These authors contributed equally to this study.
Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice†
Article first published online: 17 AUG 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 46, Issue 5, pages 1564–1573, November 2007
How to Cite
Sakamori, R., Takehara, T., Ohnishi, C., Tatsumi, T., Ohkawa, K., Takeda, K., Akira, S. and Hayashi, N. (2007), Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice. Hepatology, 46: 1564–1573. doi: 10.1002/hep.21837
Potential conflict of interest: Nothing to report.
- Issue published online: 29 OCT 2007
- Article first published online: 17 AUG 2007
- Manuscript Accepted: 25 MAY 2007
- Manuscript Received: 13 MAR 2007
- Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan
Sepsis is an infection-induced syndrome with systemic inflammatory response leading to multiorgan failure and occasionally death. During this process, signal transducer and activator of transcription 3 (STAT3) is activated in the liver, but the significance of this molecule has not been established. We generated hepatocyte-specific STAT3-deficient mice (L-STAT3 KO) and examined the susceptibility of these mice to cecal ligation and puncture–induced peritonitis, a well-established septic model. L-STAT3 KO mice showed significantly higher mortality and produced lesser amounts of various acute phase proteins than control littermates. Although blood bacterial infection did not differ between L-STAT3 KO mice and control mice, the former showed deterioration of the systemic inflammatory response as evidenced by a significant increase in various cytokines such as tumor necrosis factor α, IFN-γ, IL-6, IL-10, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β. A similar hyperinflammatory response was observed in another septic model caused by lipopolysaccharide (LPS) injection. In vitro analysis revealed that soluble substances derived from hepatocytes and dependent on STAT3 were critical for suppression of cytokine production from LPS-stimulated macrophage and splenocytes. Conclusion: STAT3 activation in hepatocytes can attenuate a systemic hyperinflammatory response and lethality in sepsis, in part by suppressing immune cell overactivation, implying a critical role of hepatocyte STAT3 signaling in maintaining host homeostasis. (HEPATOLOGY 2007.)