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Diltiazem impairs maturation and functions of human dendritic cells
Alessandra Bachetoni1, Antonella D'Ambrosio, Paola Mariani
1Dipartimento di Chirurgia Generale P.Stefanini, Università La Sapienza, Rome, Italy. alessandra.bachetoni@uniroma1.it
Insights
Diltiazem, a calcium antagonist, influences human dendritic cell (DC) differentiation. Diltiazem-treated DCs show enhanced endocytic activity but impaired T-cell responses, potentially aiding transplant rejection prevention.
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Dendritic cells (DCs) are crucial for immune responses and transplant rejection.
- Calcium channel blockers, like diltiazem, are used in transplantation but their immunomodulatory effects require further definition.
Purpose of the Study:
- To investigate the impact of diltiazem on human dendritic cell differentiation and maturation.
- To elucidate the functional consequences of diltiazem-induced DC modulation on immune cell activation.
Main Methods:
- Monocytes were differentiated into dendritic cells using granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), with or without diltiazem.
- DC characteristics, endocytic activity, and responsiveness to stimuli like lipopolysaccharide (LPS) and CD40 ligand were assessed.
- T-cell responses and interferon-gamma (IFN-γ) production by Th1 cells were evaluated.
Main Results:
- Diltiazem, alongside GM-CSF and IL-4, induced monocyte differentiation into DC-like cells.
- Diltiazem-induced DCs exhibited higher mannose receptor and Fc gamma RII expression, leading to increased endocytic activity.
- These DCs showed reduced IL-12 production and impaired T-cell alloreactivity and Th1 cell induction upon stimulation.
Conclusions:
- Diltiazem modulates DC differentiation, enhancing their endocytic capacity but diminishing their immunostimulatory potential.
- The observed effects on DC function suggest a mechanism for diltiazem's immunoregulatory role in transplantation.
- Diltiazem may reduce DC-dependent T-cell activation, contributing to its efficacy in preventing transplant rejection.
Abstract:
The aim of this study was to define the effects of diltiazem, a calcium antagonist drug used in cardiology and in clinical transplantation, on the differentiation and maturation of human dendritic cells (DC). Herein, we demonstrate that diltiazem, in association with granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), induces monocytes to differentiate into cells with many of the characteristic of DC. However, diltiazem-induced DC express high levels of mannose receptor and Fc gamma RII and, consequently, manifest a higher endocytic activity compared with GM-CSF+IL-4-induced DC. Importantly, diltiazem-induced DCs have an impaired responsiveness to lipopolysaccharide and CD40 ligand because they produce decreased levels of IL-12 and reveal a reduced ability to stimulate alloreactive T-cell responses as well as in inducing interferon-gamma producing Th1 cells. These effects may contribute to a decreased DC-dependent T-cell activation and may help to explain the immunoregulatory function of diltiazem and its effectiveness in preventing transplant rejection.