Research

Expression of leukemia inhibitory factor (LIF) and its receptor gp190 in human liver and in cultured human liver myofibroblasts. Cloning of new isoforms of LIF mRNA

Toru Hisaka^1,3,4 , Alexis Desmoulière^1,3 , Jean-Luc Taupin^2,3 , Sophie Daburon^2,3 , Véronique Neaud^1,3 , Nathalie Senant³ , Jean-Frédéric Blanc^1,3 , Jean-François Moreau^2,3 and Jean Rosenbaum^1,3

¹  INSERM, E362, Bordeaux, F-33076 France; Université Victor Segalen Bordeaux 2, Bordeaux, F-33076 France

²  CNRS, UMR 5164, Bordeaux, F-33076 France; Université Victor Segalen Bordeaux 2, Bordeaux, F-33076 France

³  IFR 66, 33076 Bordeaux France

⁴  Kurume University School of Medicine, Department of Pathology, Fukuoka, Japan

author email corresponding author email

Comparative Hepatology 2004, 3:10doi:10.1186/1476-5926-3-10

Published:	26 November 2004

Abstract

Background

The cytokine leukemia inhibitory factor (LIF) mediates its biological effects through binding to its high affinity receptor made of the low-affinity LIF receptor subunit gp190 (LIF-R) and the gp130 subunit. LIF exerts several important effects in the liver, however, data on liver expression of LIF are scarce. The aim of this study was to examine the expression of LIF and LIF-R in human liver.

Results

LIF expression, analyzed by immunohistochemistry, was barely detectable in normal liver but was strong within cirrhotic fibrous septa and was found in spindle-shaped cells compatible with myofibroblasts. Accordingly, cultured human liver myofibroblasts expressed high levels of LIF as shown by ELISA and Northern blot. Biological assay demonstrated that myofibroblast-derived LIF was fully active. RT-PCR showed expression of the LIF-D and M isoforms, and also of low levels of new variants of LIF-D and LIF-M resulting from deletion of exon 2 through alternative splicing. LIF receptor expression was detected mainly as a continuous sinusoidal staining that was enhanced in cirrhotic liver, suggestive of endothelial cell and/or hepatocyte labeling. Immunohistochemistry, flow cytometry and STAT-3 phosphorylation assays did not provide evidence for LIF receptor expression by myofibroblasts themselves. LIF secretion by cultured myofibroblasts was down regulated by the addition of interleukin-4.

Conclusions

We show for the first time the expression of LIF in human liver myofibroblasts, as well as of two new isoforms of LIF mRNA. Expression of LIF by myofibroblasts and of its receptor by adjacent cells suggests a potential LIF paracrine loop in human liver that may play a role in the regulation of intra-hepatic inflammation.