gerHeinrichs, DanielBernhagen, JürgenDie Bedeutung des Zytokins MIF bei der Entwicklung einer chronischen Leberschädigunginfo:eu-repo/classification/ddc/500Makrophagen-InhibitionsfaktorLeberfibroseNichtalkoholische FettleberhepatitisNaturwissenschaftenMIFNASHHSCmacrophage migration inhibitory factornon-alcoholic steatohepatitisliver fibrosisA previous work described that the cytokine macrophage migration inhibitory factor (MIF) showed an antifibrotic effect after an established model of chronic, toxic liver injury. In this work, it was showed that the HSC activation was an important factor after chronic, toxic liver injury. After these findings, the next experiments were performed with the immortalized stellate cell line GRX in vitro. First, the proliferation and migration of stimulated by PDGF was inhibited by MIF via the receptor CD74. These findings could be shown in vitro and in vivo. In a next step, the therapeutic application of recombinant MIF was investigated. Daily injections of recombinant MIF to wild-type mice maintained in decreased liver fibrosis compared to wild-type mice which only received the vehicle. In a further model, which provokes a non-alcoholic steatohepatitis, fibrogenesis is also detectable. Here, a profibrotic effect was displayed, because the Mif -/- mice had decreased liver damage in contrast to the wild-type mice. The intrahepatic triglyceride content in this model was significantly increased in Mif -/- mice. Furthermore, the expression of lipogenesis-related genes was significantly increased compared to the wild-type counterparts. FACS analysis of infiltrating immune cells showed no major differences, so hepatocytes were analyzed. For this study the hepatoma cell line Hepa1-6 was analyzed in vitro. The triglyceride content in this cell line was significantly increased after stimulation with oleic acid an IL-1beta. Co-stimulation with recombinant MIF inhibited the fatty degeneration in the cells. The receptor CD74 was also investigated in this experiment. After pre-incubation of the cells with the neutralizing antibody against CD74, the inhibiting effects of the recombinant MIF were totally blocked. The same effect was determined by a pre-incubation with the AMPK inhibitor Compound C. Therefore, it could be showed that the protective effects of MIF were mediated through the CD74 and the stress kinase AMPK. To confirm these results a second independent model of non-alcoholic steatohepatitis was performed. In this model, the so called high fat diet, all results from the first model were confirmed. Furthermore, an impaired glucose tolerance was determined in the Mif -/- mice. These findings correlated with a higher weight gain in the knockout mice in contrast to the wild-type mice. In these work antifibrotic effects of the cytokine MIF in chronic, toxic liver injury was displayed and these antifibrotic effects were mediated via CD74. The activation of HSCs was a crucial key in this model of liver damage. In the metabolic injury, MIF showed protective effects in the weight gain and in establishing a Diabetes mellitus. Furthermore, the liver showed less fatty degeneration. This seemed to be an effect on the hepatocytes, the main fat-storage cells within the liver.Aachen : Publikationsserver der RWTH Aachen University 115 Bl. : Ill., graph. Darst. (2013). = Aachen, Techn. Hochsch., Diss., 2013info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionPublikationsserver der RWTH Aachen University2013info:eu-repo/semantics/openAccessDEhttps://publications.rwth-aachen.de/record/210490https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-143617%22StudentsStudent Financial Aid ProvidersTeachersResearchersinfo:eu-repo/semantics/altIdentifier/urn/urn:nbn:de:hbz:82-opus-44907