Sodium Fluoride (NaF) Induces Inflammatory Responses Via Activating MAPKs/NF-κB Signaling Pathway and Reducing Anti-inflammatory Cytokine Expression in the Mouse Liver

Abstract

At present, no reports are focused on fluoride-induced hepatic inflammatory responses in human beings and animals. This study aimed to investigate the mRNA and protein levels of inflammatory cytokines and signaling molecules for evaluating the effect of different doses (0, 12, 24, and 48 mg/kg) of sodium fluoride (NaF) on inflammatory reaction in the mouse liver by using methods of experimental pathology, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis. We found that NaF in excess of 12 mg/kg caused the hepatic inflammatory responses, and the results showed that NaF activated the mitogen-activated protein kinases (MAPKs) signaling pathway by markedly increasing (p < 0.01 or p < 0.05) mRNA and protein levels of apoptosis signal-regulating kinase 1 (ASK1), mitogen-activated protein kinase kinases 1/2 (MEK1/2), extracellular signal-regulated protein kinases 1/2 (Erk1/2), mitogen-activated protein kinase kinases 4/7 (MEK4/7), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38) and mitogen-activated protein kinase kinases 3/6 (MEK3/6), and the nuclear factor-kappa B (NF-κB) signaling pathway by increasing (p < 0.01 or p < 0.05) the production of NF-κB and inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β) and reducing (p < 0.01 or p < 0.05) the production of the inhibitory kappa B (IκB). Thus, NaF that caused the hepatic inflammatory responses was characterized by increasing (p < 0.01 or p < 0.05) the production of pro-inflammatory mediators such as interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), and cyclooxygenase-2 (COX-2) via the activation of MAPKs and NF-κB pathways, and by significantly inhibiting (p < 0.01 or p < 0.05) the production of anti-inflammatory mediators including interleukin-4 (IL-4) and transforming growth factor beta (TGF-β).

Expression of the Melatonin-Associated Genes in Fibroblasts That Have Been Co-Exposed to Fluoride and a Moderate-Strength Static Magnetic Field

“…In some diseases, an increased expression of IL27RA in fibroblasts has been demonstrated [27]. Moreover, in our experiment, an increase in the expression of the receptor alpha subunit was observed under the influence of fluoride, which activates the expression of the inflammatory cytokines [29]. However, a static magnetic field can regulate cytokine disturbances, as is suggested by the obtained results.…”

Nitrate and Phosphate Transporters Rescue Fluoride Toxicity in Yeast

“…Exposure to high levels of fluoride over a period of weeks to months produces a myriad of stress effects in organisms. High fluoride causes inflammation, lipid peroxidation, and perturbation of the MAPK and NF-κB pathways in multicellular model systems. − At a single-cell level, fluoride activates S-phase cell-cycle arrest and metabolic arrest, and damages both the mitochondria and endoplasmic reticulum. − These effects are linked to the activation by fluoride of oxidative stress and the subsequent generation of free radicals, which causes DNA damage and intracellular acidification. − As the predominant effects of fluoride toxicity are inflammation and free radical damage, it is challenging to distinguish between the specific mechanism of fluoride toxicity and its downstream stress effects.…”

P-Hydroxyacetophenone Ameliorates Alcohol-Induced Steatosis and Oxidative Stress via the NF-κB Signaling Pathway in Zebrafish and Hepatocytes

“…The transcription factor k B (NF-kB) has been widely studied because of its significant role in the regulation of inflammatory genes and immune cell proliferation and apoptosis (Janssen-Heininger et al, 2000;Chen and Greene, 2004;Chen et al, 2019). It should be noted that NF-kB is the major regulator of oxidative stress (Chen and Greene, 2004).…”