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

Tsung, Allan; Klune, John R.; Zhang, Xianghong; Jeyabalan, Geetha; Cao, Ziping; Peng, Ximei; Stolz, Donna B.; Geller, David A.; Rosengart, Matthew R.; Billiar, Timothy R.

doi:10.1084/jem.20070247

Cited by 558 publications

(546 citation statements)

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“…And it is safe to say that post translational modifications play an important role in the nucleocytoplasmic redistribution. As mentioned above, oxidation, hyperacetylation and phosphorylation of HMGB1 contribute to its cytoplasmic relocation in inflammatory and cancer cells (Hoppe et al, 2006;Youn et al, 2006;Tsung et al, 2007;Kang et al, 2009;Evankovich et al, 2010;Lee et al, 2012). Experiments in Schistosoma mansoni conclusively demonstrated that acetylation and phosphorylation played roles in cellular trafficking, culminating with its secretion to the extracellular milieu de Abreu da Silva et al, 2011).…”

Section: Discussionmentioning

confidence: 92%

“…Another study reported that the conformation of Cys106, whether reduced or oxidated, was critical for regulating nucleocytoplasmic shuttling of HMGB1 (Hoppe et al, 2006). In cultured hepatocytes, HMGB1releasing was regulated by TLR4, which dependened on reactive oxygen species production (Tsung et al, 2007). Later, it has been demonstrated that decreased histone deacetylases(HDACs) activity in hepatocytes, following ischemia and reperfusion, was a mechanism that promoted hyperacetylation and secretion of HMGB1 (Evankovich et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

Zhao²,

Ding³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background:The high mobility group box 1 (HMGB1) protein is a widespread nuclear protein present in most cell types. It typically locates in the nucleus and functions as a nuclear cofactor in transcription regulation. However, HMGB1 can also localize in the cytoplasm and be released into extracellular matrix, where it plays critical roles in carcinogenesis and inflammation. However, it remains elusive whether HMGB1 is relocated to cytoplasm in clear cell renal cell carcinoma (ccRCC). Methods: Nuclear and cytoplasmic proteins were extracted by different protocols from 20 ccRCC samples and corresponding adjacent renal tissues. Western blotting and immunohistochemistry were used to identify the expression of HMGB1 in ccRCC. To elucidate the potential mechanism of HMGB1 cytoplasmic translocation, HMGB1 proteins were enriched by immunoprecipitation and analyzed by mass spectrometry (MS). Results: The HMGB1 protein was overexpressed and partially localized in cytoplasm in ccRCC samples (12/20, 60%, p<0.05). Immunohistochemistry results indicated that ccRCC of high nuclear grade possess more HMGB1 relocation than those with low grade (p<0.05). Methylation of HMGB1 at lysine 112 in ccRCC was detected by MS. Bioinformatics analysis showed that post-translational modification might affect the binding ability to DNA and mediate its translocation. Conclusion: Relocation of HMGB1 to cytoplasm was confirmed in ccRCC. Methylation of HMGB1 at lysine 112 might the redistribution of this cofactor protein.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

Zhao²,

Ding³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…17 Through the TLR4 system, HMGB1 produces an early inflammatory response, 17 leading to amplification of HMGB1 secretion. 27 Active HMGB1 secretion from phagocytes displays delayed kinetics. 3,9,20 In experimental models of endotoxemia, HMGB1 levels increase 12 to 18 hours after peak TNF-␣ levels.…”

Section: Discussionmentioning

confidence: 99%

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

et al. 2008

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High mobility group box 1 protein (HMGB1), a cytokine actively secreted by phagocytes and passively released from necrotic cells, is an inflammatory mediator in experimental hepatic ischemia/reperfusion injury. We characterized its expression in human liver transplantation. In 20 patients, in addition to systemic samples, blood was drawn from portal and hepatic veins during and after reperfusion to assess changes within the graft. Plasma HMGB1, tumor necrosis factor ␣ (TNF-␣), and interleukin-6 (IL-6) levels were measured, and HMGB1 immunohistochemistry was performed on biopsies taken before and after reperfusion. Plasma HMGB1 was undetectable before reperfusion, and levels in systemic circulation peaked after graft reperfusion. At portal declamping, HMGB1 levels were substantially higher in the caval effluent [188 (80-371) ng/mL] than in portal venous blood [0 (0-3) ng/mL, P Ͻ 0.001]. HMGB1 release from the graft continued thereafter. HMGB1 levels were not related to TNF-␣ or IL-6 levels. HMGB1 expression was up-regulated in biopsies taken after reperfusion (P ϭ 0.020), with intense hepatocyte and weak neutrophil staining. HMGB1 levels in hepatic venous blood correlated with graft steatosis (r ϭ 0.497, P ϭ 0.03) and peak postoperative alanine aminotransferase levels (r ϭ 0.588, P ϭ 0.008). Our results indicate that HMGB1 originates from the graft and is a marker of hepatocellular injury in human liver transplantation. Liver Transpl 14: 1517Transpl 14: -1525Transpl 14: , 2008

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“…[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

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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.

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

Cited by 558 publications

References 50 publications

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

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

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