Modulation of both activator protein-1 and nuclear factor-kappa B signal transduction of human T cells by amiodarone

Abstract

Amiodarone, a common and effective antiarrhythmic drug, has been reported to have anti-inflammatory effects such as reducing the activation and movement of neutrophils. However, its effects on human T cells remain unclear. The aim of this study was to elucidate the effects and possible underlying mechanisms of amiodarone on human T cells. We isolated human primary T cells from the peripheral blood of healthy volunteers and performed enzyme-linked immunosorbent assay (ELISA), flow cytometry, electrophoretic mobility shift assay, luciferase assay, and Western blotting to evaluate the modulatory effects of amiodarone on human T cells. We found that amiodarone dose dependently inhibited the production of cytokines, including interleukin-2 (IL-2), IL-4, tumor necrosis factor-alpha, and interferon-gamma in activated human T cells. By flow cytometry, we demonstrated that amiodarone suppressed the expression of IL-2 receptor-alpha (CD25) and CD69, the cell surface markers of activated T cells. Moreover, molecular investigations revealed that amiodarone down-regulated activator protein-1 (AP-1) and nuclear factor kappa-B (NF-kB) DNA-binding activities in activated human T cells and also inhibited DNA binding and transcriptional activities of both AP-1 and NF-kB in Jurkat cells. Finally, by Western blotting, we showed that amiodarone reduced the activation of c-Jun NH 2 -terminal protein kinase and P38 mitogen-activated protein kinase, and suppressed stimuli-induced I-kappa B-alpha degradation in activated human T cells. Through regulation of AP-1 and NF-kB signaling, amiodarone inhibits cytokine production and T cell activation. These results show the pleiotropic effects of amiodarone on human T cells and suggest its therapeutic potential in inflammation-related cardiovascular disorders.

Treatment of Chronic Chagasic Patients: Is Killing the Parasite the Only Option?

“…81 More recently, it was proposed that, through regulation of AP-1 and NFκB signalling, amiodarone inhibits the production of IL-2, TNF, and IFN-γ, and prevents T cell activation. 82 This last result is closely associated with the role of IL-2 as an indicator of amiodarone treatment as reported in Chagasic patients, 5 and it strongly suggests a possible role of amiodarone treatment beyond channel modulation capacity. The findings make the drug an important tool to consider in the prevention of cardiac remodelling and sudden death because of Chagas disease.…”

Differential cytokine profiling in Chagasic patients according to their arrhythmogenic-status

“…1 and Additional file 1 ). In a recent study, it was reported that amiodarone was able to inhibit in a dose dependent way the production of cytokines, IL-2, IL-4, TNF, and IFN-γ in activated human T cells through NFκβ and activate protein-1 modulation [ 39 ] and suppress the expression of IL-2 receptor-alpha (CD25) and CD69, cell surface markers of activated T cells [ 39 ]. Amiodarone has been reported to reduce polymorphonuclear leukocyte infiltration in the paw tissue and paw edema in a dose dependent way [ 40 ].…”

Remodelling in atrial fibrillation: the impact of amiodarone

“…It may limit the activation of human T cells by inhibiting (in a dose-dependent manner) the production of cytokines, including IL-4, IL-2, TNF-α and interferon-gamma. 49 Impairment of left ventricular function, irrespective of aetiology, is commonly associated with the onset of AF. AM is one of the few anti-arrhythmic drugs that can be used with beneficial results for an ejection fraction of less than 40%.…”

“…57 Treatment with AM inhibited the JNK signalling pathway and reduced the activation of JNK on human T cells. 58 Despite the fact that the activation of T cells plays an important role in the pathogenesis of AF, there is a need for studies on atrial myocytes, as the modulation of JNK and CaMKII activity may contribute to the success of AM in maintenance of sinus rhythm.…”