Ferritin—a mediator of apoptosis?

Abstract

Previously we have demonstrated an apoptosis inducing activity for a rat hepatocyte conditioned medium (CM) presumably mediated by acidic isoferritins. Here, we present support for this assumption since isoferritins purified from different rat hepatocyte CM significantly enhanced the frequency of apoptotic cells in primary rat hepatocytes, an effect completely inhibited by a neutralizing anti-H-ferritin antibody. The apoptosis induction appears to be related to a 43 kDa ferritin subunit contained in the isoferritins released from primary hepatocytes, presumably representing a ferritin heavy/light chain heterodimer. In addition, these isoferritins immunologically crossreact with antibodies raised against placental isoferritin p43-PLF (which also contains a 43 kDa ferritin subunit) and melanoma-derived H-chain ferritin, representing ferritin isoforms which reveal immunomodulatory properties. Furthermore, p53 and FasL are upregulated upon isoferritin treatment in a time dependent mode, and apoptosis induction can be suppressed by neutralizing anti-FasL antibodies. Proapoptotic Bid is upregulated too and translocated into mitochondria in primary hepatocytes exposed to the isoferritins purified from the CM. Finally, epidermal growth factor (EGF) and dexamethasone (DEX), which counteract proapoptotic mitochondrial signalling, almost completely abolished the proapoptotic effect of the hepatocyte derived isoferritins. In conclusion, our findings demonstrate that acidic isoferritins with homology to immunomodulatory ferritin isoforms (p43-PLF, melanoma-derived-H-chain ferritin) are released from hepatocytes in vitro, and are able to stimulate upregulation of p53 and mediate apoptosis involving Fas (CD95) signalling as well as addressing the intrinsic mitochondrial proapoptotic pathway.

Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages

“…Ferritin, as an acute phase signaling molecule in tissue repair and regeneration, may stimulate up-regulation of p53 to mediate apoptosis involving Fas (CD95) signaling and intrinsic mitochondrial proapoptotic pathway [3][4][5][6]. In advanced human atheroma lesions where Fas (CD95) signaling is up-regulated [25], and apoptotic macrophage-derived foam cells are rich in ferritin, suggesting that iron-catalysed reaction is involved in apoptosis [26].…”

“…Its heavy-chain also has enzymatic properties, converting Fe(II) to Fe(III) as iron is internalized and sequestered in the ferritin mineral core. Recently, ferritin has been viewed not only as an iron-storage protein, but is also related to apoptosis [3,4]. Ferritin heavy chain up-regulation by NF-jB inhibits TNFa-induced apoptosis by suppressing reactive oxygen species (ROS) [5].…”

“…The heavy-ferritin has an anti-apoptotic activity unrelated to its ferroxidase activity or its capacity to modify cellular iron metabolism [6]. However, isoferritins with homology to immunomodulatory ferritin isoforms (p43-PLF, melanoma-derived-H-chain ferritin) are able to stimulate p53 expression to mediate apoptosis via Fas (CD95) signaling [3].…”

Genomic expression profiling of peripheral blood leukocytes of pigs infected with highly virulent classical swine fever virus strain Shimen

“…A previous study showed that ferritin plays a key role in stimulating upregulation of p53 and mediates apoptosis involving Fas (CD95) signalling, as well as addressing the intrinsic mitochondrial proapoptotic pathway in cultured hepatocytes in vitro (Bresgen et al, 2007). Apoptosis causing peripheral T-lymphocyte depletion of pigs during lethal CSFV infection has been shown to be mediated through Fas-Fas ligand interactions (Summerfield et al, 1998).…”

Serum ferritin levels predict histological severity in patients with nonalcoholic fatty liver disease in India

“…Thus, ferritin may be intimately involved in many important processes related to NASH pathogenesis including inflammation, apoptosis, oxidative stress, lipid transport, and fibrogenesis. Serum ferritin has also recently been shown to be a predictor of mortality in patients with end-stage liver disease (ESLD) both before [25][26][27] and after liver transplant [27,28]. Multicenter studies have shown that hyperferritinemia with ESLD from all etiologies is associated with increased mortality after adjusting for a variety of potential confounding variables [29,30].…”