Abstract
HMGB1 is passively released by injured or dying cells and aggravates inflammatory processes. The release of HMGB1 and calcium overload have each been reported to be important mediators of H2O2-induced injury. However, a potential connection between these two processes remains to be elucidated. In the present study, we employed H2O2-induced hepatocytes to investigate how calcium overload takes place during cellular injury and how the extracellular release of HMGB1 is regulated by this overload. In addition, we investigated the use of 58-F, a flavanone extracted from Ophiopogon japonicus, as a potential therapeutic drug. We show that the PLCγ1–IP3R–SOC signalling pathway participates in the H2O2-induced disturbance of calcium homoeostasis and leads to calcium overload in hepatocytes. After a rise in intracellular calcium, two calcium-dependent enzymes, PKCα and CaMKIV, are activated and translocated from the cytoplasm to the nucleus to modify HMGB1 phosphorylation. In turn, this promotes HMGB1 translocation from the nucleus to the cytoplasm and subsequent extracellular release. 58-F effectively rescued the hepatocytes by suppressing the PLCγ1–IP3R–SOC signalling pathway and decreasing the calcium concentration in cells, thus reducing HMGB1 release.
Highlights
Calcium is a universal second messenger involved in a remarkably wide range of cellular processes.[1]
Release of High mobility group box 1 (HMGB1) following H2O2-induced hepatocyte injury/ death is involved in calcium entry sible for the H2O2-induced cytosolic calcium increase, the levels of some related proteins were assessed via western blot
To confirm the effect of H2O2 on cell injury/death, we examined the release of lactate dehydrogenase (LDH) from cells to media as well as the levels of
Summary
Calcium is a universal second messenger involved in a remarkably wide range of cellular processes.[1] Disordered cytosolic calcium signalling can lead to severe damage or result in cell death.[2,3] In non-excitable cells, Ca2+ signals are generated by the phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol bisphosphate (PIP2) to yield 1,4,5- trisphosphate (IP3), leading to the subsequent activation of the inositol trisphosphate receptor (IP3R) This mediates the release of Ca2+ from the endoplasmic reticulum (ER),[4] followed by transmembrane Ca2+ entry through the opening of store-operated calcium (SOC) channels.[5] SOC channels are the predominant mechanism of calcium entry in both excitable and non-excitable cells and are activated by the depletion of internal calcium stores, for example, from the ER. SOC channels promote calcium entry through the plasma membrane (PM), a major mechanism for Ca2+ influx.[6,7] So far, two major molecular components of the SOC channel signalling pathway have been identified: stromal interaction molecule 1 (STIM1) and Orai1.8,9 STIM1 serves as a calcium sensor that can directly bridge the ER to PM at specialized junctions, aggregating into puncta in response to calcium store depletion and triggering the activation of SOC channels located in the PM.[10]
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