CCAAT Enhancer-binding Protein α Is Required for Interleukin-6 Receptor α Signaling in Newborn Hepatocytes

Abstract

The acute phase response is an evolutionarily conserved response of the liver to inflammatory stimuli, which aids the body in host defense and homeostasis. We have previously reported that CCAAT enhancer-binding protein α (C/EBPα) is required for the induction of acute phase protein (APP) genes in newborn mice in response to lipopolysaccharide. In this paper, we describe a mechanism by which C/EBPα knock-out mice are unable to induce APP gene expression in response to inflammatory stimuli. We demonstrate that the lack of acute phase response in C/EBPα knock-out mice is because of a hepatocyte autonomous defect. C/EBPα knock-out hepatocytes do not activate STAT3 in response to recombinant interleukin (IL)-6, indicating a defect in the IL-6 pathway. C/EBPα knock-out hepatocytes also do not show activation of other IL-6 receptor (IL-6R)-mediated Janus kinase substrates, gp130 SHP-2, and Tyk2. Further examination of the IL-6 pathway demonstrated that C/EBPα knock-out hepatocytes have decreased IL-6Rα protein levels caused, in part, by reduced protein stability. However, other components of the IL-6 pathway are intact, as demonstrated by rescue of STAT3 activation and APP gene induction with recombinant-soluble IL-6R linked to IL-6 cytokine (Hyper-IL-6) or with another gp130 signaling cytokine, Oncostatin M. In conclusion, C/EBPα is required for the proper regulation of IL-6Rα protein in hepatocytes resulting in a lack of acute phase protein gene induction in newborn C/EBPα null mice in response to lipopolysaccharide or cytokines.