Proton-Pump Inhibitors Suppress T Cell Response by Shifting Intracellular Zinc Distribution

Liu, Wenlei; Jakobs, Jana; Rink, Lothar

doi:10.3390/ijms24021191

Cited by 4 publications

(1 citation statement)

References 46 publications

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“…In adaptive immunity, some Zn transporter proteins that are highly expressed in T cells, such as Zip6 and Zip8, are directly involved in T cell activation via Zn endocytosis ( 30 ). Additionally, Zn is an essential cofactor that directly affects the biological activity of thymosin, which in turn affects T-cell generation, maturation, differentiation, proliferation, and functional changes ( 31 , 32 ). Our ssGSEA results confirmed the presence of large immune cell infiltration and enrichment of immune pathways in the high-risk group, suggesting that more immune pathways were activated in the high-risk group than in the low-risk group.…”

Section: Discussionmentioning

confidence: 99%

A zinc metabolism-related gene signature for predicting prognosis and characteristics of breast cancer

Hong,

Li,

Chen

et al. 2024

Front. Immunol.

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BackgroundBreast cancer is one of the most serious and prevalent malignancies. Zinc is commonly known to play a crucial role in the development and progression of breast cancer; however, the detailed mechanisms underlying this role are not well understood. This study aimed to develop a zinc metabolism-related gene (ZMRG) signature based on a multi-database study to predict patient prognosis and investigate the relationship between drug therapy response and immune enrichment.MethodsData for breast cancer samples from The Cancer Genome Atlas and Gene Expression Omnibus databases were screened for zinc metabolism-related genes using the Molecular Signature Database. Cox and Least Absolute Shrinkage and Selection Operator regressions were performed to construct a ZMRG signature. To assess the predictive performance of the gene signature, Kaplan–Meier analysis and receiver operating characteristic curves were used. Additionally, we utilised single-sample gene set enrichment analysis, the Tumour Immune Estimation Resource, the Genomics of Drug Sensitivity in Cancer database, and the Cancer Therapeutics Response Portal to investigate the association between the tumour microenvironment and drug sensitivity. Quantitative PCR was used to assess the expression of each gene in the signature in breast cancer cell lines and patient samples.ResultsFive ZMRGs were identified (ATP7B, BGLAP, P2RX4, SLC39A11, and TH) and a risk profile was constructed for each. Two risk groups, high- and low-risk, were identified in this way, and the high-risk score subgroups were found to have worse prognosis. This risk profile was validated using the GSE42568 dataset. Tumour microenvironment and drug sensitivity analyses showed that the expression of these five ZMRGs was significantly associated with immune response. The high-risk group showed substantial immune cell infiltration and enrichment of immune pathways, and patients were more sensitive to drugs commonly used in breast cancer.ConclusionThe ZMRG signature represents a new prognostic predictor for patients with breast cancer, and may also provide new insights into individualised treatment of breast cancer.

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Section: Discussionmentioning

confidence: 99%

A zinc metabolism-related gene signature for predicting prognosis and characteristics of breast cancer

Hong,

Li,

Chen

et al. 2024

Front. Immunol.

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Gastric acid-responsive deformable sodium alginate/Bletilla striata polysaccharide in situ gel for the protection and treatment of alcohol-induced peptic ulcers

Fan,

Hong,

Sun

et al. 2024

International Journal of Biological Macromolecules

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Ca2+ signals are essential for T-cell proliferation, while Zn2+ signals are necessary for T helper cell 1 differentiation

Jakobs,

Bertram,

Rink

2024

Cell Death Discov.

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The regulation of T-cell fate is crucial for the balance between infection control and tolerance. Calcium (Ca2+) and zinc (Zn2+) signals are both induced after T-cell stimulation, but their specific roles in the fate of activation and differentiation remain to be elucidated. Are Zn2+- and Ca2+ signals responsible for different aspects in T-cell activation and differentiation and do they act in concert or in opposition? It is crucial to understand the interplay of the intracellular signals to influence the fate of T cells in diseases with undesirable T-cell activities or in Zn2+-deficient patients. Human peripheral blood mononuclear cells were stimulated with the Zn2+ ionophore pyrithione and thapsigargin, an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA). Intracellular Zn2+ and Ca2+ signals were monitored by flow cytometry and ELISA, quantitative PCR and western blot were used to evaluate T-cell differentiation and the underlying molecular mechanism. We found that Zn2+ signals upregulated the early T-cell activation marker CD69, interferon regulatory factor 1 (IRF-1), and Krüppel-like factor 10 (KLF-10) expression, which are important for T helper cell (Th) 1 differentiation. Ca2+ signals, on the other hand, increased T-bet and Forkhead box P3 (FoxP3) expression and interleukin (IL)-2 release. Most interestingly, the combination of Zn2+ and Ca2+ signals was indispensable to induce interferon (IFN)-γ expression and increased the surface expression of CD69 by several-fold. These results highlight the importance of the parallel occurrence of Ca2+ and Zn2+ signals. Both signals act in concert and are required for the differentiation into Th1 cells, for the stabilization of regulatory T cells, and induces T-cell activation by several-fold. This provides further insight into the impaired immune functions of patients with zinc deficiency.

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Proton-Pump Inhibitors Suppress T Cell Response by Shifting Intracellular Zinc Distribution

Cited by 4 publications

References 46 publications

A zinc metabolism-related gene signature for predicting prognosis and characteristics of breast cancer

A zinc metabolism-related gene signature for predicting prognosis and characteristics of breast cancer

Gastric acid-responsive deformable sodium alginate/Bletilla striata polysaccharide in situ gel for the protection and treatment of alcohol-induced peptic ulcers

Ca2+ signals are essential for T-cell proliferation, while Zn2+ signals are necessary for T helper cell 1 differentiation

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