Interferon Regulatory Factor 1 Mediates Acetylation and Release of High Mobility Group Box 1 from Hepatocytes During Murine Liver Ischemia-Reperfusion Injury

Dhupar, Rajeev; Klune, John R.; Evankovich, John; Cardinal, Jon; Zhang, Matthew; Ross, Mark A.; Murase, Noriko; Geller, David A.; Billiar, Timothy R.; Tsung, Allan

doi:10.1097/shk.0b013e3181f6aab0

Cited by 77 publications

(71 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[10][11][12] Interestingly, HMGB1 was reported to rapidly mobilize and release into system circulation from damaged liver in the setting of liver I/R injury. 34,35 Previous studies also demonstrated that serum HMGB1 level remained elevated until 12 h after reperfusion, and that the removal of excessive serum HMGB1 with adsorption column improved the lung injury score. 28 Whether or not HMGB1 was transported to the lung and whether downstream signaling pathways in lung were activated was not investigated.…”

Section: Discussionmentioning

confidence: 99%

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

Yang

Deng

et al. 2013

Laboratory Investigation

View full text Add to dashboard Cite

Acute lung injury (ALI) frequently occurs after liver transplantation and major liver surgery. Proinflammatory mediators released by damaged liver after liver ischemia/reperfusion (I/R) injury might contribute to this form of ALI, but the underlying mechanisms have not been well characterized. High-mobility group box protein 1 (HMGB1), a recently identified proinflammatory cytokine, was found to be significantly higher in the serum after liver I/R injury. This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. Extensive ALI and lung inflammation was induced in a rat model of liver I/R injury. Serum HMGB1 was significantly higher after liver I/R injury, and more importantly, expression of HMGB1 mRNA and protein in the lung tissue was also significantly increased. We further found that liver I/R injury enhanced the expression of TLR4 mRNA and protein, and the activity of p38MAPK and AP-1 in the lung tissue. Inhibition of TLR4 expression in the lung tissue by infection with pGCSIL-GFP-lentivirus-expressing small hairpin RNAs targeting the TLR4 gene (TLR4-shRNA lentivirus) significantly attenuated ALI, lung inflammation, and activity of p38MAPK and AP-1 in the lung tissue. These findings indicate that HMGB1 might contribute to the underlying mechanism for liver I/R injuryinduced ALI and that its downstream TLR4, p38MAPK, and AP-1 signaling pathways are potentially important mediators in the development of ALI.

show abstract

Section: Discussionmentioning

confidence: 99%

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

Yang

Deng

et al. 2013

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Whereas this study did not examine the role of HAT enzymes in hepatic I/R, recent findings from our laboratory suggest that HAT activation during I/R also contributes to HMGB1 acetylation (45). Our ongoing investigations are focused on understanding the balance between both HAT and HDAC activities in the mobilization and release of HMGB1.…”

Section: Discussionmentioning

confidence: 99%

High Mobility Group Box 1 Release from Hepatocytes during Ischemia and Reperfusion Injury Is Mediated by Decreased Histone Deacetylase Activity

Evankovich¹,

Cho²,

Zhang

et al. 2010

Journal of Biological Chemistry

Self Cite

213

212

View full text Add to dashboard Cite

The mobilization and extracellular release of nuclear high mobility group box-1 (HMGB1) by ischemic cells activates inflammatory pathways following liver ischemia/reperfusion (I/R) injury. In immune cells such as macrophages, post-translational modification by acetylation appears to be critical for active HMGB1 release. Hyperacetylation shifts its equilibrium from a predominant nuclear location toward cytosolic accumulation and subsequent release. However, mechanisms governing its release by parenchymal cells such as hepatocytes are unknown. In this study, we found that serum HMGB1 released following liver I/R in vivo is acetylated, and that hepatocytes exposed to oxidative stress in vitro also released acetylated HMGB1. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups and control the acetylation status of histones and various intracellular proteins. Levels of acetylated HMGB1 increased with a concomitant decrease in total nuclear HDAC activity, suggesting that suppression in HDAC activity contributes to the increase in acetylated HMGB1 release after oxidative stress in hepatocytes. We identified the isoforms HDAC1 and HDAC4 as critical in regulating acetylated HMGB1 release. Activation of HDAC1 was decreased in the nucleus of hepatocytes undergoing oxidative stress. In addition, HDAC1 knockdown with siRNA promoted HMGB1 translocation and release. Furthermore, we demonstrate that HDAC4 is shuttled from the nucleus to cytoplasm in response to oxidative stress, resulting in decreased HDAC activity in the nucleus. Together, these findings suggest that decreased nuclear HDAC1 and HDAC4 activities in hepatocytes following liver I/R is a mechanism that promotes the hyperacetylation and subsequent release of HMGB1. High Mobility Group Box Protein 1 (HMGB1)3 is a ubiquitously expressed nuclear molecule that functions as a structural protein of chromatin (1). In addition to its nuclear role, HMGB1 also functions as an inflammatory cytokine when released from necrotic cells or actively secreted from stressed cells. Its proinflammatory properties were first highlighted in experiments showing that HMGB1 is actively secreted by activated macrophages, serving as a late mediator of lethality in sepsis (2). Whereas HMGB1 is involved in the late systemic inflammatory response to sepsis, our laboratory demonstrated that HMGB1 is a central and necessary mediator of organ damage following acute, sterile organ injury (3, 4). HMGB1 is rapidly mobilized and released by hepatocytes in the setting of hepatic ischemia and reperfusion injury. Extracellular HMGB1 functions as a damage-associated molecular pattern (DAMP) molecule and activates proinflammatory signaling pathways by activating pattern recognition receptors including Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) (5, 6). Mounting evidence suggests HMGB1 may also function to facilitate the recognition of other immune co-activators such as LPS, DNA, and IL-1 through avid binding to these molecules (7-9).Thoro...

show abstract

“…266 Notably, during hepatic I/R injury-induced liver damage, the nuclear upregulation of IRF1 has been linked to the expression of functional TLR4. 267 However, whether and how other molecular signaling pathways are involved in IRFrelated I/R injury require further investigation.…”

Section: Upstream Irf Signaling In I/r Injurymentioning

confidence: 99%

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

Zhang

2015

Hypertension

View full text Add to dashboard Cite

Interferon Regulatory Factor 1 Mediates Acetylation and Release of High Mobility Group Box 1 from Hepatocytes During Murine Liver Ischemia-Reperfusion Injury

Cited by 77 publications

References 41 publications

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

High Mobility Group Box 1 Release from Hepatocytes during Ischemia and Reperfusion Injury Is Mediated by Decreased Histone Deacetylase Activity

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

Contact Info

Product

Resources

About