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01-04-2018 | Original Article

Therapy with omeprazole modulates regulatory T cell/T helper 17 immune response in children with duodenal ulcers

Authors: Chuan-Ying Li, Cheng Wu

Published in: Inflammopharmacology | Issue 2/2018

Abstract

The purpose of this study was to determine the effect of omeprazole on the regulatory T cell (Treg) and T helper 17 (Th17)-mediated response in patients with duodenal ulcers (DUs). DU patients were randomly divided into omeprazole and colloid bismuth subcitrate treatment groups. The ratios of Th17 and Treg in peripheral blood mononuclear cells (PBMCs) were measured. Cytokine production and Foxp3⁺- and RORγt-positive cells were detected. The expressions of STAT3, p-STAT3, STAT5 and p-STAT5 were detected by Western blot. The results showed that DU patients had an imbalanced Treg/Th17 response, as reflected by the higher IL-17 level and Th17 ratio and lower IL-10 level and Treg proportion in serum compared with those in the healthy volunteers. The administration of omeprazole to the patients significantly increased Treg and IL-10 levels and reduced Th17 and IL-17 levels. Omeprazole markedly increased the number of Foxp3-positive cells, decreased the number of RORγt-positive cells and restored the balanced ratio of IL-10/IL-17 in the ulcer tissue. Interestingly, we observed a negative correlation between the ratios of Treg/Th17 and the pathological scores in damaged tissues. Of note, H. pylori-infected PBMCs showed decreased Treg and an increased Th17 proportion, which could be reversed by omeprazole. Finally, omeprazole increased the expression of p-STAT5 and reduced the level of p-STAT3 without any effects on the total expression of STAT5 and STAT3. Our data suggest that omeprazole treatment restores the equilibrium of the Treg/Th17-mediated response in DU patients. Moreover, the modulation of p-STAT3 and p-STAT5 expression by omeprazole induced balanced polarisation of Treg/Th17.

Alkim H, Unal S, Okur H, Imir T (2008) Omeprazole inhibits natural killer cell functions. Dig Dis Sci 53:347–351CrossRefPubMed

Araújo MB, Borini P, Guimarães RC (2014) Etiopathogenesis of peptic ulcer: back to the past? Arq Gastroenterol 51:155–161CrossRefPubMed

Cook KW, Letley DP, Ingram RJ, Staples E, Skjoldmose H, Atherton JC, Robinson K (2014) CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa. Gut 63:1550–1559CrossRefPubMedPubMedCentral

Gardner PJ, Joshi L, Lee RW, Dick AD, Adamson P, Calder VL (2013) SIRT1 activation protects against autoimmune T cell-driven retinal disease in mice via inhibition of IL-2/Stat5 signaling. J Autoimmun 42:117–129CrossRefPubMed

Goll R, Cui G, Olsen T, Isaksen V, Gruber F, Husebekk A, Florholmen J (2008) Alterations in antral cytokine gene expression in peptic ulcer patients during ulcer healing and after Helicobacter pylori eradication. Scand J Immunol 67:57–62PubMed

Hernández C, Serrano C, Einisman H, Villagrán A, Pena A, Duarte I, Torres J, Riera F, Harris PR (2014) Peptic ulcer disease in Helicobacter pylori-infected children: clinical findings and mucosal immune response. J Pediatr Gastroenterol Nutr 59:773–778CrossRefPubMed

Holck S, Nørgaard A, Bennedsen M, Permin H, Norn S, Andersen LP (2003) Gastric mucosal cytokine responses in Helicobacter pylori-infected patients with gastritis and peptic ulcers. Association with inflammatory parameters and bacteria load. FEMS Immunol Med Microbiol 36:175–180CrossRefPubMed

Ihan A, Tepes B, Gubina M (2000) Diminished Th1-type cytokine production in gastric mucosa T-lymphocytes after H. pylori eradication in duodenal ulcer patients. Pflugers Arch 440:R89–90CrossRefPubMed

Itoh T, Seno H, Kita T, Chiba T, Wakatsuki Y (2005) Th response to Helicobacter pylori differs between patients with gastric ulcer and duodenal ulcer. Scand J Gastroenterol 40:641–647CrossRefPubMed

Knosp CA, Johnston JA (2012) Regulation of CD4 + T-cell polarisation by suppressor of cytokine signalling proteins. Immunology 135:101–111CrossRefPubMedPubMedCentral

Kondo Y, Joh T, Sasaki M, Oshima T, Itoh K, Tanida S, Kataoka H, Ohara H, Nomura T, Itoh M (2004) Helicobacter pylori eradication decreases blood neutrophil and monocyte counts. Aliment Pharmacol Ther 20:74–79CrossRefPubMed

Koosirirat C, Linpisarn S, Changsom D, Chawansuntati K, Wipasa J (2010) Investigation of the anti- inflammatory effect of Curcuma longa in Helicobacter pylori-infected patients. Int Immunopharmacol 10:815–818CrossRefPubMed

Larussa T, Suraci E, Leone I, Nazionale I, Abenavoli L, Galasso O, Amorosi A, Imeneo M, Luzza F (2010) Short-term therapy with celecoxib and lansoprazole modulates Th1/ Th2 immune response in human gastric mucosa. Helicobacter 15:449–459CrossRefPubMed

Lee JY, Orlikova B, Diederich M (2015) Signal transducers and activators of transcription (STAT) regulatory networks in marine organisms: from physiological observations towards marine drug discovery. Mar Drugs 13:4967–4984CrossRefPubMedPubMedCentral

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

Mizuno T, Ando T, Nobata K, Tsuzuki T, Maeda O, Watanabe O, Minami M, Ina K, Kusugami K, Peek RM, Goto H (2005) Interleukin-17 levels in Helicobacter pylori-infected gastric mucosa and pathologic sequelae of colonization. World J Gastroenterol 11:6305–6311CrossRefPubMedPubMedCentral

Molina-Infante J, Rivas MD, Hernandez-Alonso M, Vinagre-Rodríguez G, Mateos-Rodríguez JM, Dueñas-Sadornil C, Perez-Gallardo B, Ferrando-Lamana L, Fernandez-Gonzalez N, Bañares R, Zamorano J (2014) Proton pump inhibitor-responsive oesophageal eosinophilia correlates with downregulation of eotaxin-3 and Th2 cytokines overexpression. Aliment Pharmacol Ther 40:955–965CrossRefPubMed

Moyat M, Velin D (2014) Immune responses to Helicobacter pylori infection. World J Gastroenterol 20:5583–5593CrossRefPubMedPubMedCentral

Murawski MR, Litherland SA, Clare-Salzler MJ, Davoodi-Semiromi A (2006) Upregulation of Foxp3 expression in mouse and human Treg is IL-2/STAT5 dependent: implications for the NOD STAT5B mutation in diabetes pathogenesis. Ann N Y Acad Sci 1079:198–204CrossRefPubMed

Nagata N, Akiyama J, Marusawa H, Shimbo T, Liu Y, Igari T, Nakashima R, Watanabe H, Uemura N, Chiba T (2014) Enhanced expression of activation-induced cytidine deaminase in human gastric mucosa infected by Helicobacter pylori and its decrease following eradication. J Gastroenterol 49:427–435CrossRefPubMed

Ohara T, Arakawa T (1999) Lansoprazole decreases peripheral blood monocytes and intercellular adhesion molecule-1-positive mononuclear cells. Dig Dis Sci 44:1710–1715CrossRefPubMed

Rad R, Brenner L, Bauer S, Schwendy S, Layland L, da Costa CP, Reindl W, Dossumbekova A, Friedrich M, Saur D, Wagner H, Schmid RM, Prinz C (2006) CD25 +/Foxp3 + T cells regulate gastric inflammation and Helicobacter pylori colonization in vivo. Gastroenterology 131:525–537CrossRefPubMed

Reuben BC, Stoddard G, Glasgow R, Neumayer LA (2007) Trends and predictors for vagotomy when performing oversew of acute bleeding duodenal ulcer in the United States. J Gastrointest Surg 11:22–28CrossRefPubMed

Robinson K, Kenefeck R, Pidgeon EL, Shakib S, Patel S, Polson RJ, Zaitoun AM, Atherton JC (2008) Helicobacter pylori-induced peptic ulcer disease is associated with inadequate regulatory T cell responses. Gut 57:1375–1385CrossRefPubMed

Shamsdin SA, Alborzi A, Rasouli M, Hosseini MK, Bagheri Lankrani K, Kalani M (2015) Alterations in Th17 and the respective cytokine levels in Helicobacter pylori-induced stomach diseases. Helicobacter 20:460–475CrossRefPubMed

Shimada M, Ando T, Peek RM, Watanabe O, Ishiguro K, Maeda O, Ishikawa D, Hasegawa M, Ina K, Ohmiya N, Niwa Y, Goto H (2008) Helicobacter pylori infection upregulates interleukin-18 production from gastric epithelial cells. Eur J Gastroenterol Hepatol 20:1144–1150CrossRefPubMedPubMedCentral

Strömberg E, Edebo A, Lundin BS, Bergin P, Brisslert M, Svennerholm AM, Lindholm C (2005) Down- regulation of epithelial IL-8 responses in Helicobacter pylori-infected duodenal ulcer patients depends on host factors, rather than bacterial factors. Clin Exp Immunol 140:117–125CrossRefPubMedPubMedCentral

Suzuki T, Kato K, Ohara S, Noguchi K, Sekine H, Nagura H, Shimosegawa T (2002) Localization of antigen-presenting cells in Helicobacter pylori-infected gastric mucosa. Pathol Int 52:265–271CrossRefPubMed

Tabeefar H, Beigmohammadi MT, Javadi MR, Abdollahi M, Mahmoodpoor A, Ahmadi A, Honarmand H, Najafi A, Mojtahedzadeh M (2012) Effects of pantoprazole on systemic and gastric pro- and anti-inflammatory cytokines in critically ill patients. Iran J Pharm Res 11:1051–1058PubMedPubMedCentral

Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, Kimura A, Morita R, Asakawa M, Chinen T, Yoshimura A (2011) SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production. J Exp Med 208:2055–2067CrossRefPubMedPubMedCentral

Ueno A, Ghosh A, Hung D, Li J, Jijon H (2015) Th17 plasticity and its changes associated with inflammatory bowel disease. World J Gastroenterol 21:12283–12295CrossRefPubMedPubMedCentral

Vogtenhuber C, Bucher C, Highfill SL, Koch LK, Goren E, Panoskaltsis-Mortari A, Taylor PA, Farrar MA, Blazar BR (2010) Constitutively active Stat5b in CD4 + T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses. Blood 116:466–474CrossRefPubMedPubMedCentral

Wang AY, Peura DA (2011) The prevalence and incidence of Helicobacter pylori-associated peptic ulcer disease and upper gastrointestinal bleeding throughout the world. Gastrointest Endosc Clin N Am 21:613–635CrossRefPubMed

Yamada A, Arakaki R, Saito M, Tsunematsu T, Kudo Y, Ishimaru N (2016) Role of regulatory T cell in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 22:2195–2205CrossRefPubMedPubMedCentral

Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363CrossRefPubMed

Zhang X, Cheng E, Huo X, Yu C, Zhang Q, Pham TH, Wang DH, Spechler SJ, Souza RF (2012) Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic esophagitis cells. PLoS ONE 7:e50037CrossRefPubMedPubMedCentral

Zheng Y, Wang Z, Deng L, Zhang G, Yuan X, Huang L, Xu W, Shen L (2015) Modulation of STAT3 and STAT5 activity rectifies the imbalance of Th17 and Treg cells in patients with acute coronary syndrome. Clin Immunol 157:65–77CrossRefPubMed

Title: Therapy with omeprazole modulates regulatory T cell/T helper 17 immune response in children with duodenal ulcers
Authors: Chuan-Ying Li
Cheng Wu
Publication date: 01-04-2018
Publisher: Springer International Publishing
Published in: Inflammopharmacology / Issue 2/2018
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-017-0380-x

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Therapy with omeprazole modulates regulatory T cell/T helper 17 immune response in children with duodenal ulcers

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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