In human CD4+ T-Cells, omeprazole suppresses proliferation, downregulates V-ATPase, and promotes differentiation toward an autoimmunity-favoring phenotype.

Autor: Pissas G; Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece., Tziastoudi M; Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece., Poulianiti C; Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece., Polyzou Konsta MA; Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece., Lykotsetas E; Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece., Liakopoulos V; Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece., Stefanidis I; Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece., Eleftheriadis T; Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece. Electronic address: teleftheriadis@yahoo.com.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2025 Jan 10; Vol. 144, pp. 113728. Date of Electronic Publication: 2024 Nov 30.
DOI: 10.1016/j.intimp.2024.113728
Abstrakt: Background: Proton pump inhibitors (PPIs) represent a commonly prescribed class of medications. Triggered by findings indicating a correlation between PPI usage and susceptibility to infectious or autoimmune diseases, we studied the impact of a pharmacological concentration of omeprazole on human CD4+ T-cells.
Methods: In mixed lymphocyte reactions (MLRs), we analyzed the proliferation index and measured the concentration of key cytokines representative of distinct CD4+ T-cell subsets. In CD4+ T-cells isolated from the MLRs, we evaluated proliferation markers and pathways, the expression of signature transcription factors of CD4+ T-cell subsets, vacuolar H+- ATPase (V-ATPase) levels, and the activation status of AMP-activated kinase (AMPK) and mammalian target of rapamycin complex-1 (mTORC1).
Results: Omeprazole reduced proliferation index in MLRs, and in isolated CD4+ T-cells, it downregulated the proliferation marker Ki-67, possibly mediated by the p53- p21 pathway. Analysis of cytokines and signature transcription factors of CD4+ T-cell subsets indicated that omeprazole decreased T helper 1 (Th1) differentiation, had negligible impact on Th2 differentiation, increased Th17 differentiation, and reduced regulatory T-cell (Treg) differentiation. Omeprazole also decreased V-ATPase, a known target of PPIs and a site for AMPK and mTORC1 activation. Consequently, this led to diminished activation of these kinases, potentially elucidating the mechanism by which omeprazole influences CD4+ T-cell differentiation.
Conclusion: Omeprazole downregulates V-ATPase and inhibits activation of AMPK and mTORC1. As a result, omeprazole suppresses CD4+ T-cell clonal expansion, potentially contributing to the observed association between PPIs and susceptibility to infections. Additionally, it modulates CD4+ T-cell differentiation in a manner that favors autoimmunity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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