The liver regeneration associated factor ALR attenuates IL-6 induced acute-phase reactants during hepatic inflammation

Background and aims: Inflammatory cytokines such as Interleukin-6 (IL-6) play a key role in triggering acute phase response (APR) in the liver upon injury. In response to hepatic injury, the hepatic protein synthesis shifts from hepatic constitutive to acute phase proteins (APPs) including fibrinogen-β (FGB), haptoglobin (HP), C reactive protein (CRP) and serum amyloid A (SAA). Augmenter of Liver Regeneration (ALR), a hepatotrophic factor supporting liver regeneration, was reported to be upregulated after liver damage. The aim of our study was to investigate the expression and synthesis of acute phase proteins in liver cells upon stimulation with ALR.

Methods: HepG2 cells and primary human hepatocytes were treated with IL-6 (25 ng/ml) with or without ALR (100 ng/ml) for 6, 12 and 24 hours. The expression of HP, FGB and SAA was measured by RT-PCR and western blot techniques and the APP levels in the supernatant were determined by ELISA.

Results: We found that ALR attenuated the IL-6 dependent increase of HP mRNA levels and reduced HP protein levels in the supernatant. In addition, we could demonstrate that ALR reduces mRNA and protein expression of both FGB and SAA in liver cells.

Conclusion: Our data show that IL-6 stimulated APP expression was attenuated in the presence of ALR. We identified ALR as a novel regulator of the hepatic APP genes during inflammation. Our findings suggest that ALR could modify cytokine signaling leading to mitigate the acute phase response, a crucial event during liver regeneration.

Keywords: Acute phase response, ALR, liver regeneration, inflammation