IL‐8 induces transdifferentiation of mature hepatocytes toward the cholangiocyte phenotype

Tokio Sasaki,Ting Wang,Akiko Suzuki,Yuji Suzuki,Yasuhiro Takikawa,Kazuyuki Ishida,Keisuke Kakisaka,Hiroaki Abe,Tamotsu Sugai

doi:10.1002/2211-5463.12750

Abstract

The adult mammalian liver exhibits a remarkable regenerative capacity, with different modes of regeneration according to the type and extent of injury. Hepatocyte–cholangiocyte biphenotypic liver progenitor cell populations appear under conditions of excessive injury. It has been reported that mature hepatocytes can transdifferentiate toward a cholangiocyte phenotype and be a cellular source of progenitor cell populations. Here, we determined that among various plasma cytokines, interleukin (IL)‐8 levels were significantly elevated in acute liver failure and severe acute liver injury patients. In vitro assays revealed that administration of IL‐8 homologues increases the expression of Sry HMG box protein 9 (SOX9). In liver biopsies of acute liver injury patients, we observed the appearance of SOX9‐positive biphenotypic hepatocytes accompanied by elevation of plasma IL‐8 levels. Our results suggest that IL‐8 regulates the phenotypic conversion of mature hepatocytes toward a cholangiocyte phenotype.

Highlights

Tokio Sasaki1, Yuji Suzuki1, Keisuke Kakisaka1, Ting Wang1, Kazuyuki Ishida2, Akiko Suzuki1, Hiroaki Abe1, Tamotsu Sugai2 and Yasuhiro Takikawa1
We determined whether administration of IL-8 homologues keratinocyto-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2 affected the proliferative activity of a mature hepatocyte cell line (AML12) in vitro
We show that, among various plasma cytokines, IL-8 was significantly elevated in acute liver failure (ALF) and severe acute liver injury (SLI) patients

Summary

Introduction

When the proliferation of hepatocytes is impaired as a result of acute or chronic liver injury—such as acute liver failure (ALF), chronic viral hepatitis, and nonalcoholic fatty liver disease [6,7]—the liver stem/ progenitor cells (LPCs), which are cells with intermediate hepatocyte–cholangiocyte phenotype, emerge and expand in the liver parenchyma [8,9,10]. Sry HMG box protein 9 (SOX9) is a transcription factor that plays pivotal roles during embryonic development of several tissues, such as the testis, pancreas, bile duct, lung, heart, and central nervous system, as Abbreviations ALF, acute liver failure; ALI, acute liver injury; DAPT, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl Ester; DRs, ductular reactions; EpCAM, epithelial cell adhesion molecule; IL, interleukin; LPCs, liver stem/progenitor cells; MIP, macrophage inflammatory protein; PT-INR, prothrombin time-international normalized ratio; qRT-PCR, quantitative real-time PCR; SLI, severe acute liver injury; SOX9, Sry HMG box protein 9.

Methods

Results

Conclusion