Ferritin Functions as a Proinflammatory Cytokine via Iron-Independent Protein Kinase C Zeta/Nuclear Factor KappaB–Regulated Signaling in Rat Hepatic Stellate Cells
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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-kappaB)-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 (PKCzeta) and p44/p42-mitogen-activated protein kinase, resulting in p50/p65-NF-kappaB activation and markedly enhanced expression of hepatic proinflammatory mediators interleukin-1beta (IL-1beta), inducible nitric oxide synthase (iNOS), regulated on activation normal T cell expressed and secreted (RANTES), inhibitor of kappa Balpha (IkappaBalpha), 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-kappaB signaling pathway, and suggests a potential role in the inflammatory processes associated with hepatic fibrogenesis.
© 2009 The American Association for the Study of Liver Diseases. Published by Wiley-Blackwell. Self-archiving of manuscripts in institutional repositories is not yet supported by The American Association for the Study of Liver Diseases. Please refer to the journal link for access to the definitive, published version or contact the authors for more information.