Ethyl pyruvate inhibits HMGB1 phosphorylation and release by chelating calcium

Joo Hyun Shin, Il Doo Kim, Seung Woo Kim, Hye Kyung Lee, Yinchuan Jin, Ju Hun Park, Tae Kyung Kim, Chang Kook Suh, Jiyeon Kwak, Keun Hyeung Lee, Pyung Lim Han, Ja Kyeong Lee

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Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to have antiinflammatory effects and to confer protective effects in various pathological conditions. Recently, a number of studies have reported EP inhibits high mobility group box 1 (HMGB1) secretion and suggest this might contribute to its antiinflammatory effect. Since EP is used in a calcium-containing balanced salt solution (Ringer solution), we wondered if EP directly chelates Ca(2+) and if it is related to the EP-mediated suppression of HMGB1 release. Calcium imaging assays revealed that EP significantly and dose-dependently suppressed high K(+)-induced transient [Ca(2+)]i surges in primary cortical neurons and, similarly, fluorometric assays showed that EP directly scavenges Ca(2+) as the peak of fluorescence emission intensities of Mag-Fura-2 (a low-affinity Ca(2+) indicator) was shifted in the presence of EP at concentrations of ≥7 mmol/L. Furthermore, EP markedly suppressed the A23187-induced intracellular Ca(2+) surge in BV2 cells and, under this condition, A23187-induced activations of Ca(2+)-mediated kinases (protein kinase Cα and calcium/calmodulin-dependent protein kinase IV), HMGB1 phosphorylation and subsequent secretion of HMGB1 also were suppressed. (A23187 is a calcium ionophore and BV2 cells are a microglia cell line.) Moreover, the above-mentioned EP-mediated effects were obtained independent of cell death or survival, which suggests that they are direct effects of EP. Together, these results indicate that EP directly chelates Ca(2+), and that it is, at least in part, responsible for the suppression of HMGB1 release by EP.

Original languageEnglish
Pages (from-to)649-657
Number of pages9
JournalMolecular medicine (Cambridge, Mass.)
StatePublished - 2014

Bibliographical note

Funding Information:
This research was supported by grants from the Mid-Career Researcher Program (grant no. 2012-013195) and the Global Research Network (grant no. 220-2011-1-E00027) of the Korean National Research Foundation (NRF) to J-K Lee.


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