Short ELF-EMF Exposure Targets SIRT1/Nrf2/HO-1 Signaling in THP-1 Cells

Abstract

Extremely low frequency electromagnetic fields (ELF-EMFs) have been known to modulate inflammatory responses by targeting signal transduction pathways and influencing cellular redox balance through the generation of oxidants and antioxidants. Here, we studied the molecular mechanism underlying the anti-oxidative effect of ELF-EMF in THP-1 cells, particularly with respect to antioxidant enzymes, such as heme oxygenase-1 (HO-1), regulated transcriptionally through nuclear factor E2-related factor 2 (Nrf2) activation. Cells treated with lipopolysaccharides (LPS) were exposed to a 50 Hz, 1 mT extremely low frequency electromagnetic fields for 1 h, 6 h and, 24 h. Our results indicate that ELF-EMF induced HO-1 mRNA and protein expression in LPS-treated THP-1 cells, with peak expression at 6 h, accompanied with a concomitant migration to the nucleus of a truncated HO-1 protein form. The immunostaining analysis further verified a nuclear enrichment of HO-1. Moreover, ELF-EMF inhibited the protein expressions of the sirtuin1 (SIRT1) and nuclear factor kappa B (NF-kB) pathways, confirming their anti-inflammatory/antioxidative role. Pretreatment with LY294002 (Akt inhibitor) and PD980559 (ERK inhibitor) inhibited LPS-induced Nrf2 nuclear translocation and HO-1 protein expression in ELF-EMF-exposed cells. Taken together, our results suggest that short ELF-EMF exposure exerts a protective role in THP-1 cells treated with an inflammatory/oxidative insult such as LPS, via the regulation of Nrf-2/HO-1 and SIRT1 /NF-kB pathways associated with intracellular glutathione (GSH) accumulation.

Anti-Oxidative and Immune Regulatory Responses of THP-1 and PBMC to Pulsed EMF Are Field-Strength Dependent

“…We therefore tested the key pro- and anti-inflammatory cytokines IL1B and IL10 , as well as the chemokine IL8 , in their transcriptional regulation upon EMF exposure in LPS stimulated cells [ 49 , 50 ]. While IL1B levels increased after 24 h in stEMF exposed THP1, IL10 levels were already 6-fold elevated after 1 h of exposure, suggesting anti-inflammatory rather than pro-inflammatory signaling as immediate responses induced by EMF ( Figure 7 a,b), which is in line with previous studies [ 13 ]. No significant elevation in IL1B or IL10 was observed in PBMC ( Figure 7 d,e).…”

“…In parallel, disparities in exposure conditions, i.e., field strength, are also present in in vitro studies focused on EMF-induced effects, which renders direct comparison difficult. For example, while in vitro studies on the leukemic cell line THP1 reported no effects at exposure levels equivalent to the geomagnetic field of <50 µT, exposure to strong EMF of 1 mT seemed to protect THP1 from oxidative stress induced by lipopolysaccharides (LPS), suggesting a gradual receptivity of cells to such physical stimuli [ 12 , 13 ]. Other publications also reported diverging outcomes on cellular receptivity and mechanistic implication when employing different field strengths that range from moderate EMF emitted from power lines < 300 μT [ 14 , 15 , 16 ], to strong EMF of mT magnitude [ 17 , 18 ].…”

Manmade Electromagnetic Fields and Oxidative Stress—Biological Effects and Consequences for Health

“…In both cases, additional exposure led to changes in the immune response triggered by staphylococci or lipopolysaccharides (LPS). In this regard, 50 Hz ELF-MF exposure modulated the cellular response to the LPS treatment and underlying signaling cascades, involving the antioxidative heme oxigenase-1 (HO-1) that counteracts the induced ROS formation and changes in oxidative status [ 129 ]. An enhancing effect of 60 Hz ELF-MF (0.8 mT) on the induced immune response and NO production was found in RAW246.7 mouse macrophage tumor cells [ 130 ], whereas a reduction in NO production by LPS was reported in the same cell line exposed to 50 Hz ELF-MF (0.5 mT) [ 131 ].…”

“…There is evidence that EMF affects the response to other (stress) factors [ 38 , 124 , 125 , 126 , 129 , 130 , 137 ]. Such a crosstalk between cell responses is important in real life, since humans and animals are exposed to different and changing stress and environmental factors, in contrast to experimental studies.…”

Nicotinic Acid against Acetaminophen-Induced Hepatotoxicity via Sirt1/Nrf2 Antioxidative Pathway in Mice

“…Here, we found that antioxidative enzymes were significantly activated by NA administration, and Sirt1/ Nrf2 axis was involved in the mechanism of liver protection. Several studies had illuminated in detail that activation of Nrf2 was mediated by Sirt1 (14,26,27). In physiological states, Nrf2 was conjuncted with Keap1, inhibiting the nuclear translocation of Nrf2 and subsequently transcription of ARE, which triggers the activation of antioxidant enzymes, for instance, NQO-1 is one of these downstream transcription product, and is closely related to antioxidant stress (28,29).…”