A novel mouse model to study effects of cell-autonomous gp130 activation on infection, inflammation and tumour formation in the liver

Introduction:

Interleukin 6 (IL-6) is a pleiotropic cytokine involved in inflammation and tissue regeneration. In the liver, IL-6 has been shown to be crucial for the induction of acute-phase proteins, liver regeneration, but also tumour formation. In complex with its cognate IL-6 receptor, IL-6 binds to the signal-transducing subunit gp130. However, little is known about specific effects of IL-6 on particular cell types in the liver.

Methods:

In order to address this question, we recently generated ROSA26-transgenic mice allowing for the Cre-inducible expression of a constitutive active gp130 variant (Lgp130). These mice were bred to Alb-CreERT2, CK19-CreERT2 and LRAT-Cre mice to analyze the effects of ligand-independent gp130 activation in hepatocytes, cholangiocytes and hepatic stellate cells (HSCs). The effects of cell-autonomous gp130 activation were analysed by transcriptomics, proteomics, histological and biochemical methods.

Results:

We demonstrate that hepatocytic gp130 activation was sufficient to induce a robust acute-phase response, Kupffer cell activation, myeloid cell recruitment and defence against systemic bacterial infection. Cell-autonomous gp130 activation was stably maintained but not sufficient to induce hepatic tumours in elder mice. Activation of gp130 in HSCs and cholangiocytes induced paracrine STAT3 activation in hepatocytes without altering HSC or cholangiocyte morphology. We furthermore observed an impact of hepatic gp130 signaling on intestinal microbiota.

This model allows for the first time to analyse the gp130 signaling in specific cell types of the liver and its impact on infection, inflammation and tumorigenesis.