{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:41:04Z","timestamp":1790775664863,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,7]],"date-time":"2023-01-07T00:00:00Z","timestamp":1673049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proton-pump inhibitors (PPI), e.g., omeprazole or pantoprazole, are the most widely used drugs for various gastrointestinal diseases. However, more and more side effects, especially an increased risk of infections, have been reported in recent years. The underlying mechanism has still not yet been fully uncovered. Hence, in this study, we analyzed the T cell response after treatment with pantoprazole in vitro. Pantoprazole preincubation reduced the production and secretion of interferon (IFN)-\u03b3 and interleukin (IL)-2 after the T cells were activated with phytohemagglutinin (PHA)-L or toxic shock syndrome toxin-1 (TSST-1). Moreover, a lower zinc concentration in the cytoplasm and a higher concentration in the lysosomes were observed in the pantoprazole-treated group compared to the untreated group. We also tested the expression of the zinc transporter Zrt- and Irt-like protein (Zip)8, which is located in the lysosomal membrane and plays a key role in regulating intracellular zinc distribution after T cell activation. Pantoprazole reduced the expression of Zip8. Furthermore, we measured the expression of cAMP-responsive element modulator (CREM) \u03b1, which directly suppresses the expression of IL-2, and the expression of the phosphorylated cAMP response element-binding protein (pCREB), which can promote the expression of IFN-\u03b3. The expression of CREM\u03b1 was dramatically increased, and different isoforms appeared, whereas the expression of pCREB was downregulated after the T cells were treated with pantoprazole. In conclusion, pantoprazole downregulates IFN-\u03b3 and IL-2 expression by regulating the expression of Zip8 and pCREB or CREM\u03b1, respectively.<\/jats:p>","DOI":"10.3390\/ijms24021191","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T02:09:39Z","timestamp":1673230179000},"page":"1191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Proton-Pump Inhibitors Suppress T Cell Response by Shifting Intracellular Zinc Distribution"],"prefix":"10.3390","volume":"24","author":[{"given":"Wenlei","family":"Liu","sequence":"first","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, Pauwelsstra\u00dfe 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Jakobs","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, Pauwelsstra\u00dfe 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5658-2893","authenticated-orcid":false,"given":"Lothar","family":"Rink","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, Pauwelsstra\u00dfe 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,7]]},"reference":[{"key":"ref_1","first-page":"267","article-title":"Inappropriate Prescription of Proton Pump Inhibitors in a Community Setting","volume":"71","author":"Nguyen","year":"2018","journal-title":"Can. J. Hosp. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1007\/s10620-015-3642-8","article-title":"The Inappropriate Prescription of Oral Proton Pump Inhibitors in the Hospital Setting: A Prospective Cross-Sectional Study","volume":"60","author":"Kelly","year":"2015","journal-title":"Dig. Dis. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.5056\/jnm.2014.20.1.6","article-title":"New and future drug development for gastroesophageal reflux disease","volume":"20","author":"Fass","year":"2014","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1177\/2042098617715381","article-title":"Adverse effects of proton-pump inhibitor use in older adults: A review of the evidence","volume":"8","author":"Maes","year":"2017","journal-title":"Ther. Adv. Drug Saf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4933","DOI":"10.3748\/wjg.v25.i33.4933","article-title":"Proton pump inhibitor use increases mortality and hepatic decompensation in liver cirrhosis","volume":"25","author":"Kai","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1002\/JLB.5A0417-143R","article-title":"Proton-pump inhibitors elevate infection rate in cardiothoracic surgery patients by influencing PMN function in vitro and in vivo","volume":"103","author":"Haas","year":"2018","journal-title":"J. Leukoc. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1929727","DOI":"10.1080\/2162402X.2021.1929727","article-title":"Effects of concomitant proton pump inhibitor use on immune checkpoint inhibitor efficacy among patients with advanced cancer","volume":"10","author":"Qin","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1053\/j.gastro.2021.08.005","article-title":"Regular Use of Proton Pump Inhibitor and the Risk of Inflammatory Bowel Disease: Pooled Analysis of 3 Prospective Cohorts","volume":"161","author":"Xia","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1146\/annurev-nutr-122019-120635","article-title":"Dietary and Physiological Effects of Zinc on the Immune System","volume":"41","author":"Wessels","year":"2021","journal-title":"Annu. Rev. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1399S","DOI":"10.1093\/jn\/130.5.1399S","article-title":"The dynamic link between the integrity of the immune system and zinc status","volume":"130","author":"Fraker","year":"2000","journal-title":"J. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3263","DOI":"10.1016\/j.clnu.2020.10.052","article-title":"Zinc deficiency leads to reduced interleukin-2 production by active gene silencing due to enhanced CREM\u03b1 expression in T cells","volume":"40","author":"Kloubert","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11780","DOI":"10.1073\/pnas.1323549111","article-title":"Zinc transporter SLC39A10\/ZIP10 facilitates antiapoptotic signaling during early B-cell development","volume":"111","author":"Miyai","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15034","DOI":"10.1038\/s41598-018-33102-w","article-title":"Superiority of SpiroZin2 Versus FluoZin-3 for monitoring vesicular Zn2+ allows tracking of lysosomal Zn2+ pools","volume":"8","author":"Han","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14741","DOI":"10.1021\/acs.inorgchem.9b02419","article-title":"Ternary Zn(II) Complexes of Fluorescent Zinc Probes Zinpyr-1 and Zinbo-5 with the Low Molecular Weight Component of Exchangeable Cellular Zinc Pool","volume":"58","author":"Goch","year":"2019","journal-title":"Inorg. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e13395","DOI":"10.1111\/cmi.13395","article-title":"Dengue virus replication enhances labile zinc pools by modulation of ZIP8","volume":"23","author":"Panwar","year":"2021","journal-title":"Cell. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"126483","DOI":"10.1016\/j.jtemb.2020.126483","article-title":"Imbalance in zinc homeostasis enhances lung Tissue Loss following cigarette smoke exposure","volume":"60","author":"Knoell","year":"2020","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"924820","DOI":"10.3389\/fcell.2022.924820","article-title":"Divalent Metal Uptake and the Role of ZIP8 in Host Defense Against Pathogens","volume":"10","author":"Samuelson","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1189\/jlb.1208759","article-title":"Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-gamma expression in activated human T cells","volume":"86","author":"Aydemir","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.4049\/jimmunol.2001395","article-title":"Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia","volume":"207","author":"Hall","year":"2021","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/0192-0561(95)00064-9","article-title":"Age-related thymus involution: Zinc reverses in vitro the thymulin secretion defect","volume":"17","author":"Mocchegiani","year":"1995","journal-title":"Int. J. Immunopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"132","DOI":"10.2174\/187153009788452390","article-title":"T-lymphocytes: A target for stimulatory and inhibitory effects of zinc ions","volume":"9","author":"Rink","year":"2009","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12979-022-00295-8","article-title":"Short-term zinc supplementation of zinc-deficient seniors counteracts CREM\u03b1 - mediated IL-2 suppression","volume":"19","author":"Baarz","year":"2022","journal-title":"Immun. Ageing"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1189\/jlb.0603252","article-title":"Interferon-gamma: An overview of signals, mechanisms and functions","volume":"75","author":"Schroder","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1002\/JLB.5MIR0420-055R","article-title":"Roles of IL-2 in bridging adaptive and innate immunity, and as a tool for cellular immunotherapy","volume":"108","author":"Bendickova","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1126\/science.181845","article-title":"Selective in vitro growth of T lymphocytes from normal human bone marrows","volume":"193","author":"Morgan","year":"1976","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/0092-8674(93)90532-U","article-title":"Inducibility and negative autoregulation of CREM: An alternative promoter directs the expression of ICER, an early response repressor","volume":"75","author":"Molina","year":"1993","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e0197921","DOI":"10.1128\/mbio.01979-21","article-title":"Differential Expression of CREM\/ICER Isoforms Is Associated with the Spontaneous Control of HIV Infection","volume":"13","author":"Luo","year":"2022","journal-title":"mBio"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6500","DOI":"10.3748\/wjg.v23.i35.6500","article-title":"Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis","volume":"23","author":"Trifan","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.jhin.2017.08.017","article-title":"Updated meta-analysis of controlled observational studies: Proton-pump inhibitors and risk of Clostridium difficile infection","volume":"98","author":"Cao","year":"2018","journal-title":"J. Hosp. Infect."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/0020-711X(93)90239-B","article-title":"Lectins and superantigens: Membrane interactions of these compounds with T lymphocytes affect immune responses","volume":"25","author":"Licastro","year":"1993","journal-title":"Int. J. Biochem."},{"key":"ref_31","first-page":"272","article-title":"Zinc regulates cytokine induction by superantigens and lipopolysaccharide","volume":"84","author":"Driessen","year":"1995","journal-title":"Immunology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/329512a0","article-title":"The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens","volume":"329","author":"Bjorkman","year":"1987","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/eji.1830190225","article-title":"Mitogenic lectins bind to the antigen receptor on human lymphocytes","volume":"19","author":"Chilson","year":"1989","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Roetzer, A., Stich, N., Model, N., Schwameis, M., Firbas, C., Jilma, B., and Eibl, M.M. (2020). High Titer Persistent Neutralizing Antibodies Induced by TSST-1 Variant Vaccine Against Toxic Shock Cytokine Storm. Toxins, 12.","DOI":"10.3390\/toxins12100640"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.bbrc.2005.07.059","article-title":"Zinc ions suppress mitogen-activated interleukin-2 production in Jurkat cells","volume":"335","author":"Tanaka","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Cheng, Y., and Chen, H. (2021). Aberrance of Zinc Metalloenzymes-Induced Human Diseases and Its Potential Mechanisms. Nutrients, 13.","DOI":"10.3390\/nu13124456"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Vallee, B.L., and Auld, D.S. (1992). Functional zinc-binding motifs in enzymes and DNA-binding proteins. Faraday Discuss., 47\u201365.","DOI":"10.1039\/fd9929300047"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1073\/pnas.96.5.1936","article-title":"Inhibitory sites in enzymes: Zinc removal and reactivation by thionein","volume":"96","author":"Maret","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Pan, C.Y., Lin, F.Y., Kao, L.S., Huang, C.C., and Liu, P.S. (2020). Zinc oxide nanoparticles modulate the gene expression of ZnT1 and ZIP8 to manipulate zinc homeostasis and stress-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. PLoS ONE, 15.","DOI":"10.1101\/2020.04.22.055152"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1002\/j.1460-2075.1993.tb05759.x","article-title":"The functional versatility of CREM is determined by its modular structure","volume":"12","author":"Laoide","year":"1993","journal-title":"EMBO J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cellimm.2012.04.008","article-title":"Role of CREM in systemic lupus erythematosus","volume":"276","author":"Xu","year":"2012","journal-title":"Cell. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1136\/gutjnl-2015-311119","article-title":"Hepatic overexpression of cAMP-responsive element modulator \u03b1 induces a regulatory T-cell response in a murine model of chronic liver disease","volume":"66","author":"Kuttkat","year":"2017","journal-title":"Gut"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1179\/1476830510Y.0000000002","article-title":"Depressed hippocampal MEK\/ERK phosphorylation correlates with impaired cognitive and synaptic function in zinc-deficient rats","volume":"14","author":"Jiang","year":"2011","journal-title":"Nutr. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1039\/C7MT00288B","article-title":"Zinc ions regulate opening of tight junction favouring efflux of macromolecules via the GSK3\u03b2\/snail-mediated pathway","volume":"10","author":"Xiao","year":"2018","journal-title":"Metallomics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S0006-291X(03)01122-7","article-title":"Zinc inhibits calcineurin activity in vitro by competing with nickel","volume":"307","author":"Takahashi","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ab.2006.02.009","article-title":"Flow cytometric measurement of labile zinc in peripheral blood mononuclear cells","volume":"352","author":"Haase","year":"2006","journal-title":"Anal. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1191\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:02:43Z","timestamp":1760119363000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,7]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24021191"],"URL":"https:\/\/doi.org\/10.3390\/ijms24021191","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,7]]}}}