Richard G. Ruddell

Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells.

Circulating ferritin levels reflect body iron stores and are elevated with inflammation in chronic liver injury. H‐ferritin exhibits a number of extrahepatic immunomodulatory properties, although its role in hepatic inflammation and fibrogenesis is unknown. Hepatic stellate cells respond to liver injury through production of proinflammatory mediators that drive fibrogenesis. A specific receptor for ferritin has been demonstrated on activated hepatic stellate cells, although its identity and its role in stellate cell activation is unclear. We propose that ferritin acts as a cytokine regulating proinflammatory function via nuclear factor kappaB (NF‐κB)–regulated signaling in hepatic stellate cell biology. Hepatic stellate cells were treated with tissue ferritin and iron‐free apoferritin, recombinant H‐ferritins and L‐ferritins, to assess the role of ferritin versus ferritin‐bound iron in the production of proinflammatory mediators of fibrogenesis, and to determine whether signaling pathways act via a proposed H‐ferritin endocytosis receptor, T cell immunoglobulin‐domain and mucin‐domain 2 (Tim‐2). This study demonstrated that ferritin activates an iron‐independent signaling cascade, involving Tim‐2 independent phosphoinositide 3 (PI3)‐kinase phosphorylation, protein kinase C zeta (PKCζ) and p44/p42‐mitogen‐activated protein kinase, resulting in p50/p65‐NF‐κB activation and markedly enhanced expression of hepatic proinflammatory mediators interleukin‐1β (IL‐1β), inducible nitric oxide synthase (iNOS), regulated on activation normal T cell expressed and secreted (RANTES), inhibitor of kappa Bα (IκBα), and intercellular adhesion molecule 1 (ICAM1). Conclusions:This study has defined the role of ferritin as a proinflammatory mediator of hepatic stellate cell biology acting through the NF‐κB signaling pathway, and suggests a potential role in the inflammatory processes associated with hepatic fibrogenesis. (HEPATOLOGY 2009;49:887–900.)

The function of serotonin within the liver

Serotonin or 5-hydroxytryptamine (5-HT) is known to regulate several key aspects of liver biology and these functions include hepatic blood flow, innervation and wound healing. Given the importance of these functions it is surprising that relatively little time has been dedicated to studying the precise function and mechanisms of serotonin within the liver. Here we describe what is known about serotonin and the liver and those receptor types that mediate the observed effects with an aim to stimulating new interest in the field of serotonin and liver biology.

Iron Homeostasis, Hepatocellular Injury, and Fibrogenesis in Hemochromatosis: The Role of Inflammation in a Noninflammatory Liver Disease

Iron is a crucially important element in normal cellular function and thus the regulation of iron homeostasis is tightly controlled. When this regulation is disrupted, for instance in hereditary hemochromatosis, abnormal intestinal absorption of iron leads to cellular toxicity, tissue injury, and organ fibrosis via the deposition of this iron in parenchymal cells of a number of different organs such as the heart, pancreas, and liver. Iron-generated oxyradicals contribute to the peroxidation of lipid membranes leading to organelle fragility and cellular toxicity. This process is thought to contribute to hepatocellular necrosis and/or apoptosis in the liver with the subsequent activation of hepatic stellate cells and the development of hepatic fibrosis and cirrhosis. Understanding the processes associated with normal iron homeostasis is crucially important as this will ultimately provide clues as to how altered iron uptake and delivery leads to tissue injury and organ dysfunction in diseases of disordered iron metabolism. This review highlights recent advances in identifying major regulators associated with hepatic iron homeostasis and examines the potential mechanisms involved in the development of iron overload-induced hepatic injury and fibrogenesis.

The potential role of hepatic stellate cells in iron homeostasis

Matrix metalloproteinases and their inhibitors are altered in a time-course model of irinotecaninduced mucositis N AL-DASOOQI, R GIBSON, J BOWEN, R LOGAN, A STRINGER, D KEEFE Department of Medicine, University of Adelaide, Department of Medical Oncology, Royal Adelaide Hospital, School of Medical Sciences, University of Adelaide, Division of Surgical Pathology, SA Pathology, Oral Pathology, School of Dentistry, Faculty of Health Sciences, University of Adelaide, Cancer Council South Australia, Eastwood, Australia