Article Text


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


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.

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