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

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

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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 languageEnglish
Pages (from-to)887-900
Number of pages14
JournalHepatology
Volume49
Issue number3
DOIs
Publication statusPublished - 2009

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Hepatic Stellate Cells
Ferritins
Apoferritins
Iron
Cytokines
Liver
Cell Biology
Mucin-2
Inflammation
T-Lymphocytes
1-Phosphatidylinositol 4-Kinase
Mitogen-Activated Protein Kinase 1
Wounds and Injuries
Nitric Oxide Synthase Type II
Intercellular Adhesion Molecule-1
Endocytosis
protein kinase C zeta
Interleukin-1
Phosphorylation

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 journalArticle

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. / Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB - Regulated signaling in rat hepatic stellate cells. In: Hepatology. 2009 ; Vol. 49, No. 3. pp. 887-900.
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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.",
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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.

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