28 In addition, Peng et al. have shown that Fas ligand (FasL) gene expression is mediated by NF-κB and inhibition of NF-κB-attenuated apoptosis, but not TNF-α expression.32 In addition to expression of TNF-α and activation of the NF-κB pathway, increased ROS and OS also promote apoptosis by activation of the Jun N-terminal kinase (JNK)/activation protein
1 serine kinase-signaling cascade.33, 34 Tsukamoto and others have shown that addition of iron activates KCs both in vitro and by erythrophagocytosis, inducing LPO, NF-κB activation, and NF-κB-mediated TNF-α expression and release, which was abrogated by iron chelation treatment.31, 35-39 Last, phagocytosis by KCs results in expression of TNF-α and death receptors FasL and TNF-related apoptosis-inducing ligand, suggesting a feed-forward amplification of apoptosis.40 Taken together, these studies suggest a role of KC iron in apoptosis by the FAS, JNK, and TNFR pathways through production of ROS, cytokines, NF-κB and Selleck BIBW2992 TNF-α, which could then be amplified through phagocytosis of erythrocytes and iron-containing apoptotic hepatocytes. There are a number of cellular conditions that are thought to favor either necrosis or apoptosis, which potentially https://www.selleckchem.com/products/PD-0332991.html could explain our observations that HC iron may promote greater necrosis, compared to the other iron phenotypes. Apoptosis is a deliberate,
adenosine triphosphate (ATP)-dependent process that usually occurs gradually, whereas necrosis is a rapid event involving plasma membrane rupture subsequent to ATP depletion; thus, availability of ATP is recognized as a key determinant for which mode of cell death predominates.10 Iron-mediated mitochondrial LPO contributes to pore formation in mitochondrial membranes or mitochondria permeability transition (MPT) and subsequent release of mitochondrial ROS.41, 42 Both necrosis through ATP depletion or caspase-dependent apoptosis induced by cytochrome c release are consequences of MPT, but the degree of mitochondria involvement may determine the extent of ATP depletion and hence the development of necrosis or apoptosis.29 Casein kinase 1 Depletion of the antioxidant, glutathione (GSH), in both the mitochondrial and cytosolic compartments has been shown to promote
OS-induced necrosis, whereas selective cytosolic GSH depletion sensitizes hepatocytes to TNF-α-induced apoptosis independent of OS.43, 44 Several studies have investigated the origins of cell death by necrosis or apoptosis in cultured hepatocytes or using in vivo animal models subsequent to chemically induced superoxide formation using menadione or diquat.33, 45 Evidence from these studies suggests that when extensive oxidant damage overwhelms the cellular antioxidant capacity, necrosis may result, whereas with moderate OS, apoptotic pathways predominate. There are some limitations of our study worth noting, such as the possible effect of elevated MDA levels after prolonged serum storage,46 potentially explaining higher levels in subjects with hepatic iron.