Cell Type–Dependent Pro- and Anti-Inflammatory Role of Signal Transducer and Activator of Transcription 3 in Alcoholic Liver Injury

Horiguchi, Norio; Wang, Lei; Mukhopadhyay, Partha; Park, Ogyi; Jeong, Won Il; Lafdil, Fouad; Osei‐Hyiaman, Douglas; Moh, Akira; Fu, Xin; Pacher, Pál; Kunos, George; Gao, Bin

doi:10.1053/j.gastro.2008.01.016

Cited by 162 publications

(171 citation statements)

References 52 publications

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“…Conditional deletion of STAT3 in myeloid cells results in enhanced inflammatory response and inflammation in various organs including the liver. 18,25,26 Here, we demonstrate that deletion of IL-10 markedly increased the inflammatory responses in the liver after PHx (Figure 3). Expression of F4/80 (a marker for macrophages) and CCR2 (a marker for monocytes) in the liver was slightly induced after PHx in wild-type mice but was induced up to 60-fold in IL-10 Ϫ/Ϫ mice.…”

Section: Il-10 Plays An Important Role In Tempering Inflammatory Respmentioning

confidence: 55%

“…Hepatocyte-specific STAT3 knockout (KO) (STAT3 HepϪ/Ϫ ) mice were described previously. 18 Male IL-10 Ϫ/Ϫ were bred with female STAT3 HepϪ/Ϫ mice for several steps to generate IL-10 Ϫ/Ϫ STAT3 HepϪ/Ϫ mice in which the STAT3 gene was deleted in hepatocytes, whereas the IL-10 gene was deleted globally. All knockout strains mentioned above were developmentally normal and have normal life spans.…”

Section: Animalsmentioning

confidence: 99%

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Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Yin

Wang

Park

et al. 2011

The American Journal of Pathology

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Emerging evidence suggests that proinflammatory cytokines, including tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6), play a critical role in the initiation and progression of liver regeneration; however, relatively little is known about the role of antiinflammatory cytokine IL-10 in liver regeneration after partial hepatectomy (PHx). Here, we examined the role of IL-10 in liver regeneration using a model of PHx in several strains of genetically modified mice. After PHx, expression of IL-10 mRNA in the liver and spleen was significantly elevated. Such elevation was diminished in TLR4 mutant mice. Compared with wild-type mice, IL-10 ؊/؊ mice had higher levels of expression of proinflammatory cytokines (IL-6, TNF-␣, and IFN-␥) and inflammatory markers (CCR2 and F4/80) in the liver, as well as higher serum levels of proinflammatory cytokines after PHx. The number of neutrophils and macrophages was also higher in the livers of IL-10 ؊/؊ mice than in wild-type mice after PHx. Liver regeneration as determined by BrdU incorporation after PHx was higher in IL-10 ؊/؊ mice than in wild-type mice, which was associated with higher levels of activation of IL-6 downstream signal STAT3 in the liver. An additional deletion of STAT3 in hepatocytes significantly reduced liver regeneration in IL-10 ؊/؊ mice after PHx. Collectively, IL-10 plays an important role in negatively regulating liver regeneration via limiting inflammatory response and subsequently tempering hepatic STAT3 activation.

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Section: Il-10 Plays An Important Role In Tempering Inflammatory Respmentioning

confidence: 55%

Section: Animalsmentioning

confidence: 99%

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Yin

Wang

Park

et al. 2011

The American Journal of Pathology

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“…In hepatocyte-specific STAT3 knockout mice, CCl 4 injection induced greater liver damage than wild-type mice (14). In another alcoholic liver injury model, STAT3 in hepatocytes otherwise promotes inflammation, whereas STAT3 in macrophages/Kupffer cells suppresses inflammation (15). In Kupffer cells, the transient activation of STAT3 by IL-6 is proinflammatory, promoting HSC survival and proliferation (10).…”

Section: Discussionmentioning

confidence: 99%

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Shiau²,

Jao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery.hepatic stellate cell | STAT3 | SHP-1 | hepatitis B | liver fibrosis

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“…Activation of STAT3 causes induction of anti-inflammatory signal to inhibit inflammation during alcohol mediated injury [63]. Hepatic knock out of STAT3 in mice increases hepatosteatosis and increased expression of lipogenic genes after ethanol exposure [68].…”

Section: Activation Of Transcription Factorsmentioning

confidence: 99%

Role of Angiotensin Peptides Precursor in Ethanol Mediated Hepato toxicity: Perspective on Angiotensinogen

Ansari¹

2012

TOGASJ

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Alcohol usage poses serious social and economical challenges. Its overuse is responsible for loss of billions of dollars due to fatal accidents and causes multiple diseases. Chronic alcoholism leads to liver disorders, including steatosis, hepatitis, fibrosis and cirrhosis. Both binge and chronic alcohol drinking result in blood pressure elevation and hypertension. As a significant mechanism, changes in the levels of angiotensinogen-released peptides play an important role in advanced alcohol liver disease. This review summarizes some of the studies that have demonstrated their role in liver fibrosis, cirrhosis and hypertension. Further, the individual variants and polymorphic sites may play a role in alcoholmediated regulation of angiotensinogen. Possible role of human angiotensinogen on alcohol hepatotoxicity is also discussed.

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Cell Type–Dependent Pro- and Anti-Inflammatory Role of Signal Transducer and Activator of Transcription 3 in Alcoholic Liver Injury

Abstract: Background and Aims-Signal transducer and activator of transcription 3 (STAT3) is known to be activated in human alcoholic liver disease, but its role in the pathogenesis of alcoholic liver injury remains obscure.

Cited by 162 publications

References 52 publications

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Role of Angiotensin Peptides Precursor in Ethanol Mediated Hepato toxicity: Perspective on Angiotensinogen

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