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-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.
Ruddell
Richard G
RG
The Hepatic Fibrosis Group, Queensland Institute of Medical Research and The University of Queensland, P. Royal Brisbane and Women's Hospital, Brisbane, Australia.
Hoang-Le
Diem
D
Barwood
Joanne M
JM
Rutherford
Paul S
PS
Piva
Terrance J
TJ
Watters
Dianne J
DJ
Santambrogio
Paolo
P
Arosio
Paolo
P
Ramm
Grant A
GA
D000818:Animals; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000502:physiology*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099221:Protein Kinase C zeta
D018946:Chemokine CCL5; D005293:Ferritins; D018799:Intercellular Adhesion Molecule-1; D053583:Interleukin-1beta; D048369:MAP Kinase Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta