Abstract

Ethyl pyruvate (EP), a stable form of pyruvate, has shown beneficial effects in animal models of shock, ischemia/reperfusion injury, and sepsis due to its potent anti-oxidant and anti-inflammatory properties. Our recent study demonstrated that EP application prevented the clinical manifestation of type 1 diabetes in mice by augmenting regulatory T cell (Treg) number and function. Our present study shows that EP increases Treg proliferation and suppressive function (perforin and IL-10 expression) during in vitro differentiation from conventional CD4+CD25− T cells. Enhanced expansion of Treg after EP treatment correlated with increased ATP levels and relied on increased glycolysis. Inhibition of oxidative phosphorylation did not attenuate EP stimulatory effects, suggesting that this metabolic pathway was not mandatory for EP-driven Treg proliferation. Moreover, EP lowered the expression of carnitine palmitoyltransferase I, an enzyme involved in fatty acid oxidation. Further, the stimulatory effect of EP on Treg proliferation was not mediated through inhibition of the mTOR signaling pathway. When given in vivo either intraperitoneally or orally to healthy C57BL/6 mice, EP increased the number of Treg within the peritoneal cavity or gut-associated lymphoid tissue, respectively. In conclusion, EP promotes in vitro Treg proliferation through increased glycolysis and enhances Treg proliferation when administered in vivo.

Highlights

  • Ethyl pyruvate (EP) is an aliphatic ester composed of ethanol and pyruvate

  • In order to determine the timeline of EP effect on Treg differentiation in vitro, CD4+ CD25− cells isolated from spleens of C57BL/6 mice were stimulated with the conventional Treg differentiation cocktail that is comprised of plate-bound anti-CD3 and soluble anti-CD28 antibodies together with

  • As we have previously shown, EP can act as an anti-inflammatory agent by inhibiting the action of effector T cells and by promoting the regulatory phenotype of dendritic and T cells [8,18]

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Summary

Introduction

Ethyl pyruvate (EP) is an aliphatic ester composed of ethanol and pyruvate It is commonly used in the food industry as an additive. The diverse pharmacological effects of EP include the inhibition of pro-inflammatory cytokines secretion, attenuation of reactive oxygen species (ROS)-mediated damage to cells and tissues, inhibition or promotion of apoptosis (depending on the circumstances), and boosting of cellular ATP synthesis. These activities of EP have been shown in numerous animal models of inflammatory diseases, including uveitis [4], sepsis [5], and ischemia/reperfusion injury [6]. The effects of EP are Molecules 2020, 25, 4112; doi:10.3390/molecules25184112 www.mdpi.com/journal/molecules

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