional information

A. Amedei and F. Munari equally contributed to the work.

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Amedei, A., Munari, F., Bella, C.D. et al. Helicobacter pylori secreted peptidyl prolyl cis, trans-isomerase drives Th17 inflammation in gastric adenocarcinoma. Intern Emerg Med 9, 303–309 (2014). https://doi.org/10.1007/s11739-012-0867-9

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  • DOI: https://doi.org/10.1007/s11739-012-0867-9

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