ME3738 protects from concanavalin A-induced liver failure via an IL-6-dependent mechanism.

Abstract

ME3738 is a new compound that attenuates liver disease in several models of acute and chronic liver inflammation. We used the concanavalin A (Con A) model to elucidate the molecular mechanisms of ME3738 to block liver cell damage. Pretreatment of BALB/c mice with ME3738 prior to Con A injection resulted in a significant reduction in liver injury. The protective effect of ME3738 prior to Con A injection was associated with a reduction in IL-6 serum levels and NF-kappaB DNA binding in liver nuclear extracts. However, STAT3 DNA binding was induced via ME3738 prior to Con A injection. Further analysis showed that ME3738 induces IL-6 serum levels and activates STAT3 DNA binding and target gene transcription. The relevance of this finding was assessed in IL-6(-/-) mice. In these animals, ME3738 induced no increase in IL-6 serum expression, and activation of IL-6-dependent pathways was not found. In addition, ME3738 did not protect IL-6(-/-) animals from Con A-induced liver failure, while IL-6 injection was still effective. Therefore, we demonstrate that ME3738 triggers IL-6 expression, which activates pathways that are relevant to protect from Con A-induced liver failure.

• Authors: Christian Klein, Torsten Wüstefeld, Peter C Heinrich, Konrad L Streetz, Michael P Manns, Christian Trautwein
• Journal: European journal of immunology (Eur J Immunol) Vol. 33 Issue 8 Pg. 2251-61 (Aug 2003) ISSN: 0014-2980 [Print] Germany
• PMID: 12884300 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Immunosuppressive Agents
• Interleukin-6
• ME3738
• NF-kappa B
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Trans-Activators
• Tumor Necrosis Factor-alpha
• Concanavalin A
• soyasapogenol A
• Oleanolic Acid

Topics

• Acute-Phase Reaction (genetics, immunology)
• Animals
• Concanavalin A (toxicity)
• DNA-Binding Proteins (metabolism)
• Gene Expression (drug effects)
• Immunosuppressive Agents (chemistry, pharmacology)
• Interleukin-6 (deficiency, genetics, metabolism)
• Liver Failure (chemically induced, immunology, pathology, prevention & control)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• NF-kappa B (metabolism)
• Oleanolic Acid (analogs & derivatives, chemistry, pharmacology)
• STAT3 Transcription Factor
• Trans-Activators (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)