A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation

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. METHODS AND FINDINGS: 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.

Li, Wei
Zhu, Shu
Li, Jianhua
Huang, Yan
Zhou, Rongrong
Fan, Xuegong
Yang, Huan
Gong, Xing
Eissa, N. Tony
Jahnen-Dechent, Willi
Wang, Ping
Tracey, Kevin J.
Sama, Andrew E.
Wang, Haichao
Item Type: 
Journal Article
Publication Title: 
PloS One
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Publication Date: 
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Library Catalog: 
NCBI Published Medical (?)
PMID: 21347455 PMCID: PMC3035675

Turabian/Chicago Citation

Wei Li, Shu Zhu, Jianhua Li, Yan Huang, Rongrong Zhou, Xuegong Fan, Huan Yang, Xing Gong, N. Tony Eissa, Willi Jahnen-Dechent, Ping Wang, Kevin J. Tracey, Andrew E. Sama and Haichao Wang. 2011. "A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation." PloS One 6: 2: e16945. 10.1371/journal.pone.0016945.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1371/journal.pone.0016945 | issn = 1932-6203 | volume = 6 | pages = e16945 | last = Li | first = Wei | coauthors = Zhu, Shu, Li, Jianhua, Huang, Yan, Zhou, Rongrong, Fan, Xuegong, Yang, Huan, Gong, Xing, Eissa, N. Tony, Jahnen-Dechent, Willi, Wang, Ping, Tracey, Kevin J., Sama, Andrew E., Wang, Haichao | title = A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation | journal = PloS One | date = 2011 | pmid = | pmc = }} </ref>