Interleukin-22 promotes liver progenitor cell proliferation in mice and patients with in viral hepatitis (44.16)

Abstract

Abstract The proliferation of liver progenitor cells (LPCs), which have bipotential capabilities to differentiate into hepatocytes and biliary epithelial cells, is often observed in the inflammatory region of chronic liver diseases; however, how inflammation promotes LPC proliferation remains obscure. We examined the role of IL-22 on LPC proliferation on human viral hepatitis patients and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding mice model. We found that interleukin-22 (IL-22), a survival factor for hepatocytes, is highly elevated and correlates with the grade of inflammation and LPC proliferation in patients with viral hepatitis. In a murine model of LPC proliferation induced by feeding DDC diet, overexpression of IL-22 in the liver via the generation of liver-specific IL-22 transgenic (IL-22TG) mice or injection of IL-22 adenovirus markedly increases LPC proliferation. STAT3, the major downstream signal of IL-22, is highly activated in the LPCs from DDC-fed IL-22TG mice. An additional deletion of hepatocyte-specific STAT3 in IL-22TG mice diminishes LPC proliferation. In vitro IL-22 treatment activates STAT3 and increases cell proliferation of isolated EpCAM+CD45-LPCs from DDC-fed mice and BMOL cells (a mouse LPC line), both of which are detected expression of IL-22R1. Conclusion: inflammatory cell-derived IL-22 promotes LPC proliferation via an STAT3-dependent manner, and IL-22 is a key link between inflammation and LPC proliferation in viral hepatitis.