The Journal of Experimental Medicine
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Published online November 5, 2007
doi:10.1084/jem.20070247
The Journal of Experimental Medicine, Vol. 204, No. 12, 2913-2923
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Tsung et al.
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ARTICLE

 HMGB1 release induced by liver ischemia involves Toll-like receptor 4–dependent reactive oxygen species production and calcium-mediated signaling

Allan Tsung1, John R. Klune1, Xianghong Zhang1, Geetha Jeyabalan1, Zongxian Cao1, Ximei Peng1, Donna B. Stolz2, David A. Geller1, Matthew R. Rosengart1, and Timothy R. Billiar1

1 Department of Surgery and 2 Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15213

CORRESPONDENCE Timothy R. Billiar: billiartr{at}upmc.edu

Ischemic tissues require mechanisms to alert the immune system of impending cell damage. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from ischemic cells. We elucidate the mechanism by which HMGB1, one of the key alarm molecules released during liver ischemia/reperfusion (I/R), is mobilized in response to hypoxia. HMGB1 release from cultured hepatocytes was found to be an active process regulated by reactive oxygen species (ROS). Optimal production of ROS and subsequent HMGB1 release by hypoxic hepatocytes required intact Toll-like receptor (TLR) 4 signaling. To elucidate the downstream signaling pathways involved in hypoxia-induced HMGB1 release from hepatocytes, we examined the role of calcium signaling in this process. HMGB1 release induced by oxidative stress was markedly reduced by inhibition of calcium/calmodulin-dependent kinases (CaMKs), a family of proteins involved in a wide range of calcium-linked signaling events. In addition, CaMK inhibition substantially decreased liver damage after I/R and resulted in accumulation of HMGB1 in the cytoplasm of hepatocytes. Collectively, these results demonstrate that hypoxia-induced HMGB1 release by hepatocytes is an active, regulated process that occurs through a mechanism promoted by TLR4-dependent ROS production and downstream CaMK-mediated signaling.

Abbreviations used: 4-HAE, 4-hydroxyalkenal; CaMK, calcium/calmodulin-dependent kinase; CaMKK, CaMK kinase; DAMP, damage-associated molecular pattern; DCF, 2',7'-dichlorofluorescein; HMGB1, high-mobility group box 1; I/R, ischemia/reperfusion; MDA, malondialdehyde; mRNA, messenger RNA; NAC, N-acetylcysteine; ROS, reactive oxygen species; sALT, serum alanine aminotransferase; siRNA, small interfering RNA; TLR, Toll-like receptor.

M.R. Rosengart and T.R. Billiar contributed equally to this work.


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