Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury

Andrew M. Miller, Hua Wang, Ogyi Park, Norio Horiguchi, Fouad Lafdil, Partha Mukhopadhyay, Akira Moh, Xin Yuan Fu, George Kunos, Pal Pacher, Bin Gao

Research output: Contribution to journalArticle

Abstract

Background: It is generally believed that the hepatoprotective effect of interleukin-6 (IL-6) is mediated via activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. IL-6-deficient mice are more susceptible to alcohol-induced hepatocyte apoptosis and steatosis and elevation of serum alanine transaminase (ALT); however, whereas hepatocyte-specific STAT3 knockout mice are more susceptible to alcohol-induced hepatic steatosis, they have similar hepatocyte apoptosis and serum ALT after alcohol feeding compared with wild-type mice. This suggests that the hepatoprotective effect of IL-6 in alcoholic liver injury may be mediated via activation of STAT3-independent signals in hepatocytes, activation of STAT3 in nonparenchymal cells, or both. We have previously shown that IL-6 also activates STAT3 in sinusoidal endothelial cells (SECs). Thus, the purpose of this study was to investigate whether STAT3 in endothelial cells also plays a protective role in alcoholic liver injury. Methods: Wild-type and endothelial cell-specific STAT3 knockout (STAT3E-/-) mice were pair-fed and fed ethanol containing diet for 4 weeks. Liver injury and inflammation were determined. Results: Feeding mice with ethanol-containing diet for 4 weeks induced greater hepatic injury (elevation of serum ALT) and liver weight in STAT3E-/- mice than wild-type control groups. In addition, ethanol-fed STAT3 E-/- mice displayed greater hepatic inflammation and substantially elevated serum and hepatic levels of IL-6 and TNF-α compared with wild-type mice. Furthermore, ethanol-fed STAT3E-/- mice displayed a greater abundance of apoptotic SECs and higher levels of serum hyaluronic acid than wild-type controls. Conclusions: These data suggest that endothelial cell STAT3 plays important dual functions of attenuating hepatic inflammation and SEC death during alcoholic liver injury.

Original languageEnglish (US)
Pages (from-to)719-725
Number of pages7
JournalAlcoholism: Clinical and Experimental Research
Volume34
Issue number4
DOIs
StatePublished - Apr 2010
Externally publishedYes

Fingerprint

STAT3 Transcription Factor
Endothelial cells
Liver
Anti-Inflammatory Agents
Endothelial Cells
Wounds and Injuries
Interleukin-6
Hepatocytes
Ethanol
Alanine Transaminase
Serum
Chemical activation
Alcohols
Nutrition
Inflammation
Knockout Mice
Apoptosis
Diet
Cell death
Hyaluronic Acid

Keywords

  • Alcoholic Liver Injury
  • Endothelial Cells
  • IL-6
  • STAT3

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury. / Miller, Andrew M.; Wang, Hua; Park, Ogyi; Horiguchi, Norio; Lafdil, Fouad; Mukhopadhyay, Partha; Moh, Akira; Fu, Xin Yuan; Kunos, George; Pacher, Pal; Gao, Bin.

In: Alcoholism: Clinical and Experimental Research, Vol. 34, No. 4, 04.2010, p. 719-725.

Research output: Contribution to journalArticle

Miller, AM, Wang, H, Park, O, Horiguchi, N, Lafdil, F, Mukhopadhyay, P, Moh, A, Fu, XY, Kunos, G, Pacher, P & Gao, B 2010, 'Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury', Alcoholism: Clinical and Experimental Research, vol. 34, no. 4, pp. 719-725. https://doi.org/10.1111/j.1530-0277.2009.01141.x
Miller, Andrew M. ; Wang, Hua ; Park, Ogyi ; Horiguchi, Norio ; Lafdil, Fouad ; Mukhopadhyay, Partha ; Moh, Akira ; Fu, Xin Yuan ; Kunos, George ; Pacher, Pal ; Gao, Bin. / Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury. In: Alcoholism: Clinical and Experimental Research. 2010 ; Vol. 34, No. 4. pp. 719-725.
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AU - Wang, Hua

AU - Park, Ogyi

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AU - Lafdil, Fouad

AU - Mukhopadhyay, Partha

AU - Moh, Akira

AU - Fu, Xin Yuan

AU - Kunos, George

AU - Pacher, Pal

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AB - Background: It is generally believed that the hepatoprotective effect of interleukin-6 (IL-6) is mediated via activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. IL-6-deficient mice are more susceptible to alcohol-induced hepatocyte apoptosis and steatosis and elevation of serum alanine transaminase (ALT); however, whereas hepatocyte-specific STAT3 knockout mice are more susceptible to alcohol-induced hepatic steatosis, they have similar hepatocyte apoptosis and serum ALT after alcohol feeding compared with wild-type mice. This suggests that the hepatoprotective effect of IL-6 in alcoholic liver injury may be mediated via activation of STAT3-independent signals in hepatocytes, activation of STAT3 in nonparenchymal cells, or both. We have previously shown that IL-6 also activates STAT3 in sinusoidal endothelial cells (SECs). Thus, the purpose of this study was to investigate whether STAT3 in endothelial cells also plays a protective role in alcoholic liver injury. Methods: Wild-type and endothelial cell-specific STAT3 knockout (STAT3E-/-) mice were pair-fed and fed ethanol containing diet for 4 weeks. Liver injury and inflammation were determined. Results: Feeding mice with ethanol-containing diet for 4 weeks induced greater hepatic injury (elevation of serum ALT) and liver weight in STAT3E-/- mice than wild-type control groups. In addition, ethanol-fed STAT3 E-/- mice displayed greater hepatic inflammation and substantially elevated serum and hepatic levels of IL-6 and TNF-α compared with wild-type mice. Furthermore, ethanol-fed STAT3E-/- mice displayed a greater abundance of apoptotic SECs and higher levels of serum hyaluronic acid than wild-type controls. Conclusions: These data suggest that endothelial cell STAT3 plays important dual functions of attenuating hepatic inflammation and SEC death during alcoholic liver injury.

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