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

✍ Scribed by Richard G. Ruddell; Diem Hoang-Le; Joanne M. Barwood; Paul S. Rutherford; Terrance J. Piva; Dianne J. Watters; Paolo Santambrogio; Paolo Arosio; Grant A. Ramm

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 921 KB
• Volume: 49
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.22716

✦ Synopsis

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-B)-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 (PKC) and p44/p42-mitogen-activated protein kinase, resulting in p50/p65-NF-B activation and markedly enhanced expression of hepatic proinflammatory mediators interleukin-1␤ (IL-1␤), inducible nitric oxide synthase (iNOS), regulated on activation normal T cell expressed and secreted (RANTES), inhibitor of kappa B␣ (IB␣), 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-B signaling pathway, and suggests a potential role in the inflammatory processes associated with hepatic fibrogenesis. (HEPATOLOGY 2009;49:887-900.)

T issue ferritin is an important site for the physiological storage of iron in a nontoxic but biologically available form. The ferritin molecule comprises 24 subunits of two structurally distinct subunit types: the acidic, heavy or H-chain and the basic, light or L-chain. H-ferritin has been shown to regulate immune function, hematopoiesis, hepatocyte apoptosis, and cell differentiation. 1 Ferritin is measured in the serum as an