title: A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation.
abstract: BACKGROUND
  A liver-derived protein, fetuin-A, was first purified from calf fetal serum in 1944, but its potential role in lethal systemic inflammation was previously unknown. This study aims to delineate the molecular mechanisms underlying the regulation of hepatic fetuin-A expression during lethal systemic inflammation (LSI), and investigated whether alterations of fetuin-A levels affect animal survival, and influence systemic accumulation of a late mediator, HMGB1.
  
  
  RESULTS
  LSI was induced by endotoxemia or cecal ligation and puncture (CLP) in fetuin-A knock-out or wild-type mice, and animal survival rates were compared. Murine peritoneal macrophages were challenged with exogenous (endotoxin) or endogenous (IFN-γ) stimuli in the absence or presence of fetuin-A, and HMGB1 expression and release was assessed. Circulating fetuin-A levels were decreased in a time-dependent manner, starting between 26 h, reaching a nadir around 24-48 h, and returning towards base-line approximately 72 h post onset of endotoxemia or sepsis. These dynamic changes were mirrored by an early cytokine IFN-γ-mediated inhibition (up to 50-70%) of hepatic fetuin-A expression. Disruption of fetuin-A expression rendered animals more susceptible to LSI, whereas supplementation of fetuin-A (20-100 mg/kg) dose-dependently increased animal survival rates. The protection was associated with a significant reduction in systemic HMGB1 accumulation in vivo, and parallel inhibition of IFN-γ- or LPS-induced HMGB1 release in vitro.
  
  
  CONCLUSIONS
  These experimental data suggest that fetuin-A is protective against lethal systemic inflammation partly by inhibiting active HMGB1 release.
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Rongrong
authors.initials: R
authors.lastname: Zhou
authors.forename: Xuegong
authors.initials: X
authors.lastname: Fan
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.forename: Xing
authors.initials: X
authors.lastname: Gong
authors.forename: N Tony
authors.initials: NT
authors.lastname: Eissa
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Sama
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004198:Disease Susceptibility; D019446:Endotoxemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D024243:HMGB1 Protein / Q000378:metabolism; D008099:Liver; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors; D060749:alpha-2-HS-Glycoprotein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000209:Acute-Phase Proteins; D016207:Cytokines; D024243:HMGB1 Protein; D060749:alpha-2-HS-Glycoprotein