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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #331282

Research Project: Molecular Targets of Tomato Carotenoids and their Metabolites in Cancer Prevention

Location: Jean Mayer Human Nutrition Research Center On Aging

Title: Deletion of tumor progression locus 2 attenuates alcohol induced hepatic inflammation

Author
item STICE, CAMILLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item HUSSAIN, SAJID - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item AUSMAN, LYNNE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Hepatobiliary Surgery and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/10/2015
Publication Date: 2/1/2016
Citation: Stice, C.P., Hussain, S., Liu, C., Ausman, L., Wang, X., Greenberg, A. 2016. Deletion of tumor progression locus 2 attenuates alcohol induced hepatic inflammation. Hepatobiliary Surgery and Nutrition. 5(1):29-37.

Interpretive Summary: Tumor progression locus 2 (TPL2), which is an enzyme, functions as a critical regulator of inflammatory pathways by up regulating production of inflammatory cytokines. The present study filled the gap in knowledge regarding the involvement of TPL2 in the mechanism of alcohol induced liver inflammation. We demonstrated that the absence of TPL2 decreased risk for alcohol induced liver disease and provides evidence of a novel role for TPL2 in the development of alcoholic liver disease.

Technical 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-alpha (TNF-alpha), and interleukin 1-beta (IL-1 beta) 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.