TY - JOUR
T1 - Role of STAT3 in liver regeneration
T2 - Survival, DNA synthesis, inflammatory reaction and liver mass recovery
AU - Moh, Akira
AU - Iwamoto, Yoshiki
AU - Chai, Gui Xuan
AU - Zhang, Samual Shao Min
AU - Kano, Arihiro
AU - Yang, Derek D.
AU - Zhang, Wenjun
AU - Wang, Jun
AU - Jacoby, Joerg J.
AU - Gao, Bin
AU - Flavell, Richard A.
AU - Fu, Xin Yuan
N1 - Funding Information:
We thank Klaus Rajewsky for providing the polbF/F mouse line, Koji Eshima for his expertise and help in the general mouse work, and Pandelakis Koni for breeding polbF/F mice. We are grateful to James Boyer for his critical evaluation of liver sections and helpful discussions. We also thank Lan Ji for technical assistance, and Thomas Welte and Nancy Bennett for critical reading of the manuscript. Y Iwamoto was supported by a fellowship of the United States Army Medical Research and Material Command (DAMD 17-97-1-7222). RA Flavell is an investigator of the Howard Hughes Medical Institute. This study was supported by a pilot project from Yale Liver Center (DK34989) and grants from the National Institutes of Health (RO1-AI34522 and RO1-AR44906) to X-Y Fu, who was also a recipient of a Career Development Award from NIH.
PY - 2007/10
Y1 - 2007/10
N2 - The hepatoprotective effect of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) has been well documented. However, reports on the role of IL-6/STAT3 in liver regeneration are conflicting probably due to the fact that the model of Stat3 knockout mice were complicated with obesity and fatty liver, which may cause some secondary effects on liver regeneration. To study the direct role of STAT3 and to circumvent the problems of obesity and fatty liver in liver regeneration, we generated conditional STAT3 knockout in the liver (L-Stat3-/-) using a transthyretin-driven Cre-lox method. The L-Stat3-/- mice were born with the expected Mendelian frequency and showed no obesity or other obvious phenotype. After partial hepatectomy, mortality in the L-Stat3-/- mice was significantly higher than the littermate Stat3f/+ controls in the early time points (<24 h). Hepatocyte DNA synthesis in the survived L-Stat3-/- mice slightly decreased as compared with Stat3f/+ mice at 40 h after partial hepatectomy, whereas similar hepatocyte DNA synthesis was found at other time points and liver mass could be completely recovered in the L-Stat3-/- mice. In another model of liver regeneration induced by subcutaneous injection of carbon tetrachloride (CCl4), hepatocyte DNA synthesis in the CCl4-treated L-Stat3-/- mice also decreased as compared with Stat3f/+ mice at 40 h after injection but not at other time points. In addition, infiltration of neutrophils and monocyte increased in the liver of CCl4-treated L-Stat3-/- mice compared to wild-type mice. In conclusion, STAT3 is required for survival in the acute stage after 70% hepatectomy and plays a role in inflammatory reaction after hepatocyte necrosis. However, the hepatocytic STAT3 may have limited role in liver mass recovery although DNA synthesis may be impaired.
AB - The hepatoprotective effect of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) has been well documented. However, reports on the role of IL-6/STAT3 in liver regeneration are conflicting probably due to the fact that the model of Stat3 knockout mice were complicated with obesity and fatty liver, which may cause some secondary effects on liver regeneration. To study the direct role of STAT3 and to circumvent the problems of obesity and fatty liver in liver regeneration, we generated conditional STAT3 knockout in the liver (L-Stat3-/-) using a transthyretin-driven Cre-lox method. The L-Stat3-/- mice were born with the expected Mendelian frequency and showed no obesity or other obvious phenotype. After partial hepatectomy, mortality in the L-Stat3-/- mice was significantly higher than the littermate Stat3f/+ controls in the early time points (<24 h). Hepatocyte DNA synthesis in the survived L-Stat3-/- mice slightly decreased as compared with Stat3f/+ mice at 40 h after partial hepatectomy, whereas similar hepatocyte DNA synthesis was found at other time points and liver mass could be completely recovered in the L-Stat3-/- mice. In another model of liver regeneration induced by subcutaneous injection of carbon tetrachloride (CCl4), hepatocyte DNA synthesis in the CCl4-treated L-Stat3-/- mice also decreased as compared with Stat3f/+ mice at 40 h after injection but not at other time points. In addition, infiltration of neutrophils and monocyte increased in the liver of CCl4-treated L-Stat3-/- mice compared to wild-type mice. In conclusion, STAT3 is required for survival in the acute stage after 70% hepatectomy and plays a role in inflammatory reaction after hepatocyte necrosis. However, the hepatocytic STAT3 may have limited role in liver mass recovery although DNA synthesis may be impaired.
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U2 - 10.1038/labinvest.3700630
DO - 10.1038/labinvest.3700630
M3 - Article
C2 - 17660847
AN - SCOPUS:34548719343
SN - 0023-6837
VL - 87
SP - 1018
EP - 1028
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 10
ER -
