ME3738 protects from concanavalin A-induced liver failure via an IL-6-dependent mechanism.
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.
Klein
Christian
C
Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
Wüstefeld
Torsten
T
Heinrich
Peter C
PC
Streetz
Konrad L
KL
Manns
Michael P
MP
Trautwein
Christian
C
D000210:Acute-Phase Reaction / Q000235:genetics / Q000276:immunology; D000818:Animals; D003208:Concanavalin A / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017093:Liver Failure / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D015850:Interleukin-6; C477463:ME3738; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; C116604:soyasapogenol A; D009828:Oleanolic Acid