In this study, we investigated the effects of specific low frequency electromagnetic fields sequences on U937 cells, an in vitro model of human monocyte/macrophage differentiation. U937 cells were exposed to electromagnetic stimulation by means of the SyntheXer system using two similar sequences, XR-BC31 and XR-BC31/F. Each sequence was a time series of twenty-nine wave segments. Here, we report that exposure (4 days, once a day) of U937 cells to the XR-BC31 setting, but not to the XR-BC31/F, resulted in increased expression of the histone demethylase KDM6B along with a global reduction in histone H3 lysine 27 (H3K27) tri-methylation. Furthermore, exposure to the XR-BC31 sequence induced differentiation of U937 cells towards a macrophage-like phenotype displaying a KDM6B dependent increase in expression and secretion of the anti-inflammatory interleukins (ILs), IL-10 and IL-4. Importantly, all the observed changes were highly dependent on the sequence's nature. Our results open a new way of interpretation for the effects of low frequency electromagnetic fields observed in vivo. Indeed, it is conceivable that a specific low frequency electromagnetic fields treatment may cause changes in chromatin accessibility and consequently in the expression of anti-inflammatory mediators and in cell differentiation.
Low frequency Pulsed Electro Magnetic Fields (PEMF) have been found to produce a variety of beneficial effects and therefore successfully employed as adjunctive therapy for a wide range of clinical conditions [1][2][3][4]. Although properly configured electromagnetic signals demonstrate to regulate major cellular functions, including proliferation, differentiation and apoptosis [5][6][7], little is known about their biological mechanism of action.
In general, an electromagnetic radiation is generated when charged particles, as electrons, move through conductive materials. Such a radiation may diffuse in the surrounding environment and be absorbed by organic matter, including human cells, tissues and organs [8]. The electrical currents may occur as a constant flow of electrons, either in continuous or pulsed waves, resulting in the generation of an electromagnetic field whose intensity and characteristics are proportional to the applied electrical power and waveform.
Despite intense investigations carried out worldwide until now, it is not fully clear how low frequency electromagnetic fields affect the cellular physiology and the understanding about the role of wave parameters is still far away.
From the biological point of view, it is well established that signals from the environment, whether they are physical, chemical, or hormonal, regulate intracellular metabolic processes such as enzyme activities and gene expression involved in cell differentiation and proliferation. Such metabolic mechanisms by which cells sense and respond to these signals are known as signal transduction mechanisms. Membrane signal transduction processes in particular have been an area of interest in research designed to elucidate effects of EMFs on cells.
Regardless of the large number of possible variables which can be sensed by signal transduction systems, there is a relatively limited number of mechanisms by which the information contained in these signals can be transmitted (transduced) across the cell membrane. In all known signal transduction systems, a molecule interacts with a protein located on the membrane (the receptor) and triggers conformational changes in the receptor which result in further modifications of cellular metabolism. Signalling agents which have limited ability to penetrate the cell membrane (e.g. peptide hormones, neurotransmitters and growth factors) interact with receptors which span the cell membrane. Interaction of the intracellular portion of the receptor with other intracellular (effector) molecules causes changes in the activities of cellular pathways [9].
For a living cell or tissue to respond functionally to an exogenous electromagnetic field, it is necessary that the radiation reaches and can be detected at appropriate molecular, cellular, or tissue site. Although still not completely elucidated, the mechanism of action of EMF signals at molecular and cellular level has been analyzed and a huge amount of literature strongly suggests ion or ligand binding in a regulatory cascade could be the signal transduction pathway [10][11][12][13].
One of the first models of interaction was created using a biophysical approach [10,14,15] in which an electrochemical model of the cell membrane was employed to theoretically predict a range of waveform parameters for which bioeffects might be expected. This approach was based on the assumption that voltage-dependent processes, such as ion or ligand binding and ion transport at, and across the electrified interface of the cell membrane, were the most likely EMF targets.
Several studies further developed this framework using Lorentz force considerations [16][17][18][19][20], and more specificity was hypothesized by including ion resonance and Zeeman-Stark effect [21]. These models suggested that combined actions from low-frequency alternating current (AC) and static magnetic fields as the geomagnetic one, could stimulate ion or ligand Larmor precession in a molecular binding site and thereby affect binding kinetics [22][23][24][25][26][27]. Direct action of the Lorentz force on free electrons in macromolecules such as DNA has also been proposed [28,29].
At the present, the most accepted, basic biophysical transduction step is ion or ligand binding at cell surfaces and junctions, which modulate a cascade of biochemical processes resulting in the observed physiological effect [24][25][26][27]30]. Several theoretical models have been formulated to quantify, by practical calculations, the effects of field interaction. Among them, it has been proposed a detailed physical interpretation of the forced-vibration of free ions present on the external surface of the plasma membrane, which in the end changes the cell electrochemical balance and function [31,32].
Not long ago, new insights on the biological role of electromagnetic interactions also arise from the molecular investigation on endogenous bioelectric signals during pattern formation in growing tissues [33
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