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Akira Moh, Yoshiki Iwamoto,
Gui-Xuan Chai,
Samual Shao-Min Zhang,
Arihiro Kano,
Derek D Yang,
Wenjun Zhang,
Jun Wang,
Joerg J Jacoby,
Bin Gao,
Richard A Flavell,
Xin-Yuan Fu
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ABSTRACT: 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 Stat3(f/+) controls in the early time points (<24 h). Hepatocyte DNA synthesis in the survived L-Stat3(-/-) mice slightly decreased as compared with Stat3(f/+) 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 (CCl(4)), hepatocyte DNA synthesis in the CCl(4)-treated L-Stat3(-/-) mice also decreased as compared with Stat3(f/+) mice at 40 h after injection but not at other time points. In addition, infiltration of neutrophils and monocyte increased in the liver of CCl(4)-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.
Laboratory Investigation 10/2007; 87(10):1018-28. · 3.64 Impact Factor
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ABSTRACT: Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3E-/-). STAT3E-/- mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3E-/- mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor beta. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon gamma. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.
Journal of Experimental Medicine 12/2003; 198(10):1517-25. · 13.85 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced
endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer
and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity.
Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in
endothelium (STAT3E−/−). STAT3E−/− mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific
(i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge.
The LPS response in STAT3E−/− mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum
alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines
are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory
cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived
from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within
endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.
Journal of Experimental Medicine 11/2003; 198(10):1517-1525. · 13.85 Impact Factor
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Jörg J Jacoby,
April Kalinowski,
Mu-Gen Liu,
Samuel S-M Zhang,
Qian Gao,
Gui-Xuan Chai,
Lan Ji, Yoshiki Iwamoto,
En Li,
Michael Schneider,
Kerry S Russell,
Xin-Yuan Fu
[show abstract]
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ABSTRACT: Cytokines and inflammation have been implicated in the pathogenesis of heart failure. For example, IL-6 family cytokines and the gp130 receptor play important roles in cardiac myocyte survival and hypertrophy. Signal transducer and activator of transcription 3 (STAT3) is a major signaling protein that is activated through gp130. We have created mice with a cardiomyocyte-restricted deletion of STAT3. As measured by serial echocardiograms, mice with cardiac specific deletion of STAT3 are significantly more susceptible to cardiac injury after doxorubicin treatment than age-matched controls. Intriguingly, STAT3 appears to have a critical role in protection of inflammation-induced heart damage. STAT3-deficient mice treated with lipopolysaccharide demonstrated significantly more apoptosis than their WT counterparts. At the cellular level, cardiomyocytes with STAT3 deleted secrete significantly more tumor necrosis factor in response to lipopolysaccharide than those with WT STAT3. Furthermore, histologic examination of the cardiomyocyte-restricted STAT3-deficient mice reveals a dramatic increase in cardiac fibrosis in aged mice. Although no overt signs of heart failure are present in young STAT3-deficient mice, they spontaneously develop heart dysfunction with advancing age. These results indicate the crucial functions of STAT3 in cardiomyocyte resistance to inflammation and other acute injury and in pathogenesis of age-related heart failure.
Proceedings of the National Academy of Sciences 11/2003; 100(22):12929-34. · 9.68 Impact Factor
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Thomas Welte,
Samuel S. M. Zhang,
Tian Wang,
Zhiyuan Zhang,
David G. T. Hesslein,
Zhinan Yin,
Arihiro Kano, Yoshiki Iwamoto,
En Li,
Joseph E. Craft,
Alfred L. M. Bothwell,
Erol Fikrig,
Pandelakis A. Koni,
Richard A. Flavell,
Xin-Yuan Fu
[show abstract]
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ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional mediator for many cytokines and is essential
for normal embryonic development. We have generated a unique strain of mice with tissue-specific disruption of STAT3 in bone
marrow cells during hematopoiesis. This specific STAT3 deletion causes death of these mice within 4–6 weeks after birth with
Crohn's disease-like pathogenesis in both the small and large intestine, including segmental inflammatory cell infiltration,
ulceration, bowel wall thickening, and granuloma formation. Deletion of STAT3 causes significantly increased cell autonomous
proliferation of cells of the myeloid lineage, both in vivo and in vitro. Most importantly, Stat3 deletion during hematopoiesis causes overly pseudoactivated innate immune responses. Although inflammatory
cytokines, including tumor necrosis factor α and IFN-γ, are overly produced in these mice, the NAPDH oxidase activity, which
is involved in antimicrobial and innate immune responses, is inhibited. The signaling responses to lipopolysaccharide are
changed in the absence of STAT3, leading to enhanced NF-κB activation. Our results suggest a model in which STAT3 has critical
roles in the development and regulation of innate immunity, and deletion of STAT3 during hematopoiesis results in abnormalities
in myeloid cells and causes Crohn's disease-like pathogenesis.
Proceedings of the National Academy of Sciences 02/2003; 100(4):1879-1884. · 9.68 Impact Factor
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Thomas Welte,
Samuel S M Zhang,
Tian Wang,
Zhiyuan Zhang,
David G T Hesslein,
Zhinan Yin,
Arihiro Kano, Yoshiki Iwamoto,
En Li,
Joseph E Craft,
Alfred L M Bothwell,
Erol Fikrig,
Pandelakis A Koni,
Richard A Flavell,
Xin-Yuan Fu
Proceedings of the National Academy of Sciences 01/2002; · 9.68 Impact Factor
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[show abstract]
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ABSTRACT: Burkitt's lymphoma cell line, BL2 was stimulated by surface BCR cross-linking and altered gene expression was analyzed by RDA methodology. Consistent with previous reports, we detected up-regulated MDC, IL6R and adhesion molecule LFA1. We also detected gene expression of SIRPα, anti-apoptotic A-20, signal regulatory SLP76 and BCAR3, DNA binding proteins EGR2 and DEC1 in addition to some new genes.
Biochemical and Biophysical Research Communications.
