Augmenter of Liver Regeneration (ALR) regulates the proinflammatory marker intracellular adhesion molecule-1 (ICAM-1, CD54) in liver cells

Inflammatory responses within the hepatic tissue play a pivotal role in the elimination of infectious agents as well as development and progression of chronic liver diseases. Intracellular adhesion molecule-1 (ICAM-1, CD54), an inducible glycoprotein of the immunoglobulin supergene family of cell surface receptors, is expressed on the surface of several human cell types e.g. epithelial cells and hepatocytes. ICAM-1 is constitutively expressed on the cell surface and is upregulated in response to a variety of inflammatory mediators, including pro-inflammatory cytokines, virus infection and oxidative stress. It is well known that ICAM-1 is involved in the recruitment/trans-endothelial migration of leukocytes and its strong expression on the hepatocyte surface in liver inflammation has been shown to play a key role in the hepatic parenchymal infiltration and adhesion of inflammatory leukocytes. Augmenter of Liver Regeneration (ALR), a hepatotrophic factor supporting liver regeneration, was reported to be upregulated and released after liver damage. Recently, we have shown that ALR, dependent on its localization, changes the acute phase response and the expression of several acute phase proteins at least in part, by modifying STAT3 activation. The aim of our study was to investigate the potential regulatory effect of endogenous and exogenous ALR on the expression and synthesis of ICAM-1 in liver cells.

Primary human hepatocytes (PHHs), HepG2 and small form ALR-overexpressing HepG2 cells (HepG2-sfALR) were treated with IL-6 (25 ng/ml) with or without ALR (100 ng/ml) for 24 hours and the mRNA and protein expression of ICAM-1 were measured by RT-PCR, western blot techniques.

We found that exogenous ALR attenuated the IL-6-mediated increase of ICAM-1 mRNA and protein expression in PHHs and HepG2 cells. In addition, HepG2 cells expressing sfALR (HepG2-sfALR) exhibited higher mRNA and protein expression of ICAM-1 upon IL-6 treatment comparing to IL-6-stimulated HepG2 control cells.

Our data show that IL-6-induced ICAM-1 expression may be regulated by twofold directions dependent on the localization of the protein: exogenous ALR attenuated and endogenous ALR increased ICAM-1 expression. We identified ALR as a novel regulator of ICAM-1 during hepatic inflammation. Our findings suggest that ALR could modify cytokine signaling and regulate the initiation of the local inflammatory reaction in the liver.

Keywords: ICAM-1, CD54, ALR, inflammation, intracellular adhesion molecule-1.