The role of the Interleukin-6 receptor in liver damage and regeneration

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The interference of immune response and liver damage/-regeneration is controlled by cytokines of the Interleukin (IL-)6 family. Recently, we have demonstrated that mainly IL-6 trans-signalling directly and indirectly promotes hepatocyte proliferation and is sufficient for liver regeneration following partial hepatectomy (PHX). In addition to IL-6, other IL-6 type cytokines including IL-11, OSM and LIF affect liver regeneration. In this research project, we will unravel the cell-type specific contribution of IL-6 pathways during liver regeneration following PHX using a variety of transgenic mouse models. First of all, we will analyze which cell types of the liver express IL-6 type cytokines and their receptors during PHX including IL-6, IL-11, OSM, and LIF. Since IL-6R deficient mice have a disfunctional liver regeneration, the potential to rescue this phenotype by these cytokines following PHX will be determined. Moreover, we will define the target cells of IL-6 signalling during liver regeneration following PHX. To this end, liver regeneration after PHX will be monitored in mice displaying a tissue specific conditional IL-6R deficiency in hepatocytes, hepatic stellate cells, macrophages, or T cells. Vice versa gain-of-function will be studied using tissue specific expression of L-gp130 and GVHH-gp130. L-gp130 is a synthetic ligand-independent, constitutive active gp130 receptor variant, which is able to initiate and maintain cell-autonomous IL-6 signal transduction. GVHH-gp130 is a switchable synthetic gp130 cytokine receptor, which can be activated by dimeric GFP (green fluorescent protein)-ligands. For GVHH-gp130, we will induce synthetic IL-6 signalling by injection of recombinant homodimeric GFP fusion proteins, to determine the optimal regenerative time window of IL-6 signalling. Expression of L-gp130 and GVHH-gp130 in transgenic mice will be initiated after crossing to Cre-recombinase expressing mice, which facilitates tissue specific expression in hepatocytes, hepatic stellate cells, macrophages, or T cells. These mice will be crossed onto the IL-6R deficient background to disable endogenous, natural IL-6 signalling before monitoring the liver regeneration following PHX. This analysis will allow the characterization of IL-6-dependent, regeneration competent cell types of the liver during the damage and regeneration phases. The project aims to elucidate the currently unknown cell-type specific function of IL-6 in liver regeneration following PHX using/employing common loss-of-function and novel gain-of-function transgenic mouse models.