Tumor Necrosis Factor Alpha Inhibits Hepatocyte Mitochondrial Respiration and Induces Release of Cytoplasmic Enzymes

Tumor necrosis factor alpha (TNFα) has been identified as a major mediator of physiologic and pathophysiologic responses to infections and traumatic insults. While TNFα enhances tissue repair and host defense against microbials [1] at low concentrations, high concentrations lead to tissue damage and to a typical shock syndrome [2]. As endotoxin was shown to be one of the most important stimuli for TNFα release, it was subsequently demonstrated that many features of the septic shock syndrome are induced by TNFα [3]. In sepsis, Kupffer cells, the largest population of fixed macrophages in the body, are thought to be a major source of TNFα [4]. Due to their close relationship to Kupffer cells, hepatocytes are exposed to TNFα released from Kupffer cells in addition to TNFα coming from the intenstine into the portal bloodstream. Therefore, it may be relevant to investigate whether TNFα contributes to hepatocellular dysfunction, which is a serious problem in sepsis [5]. The mechanisms of TNFα-mediated cytotoxicity are not very well understood. One of the established effects of TNFα at the subcellular level is mitochondrial swelling [6] and a decrease of mitochondrial respiration in tumor cell lines [7]. Because endotoxemia also results in impaired mitochondrial function of hepatocytes [8] we undertook the following experiments to demonstrate whether this effect is also mediated by TNFα.