title: Deletion of tumor progression locus 2 attenuates alcohol-induced hepatic inflammation.
abstract: BACKGROUND
  The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine-threonine kinase that functions as a critical regulator of inflammatory pathways by up-regulating production of inflammatory cytokines. The present study aims to fill the gap in knowledge regarding the involvement of TPL2 in the mechanism of alcohol-induced hepatic inflammation.
  
  
  METHODS
  Male TPL2(-/-) knockout (TPL2KO) mice and TPL2(+/+) wild-type (WT) mice were group pair-fed with Lieber-DeCarli liquid ethanol diet (EtOH diet, 27% energy from EtOH) or control diet (ctrl diet) for 4 weeks. Both histological and molecular biomarkers involved in the induction of hepatic inflammation by alcohol consumption were examined.
  
  
  RESULTS
  Consumption of the EtOH diet in WT mice lead to a significant induction of TPL2 mRNA expression as compared with WT mice fed ctrl diet. A significant induction in inflammatory foci and steatosis was also observed in WT mice fed EtOH diet. The deletion of TPL2 significantly reduced inflammatory foci in the liver of mice consuming both ctrl and EtOH diets as compared to their respective WT controls. This reduction was associated with suppression of hepatic inflammatory gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) and macrophage marker F4/80. In addition, histological analysis of livers revealed that TPL2 deletion resulted in reduced steatosis in both ctrl (significant) and EtOH (non-significant) diet-fed mice as compared to their respective WT controls.
  
  
  CONCLUSIONS
  The demonstration that TPL2 deletion attenuates alcohol-induced hepatic inflammation provides evidence of a novel role for TPL2 in the pathogenesis of ALD.
authors.affiliation: 1 Nutrition and Cancer Biology Laboratory, 2 Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: Camilla P
authors.initials: CP
authors.lastname: Stice
authors.affiliation: 1 Nutrition and Cancer Biology Laboratory, 2 Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: Sajid
authors.initials: S
authors.lastname: Hussain
authors.affiliation: 1 Nutrition and Cancer Biology Laboratory, 2 Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: 1 Nutrition and Cancer Biology Laboratory, 2 Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Ausman
authors.affiliation: 1 Nutrition and Cancer Biology Laboratory, 2 Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Wang
authors.affiliation: 1 Nutrition and Cancer Biology Laboratory, 2 Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
keywords: Alcohol; inflammation; liver disease; tumor progression locus 2 (TPL2)