Human but Not Mouse Hepatocytes Respond to Interferon-Lambda In Vivo

The type III interferon (IFN) receptor is preferentially expressed by epithelial cells. It is made of two subunits: IFNLR1, which is specific to IFN-lambda (IFN-lambda) and IL10RB, which is shared by other cytokine receptors. Human hepatocytes express IFNLR1 and respond to IFN-lambda. In contrast, the IFN-lambda response of the mouse liver is very weak and IFNLR1 expression is hardly detectable in this organ. Here we investigated the IFN-lambda response at the cellular level in the mouse liver and we tested whether human and mouse hepatocytes truly differ in responsiveness to IFN-lambda. When monitoring expression of the IFN-responsive Mx genes by immunohistofluorescence, we observed that the IFN-lambda response in mouse livers was restricted to cholangiocytes, which form the bile ducts, and that mouse hepatocytes were indeed not responsive to IFN-lambda. The lack of mouse hepatocyte response to IFN-lambda was observed in different experimental settings, including the infection with a hepatotropic strain of influenza A virus which triggered a strong local production of IFN-lambda. With the help of chimeric mice containing transplanted human hepatocytes, we show that hepatocytes of human origin readily responded to IFN-lambda in a murine environment. Thus, our data suggest that human but not mouse hepatocytes are responsive to IFN-lambda in vivo. The non-responsiveness is an intrinsic property of mouse hepatocytes and is not due to the mouse liver micro-environment.