Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 887-900 |
| Number of pages | 14 |
| Journal | Hepatology |
| Volume | 49 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2009 |
Fingerprint
ASJC Scopus subject areas
- Medicine(all)
- Hepatology
Cite this
Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB - Regulated signaling in rat hepatic stellate cells. / Ruddell, Richard G.; Hoang-Le, Diem; Barwood, Joanne M.; Rutherford, Paul S.; Piva, Terrance J.; Watters, Dianne J.; Santambrogio, Paolo; Arosio, Paolo; Ramm, Grant A.
In: Hepatology, Vol. 49, No. 3, 2009, p. 887-900.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB - Regulated signaling in rat hepatic stellate cells
AU - Ruddell, Richard G.
AU - Hoang-Le, Diem
AU - Barwood, Joanne M.
AU - Rutherford, Paul S.
AU - Piva, Terrance J.
AU - Watters, Dianne J.
AU - Santambrogio, Paolo
AU - Arosio, Paolo
AU - Ramm, Grant A.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=63349103637&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=63349103637&partnerID=8YFLogxK
U2 - 10.1002/hep.22716
DO - 10.1002/hep.22716
M3 - Article
C2 - 19241483
AN - SCOPUS:63349103637
VL - 49
SP - 887
EP - 900
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 3
ER -