ObjectiveStellate cells are responsible for liver and pancreas fibrosis and strictly correlate with tumourigenesis. Although their activation is reversible, an exacerbated signalling triggers chronic fibrosis. Toll-like receptors (TLRs) modulate stellate cells transition. TLR5 transduces the signal deriving by the binding to bacterial flagellin from invading mobile bacteria.DesignHuman hepatic and pancreatic stellate cells were activated by the administration of transforming growth factor-beta (TGF-β). TLR5 was transiently knocked down by short-interference RNA transfection. Reverse Transcription-quantitativePCR and western blot were performed to analyse the transcript and protein level of TLR5 and the transition players. Fluorescence microscopy was performed to identify these targets in spheroids and in the sections of murine fibrotic liver.ResultsTGF-β-activated human hepatic and pancreatic stellate cells showed an increase ofTLR5expression.TLR5knockdown blocked the activation of those stellate cells. Furthermore, TLR5 busted during murine liver fibrosis and co-localised with the inducible Collagen I. Flagellin suppressedTLR5,COL1A1andACTA2expression after the administration of TGF-β. Instead, the antagonist of TLR5 did not block the effect of TGF-β. Wortmannin, a specific AKT inhibitor, inducedTLR5but notCOL1A1andACTA2transcript and protein level.ConclusionTGF-β-mediated activation of hepatic and pancreatic stellate cells requires the over-expression of TLR5. Instead, its autonomous signalling inhibits the activation of the stellate cells, thus prompting a signalling through different regulatory pathways.
Climate change litigation is becoming increasingly important. This thesis deals with the question whether state liability claims against Germany or the EU can be justified, if commitments to reduce greenhouse gas emissions are not met. For this purpose, the claim under public liability according to § 839 German Civil Code in connection with Art. 34 German Basic Law, the liability of the EU-Member States and the liability of the European Union according to Art. 340 II TFEU are discussed. At the end of the thesis, considerations on the practical perspectives of state liability are made in order to improve their prospects of success.
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