Within the diseased liver, free-radical production in the form of reactive oxygen species (ROS) and nitrogen species is initiated by cells of the immune system, including recruited neutrophils, monocytes, and KCs. These oxidizing components are normally balanced through redox regulation by antioxidant pathways (glutathione and superoxide dismutase) in healthy tissue. However, the robust immunologic milieu of the liver microenvironment can disrupt this balance during inflammation by deploying antipathogenic HM781-36B ic50 antioxidants. Hepatocytes sustain oxidative damage directly through
chemical modification of proteins, lipids, and nucleic acids. Additionally, apoptosis and
necrosis programs can be triggered from alterations induced in mitochondrial permeability by the altered intracellular redox state.5 These combined processes, collectively referred to as oxidative stress, further amplify the inflammatory response through the release of DAMPS KU-60019 price (danger-associated molecular patterns) and stress-related signaling molecules, culminating in chromosomal instability and oncogenic gene mutations. Furthermore, nitric oxide (NO) has been shown to protect virally infected hepatocytes from apoptosis through activation of nuclear factor kappa B (NF-κB) and suppression of T-helper 1 (Th1) antitumor immune surveillance. Integration of diverse inflammatory signals initiated
by oxidative stress, gut-derived microbes, and endotoxins from the blood occurs through the modulation of pattern recognition receptors on resident KC. Although KCs can be involved in antitumor immunity, numerous human and mouse studies have recently uncovered their multifaceted ability to contribute to promotion of liver tumorigenesis. In addition to the roles for antioxidants described above, chronic inflammation Oxymatrine can also be mediated by KCs through the constant production of cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-β (TGF-β). The contributions of these cytokines to chronic inflammation will be described below. IL-6 and TNF-α are active contributors to acute inflammatory responses.6 Expression of IL-6 and TNF-α is elevated in both liver cirrhosis and HCC.7 Although the mechanisms by which elevated IL-6 and TNF-α promote liver cancer are not clear, their signals regulate gene expression through the latent transcription factors STAT3 and NF-κB.