Generation of a mouse model of T-cell lymphoma based on chronic LPS challenge and TGF-β signaling disruption

Abstract

Alcoholic liver disease has various manifestations: asymptomatic steatosis, alcoholic hepatitis and alcoholic cirrhosis, conditions that substantially increase the risk for developing hepatocellular carcinoma(HCC). The Transforming Growth Factor-β (TGF-β) signaling pathway is a major regulator in chronic liver diseases contributing to liver disease progression from liver injury, inflammation and fibrosis to HCC. With the aim of generating a mouse model of alcoholic liver disease that would rapidly develop steatosis, inflammation as well as fibrosis, we formulated a regimen that combined chronic injections of low dose (2mg/kg) lipopolysaccharide (LPS) with Lieber DeCarli-based diet containing 6.7% ethanol feeding to mice with impaired TGF-β signaling through constitutive disruption of β2-spectrin and/or Smad3. Unexpectedly, the mice treated with chronic low dose LPS and fed the alcohol-containing diet developed very aggressive T-cell lymphomas to which the TGF-β mutant mice succumbed more rapidly than the wild type mice. In contrast, their liver phenotype was mild as they only developed steatosis but not hepatitis or significant fibrosis. To our knowledge, this is the first report of a mouse model of aggressive T- cell lymphoma based on chronic challenge with low dose LPS and TGF-β disruption.