Function of Thymosin Beta-4 in Ethanol-Induced Microglial Activation

Abstract

Background/Aims: Neuroinflammation mediated by activated microglia may play a pivotal role in a variety of central nervous system (CNS) pathologic conditions, including ethanolinduced neurotoxicity. The purpose of this study was to investigate the function of Tβ4 in ethanol-induced microglia activation. Methods: Quantitative real-time PCR was conducted to assess the expression of Tβ4 and miR-339-5p. Western blot analysis was used to measure the expression of Tβ4, phosphorylated p38, ERK, JNK, Akt, and NF-κB p65. The concentration of TNF-α and IL-1β was determined using ELISA. NO concentration was measured using a nitric oxide colorimetric BioAssay Kit. Double immunofluorescence was performed to determine Tβ4 expression, in order to assess microglial activation in neonatal mouse FASD model. Results: Increased Tβ4 expression was observed in ethanol treated microglia. Knockdown of Tβ4 enhanced ethanol-induced inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and nitric oxide (NO) in BV-2 cells was performed. Exogenous Tβ4 treatment significantly inhibited expression and secretion of these inflammatory mediators. Tβ4 treatment attenuated p38, ERK MAPKs, and nuclear factor-kappa B (NF-κB) pathway activation, and enhanced miR-339-5p expression induced by ethanol exposure in microglia. A neonatal mouse fetal alcohol spectrum disorders (FASD) model showed that Tβ4 expression in the microglia of the hippocampus was markedly enhanced, while Tβ4 treatment effectively blocked the ethanol-induced increase in inflammatory mediators, to the level expressed in vehicle-treated control animals. Conclusion: This study is the first to demonstrate the function of Tβ4 in ethanol-induced microglia activation, thus contributing to a more robust understanding of the role of Tβ4 treatment in CNS disease.

Ethanol Decreases Inflammatory Response in Human Lung Epithelial Cells by Inhibiting the Canonical NF-kB-Pathway

“…Interestingly, positive BAC has been associated with lower leukocyte counts as well as systemic IL-6 levels in severe TBI or in major trauma patients [8, 16]. However, contradictory data showing deteriorating effects of an alcohol intoxication also on patients´ outcome have been reported as well [43, 56, 57]. Nonetheless, the therapeutic use of alcohol is surely to be assessed critically because of its well-described side effects, notably regarding the central nervous system, e.g.…”

Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

“…In animal models, ethanol-induced neurotoxicity has been shown to cause oxidative stress, apoptosis, and neuroinflammation, ultimately causing neurodegeneration (Ullah et al, 2012, 2013; Naseer et al, 2014; Tajuddin et al, 2014; Ahmad et al, 2016; Wang P. et al, 2017). Ethanol has been shown to produce neurotoxicity in cellular studies on BV-2 microglia, PC12 cells, and HT22 cells (Casañas-Sánchez et al, 2016; Zhang J. et al, 2016; Huang et al, 2017). As a potent inhibitor of NMDARs, it acts on glutamate receptors and impairs the functionality of NMDARs and AMPARs.…”

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“…In addition to inflammatory cells (which infiltrate from peripheral circulation), microglia, the resident innate immune cells of the CNS, are activated by neuroinflammation and play a pivotal role in onset and pathological changes of disease. Thus, the effect of exogenous Tβ4 treatment on inhibition of microglial activation after damage may contribute to reduce the secretion of inflammatory mediators (Zhang et al, 2016b;Zhou et al, 2015), and thereby prevent and/or reduce damage of OLs after EAE by attenuating immune onslaught (neuroprotection).…”