Article Text

PDF

Basic science (liver)
PMO-120 Kupffer cell derived interleukin (IL)-18 induces hepatic inflammation by promoting lymphocyte subsets recruitment on hepatic endothelial cells
  1. E Liaskou1,
  2. D Withers2,
  3. E Humphreys1,
  4. J C Shaw1,
  5. L Tuohey1,
  6. P Klenerman3,
  7. D H Adams1,
  8. Y H Oo1
  1. 1Division of Immunity and Infection, Centre for Liver Research & NIHR BRU, UK
  2. 2MRC Centre for Immune Regulation, University of Birmingham, Birmingham, UK
  3. 3Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK

Abstract

Introduction IL-18, known as interferon-γ inducing factor, is a potent pro-inflammatory cytokine implicated in liver allograft rejection, viral hepatitis and hepatocellular carcinoma progression, where it plays an important role in cell-mediated immune responses and inflammatory injury. We hypothesise that IL-18 promotes hepatic inflammation by supporting effector T cells migration across hepatic sinusoidal endothelium. In this study, we investigated the expression and cellular regulation of IL-18 secretion in the human liver and demonstrated a role in promoting T cell recruitment to the liver.

Methods IL-18 mRNA expression levels were measured in normal and diseased human livers using QRT-PCR and tissue localisation assessed by immunohistochemistry and confocal microscopy. Human hepatic sinusoidal endothelial cells were treated with Il-18 in vitro and flow cytometry used to assess induction of adhesion molecules. The functional significance of these responses to IL-18 was investigated in flow based adhesion assays using IL-18 treated HSEC and CD4 and CD8 T cell subsets under physiological flow.

Results IL-18 mRNA expression was significantly higher in liver tissue form patients with ALD (19-fold), PBC (7.6-fold) and seronegative hepatitis (30.6-fold) (p<0.05) compared with normal liver. IL-18 protein expression was restricted to hepatic sinusoids where it colocalized with CD68+ Kupffer cells, whereas CD31+ endothelial cells were IL-18neg. HSEC stimulated with IL-18 lead upregulation of cell adhesion molecules ICAM-1 and VCAM-1 which translated into a 2.5-fold increase in their functional ability to recruit CD4 and CD8 T cells in flow-based adhesion assays. Total adhesion of CD4 and CD8 T cells was significantly (p<0.05) reduced when ICAM-1, VCAM-1, and CXCR3 molecules were blocked or if G protein coupled receptors were inhibited with pertussis toxin (PTX). CD8 T cell adhesion was also dependent on vascular adhesion protein-1.

Conclusion We report high IL-18 expression by Kupffer cells in inflammatory liver disease. The ability of IL-18 to enhance T cell recruitment via sinusoidal endothelium suggests it acts to promote lymphocyte recruitment during the development of chronic hepatitis and is thus a potential novel therapeutic target in inflammatory liver disease.

Competing interests None declared.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.