Inhibition of proteasome function leads to NF-κB-independent IL-8 expression in human hepatocytes

Authors

  • Swati Joshi-Barve,

    1. Department of Internal Medicine, University of Louisville Medical Center, Louisville, KY
    Search for more papers by this author
  • Shirish S. Barve,

    1. Department of Internal Medicine, University of Louisville Medical Center, Louisville, KY
    2. Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY
    Search for more papers by this author
  • Waseem Butt,

    1. Department of Internal Medicine, University of Louisville Medical Center, Louisville, KY
    Search for more papers by this author
  • Jon Klein,

    1. Department of Internal Medicine, University of Louisville Medical Center, Louisville, KY
    2. Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY
    3. Louisville VA Medical Center, Louisville, KY
    Search for more papers by this author
  • Craig J. McClain M.D.

    Corresponding author
    1. Department of Internal Medicine, University of Louisville Medical Center, Louisville, KY
    2. Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY
    3. Louisville VA Medical Center, Louisville, KY
    • Vice Chair for Research and Director, Clinical Research Center, Professor of Internal Medicine, Pharmacology and Toxicology, University of Louisville Medical Center, 550 S. Jackson Street, ACB 3rd Floor, Louisville, KY 40292. fax: 502-562-4271
    Search for more papers by this author

Abstract

Breakdown of cellular proteins is a highly regulated process, and the ubiquitin-proteasome pathway is the major proteolytic system in the cell. It regulates the levels of numerous proteins that control gene expression and cell division, as well as responses to stress and inflammation. Recent studies have reported abnormalities in proteasome function in alcoholic liver disease (ALD). Moreover, a direct relation has been reported between impaired proteasome function and oxidative stress in experimental models of ALD. Neutrophil infiltration is a hallmark of ALD, and activated neutrophils are thought to play a role in the pathology of ALD. As a potent neutrophil chemoattractant and activator, interleukin 8 (IL-8) likely plays a key mechanistic role in many forms of liver injury. In this study, we evaluated the effects of inhibition of proteasome function on expression and release of IL-8 by human fetal hepatocytes and hepatoma cells. Our data demonstrate that inhibition of proteasome function in hepatocytes leads to apoptotic cell death. Decreased hepatocyte survival coincides with enhanced expression of IL-8, both at the protein and the messenger RNA (mRNA) levels. This increase in IL-8 is independent of nuclear factor κB (NF-κB) activation and is associated with an increase in c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) activity. In conclusion, hepatocytes dying because of inhibition of proteasome function produce massive quantities of the proinflammatory chemokine IL-8, possibly resulting in neutrophil infiltration, increased inflammation, and liver injury.

Ancillary