Zinc regulates the acute phase response and serum amyloid a production in response to sepsis through JAK-STAT3 signaling

Ming Jie Liu, Shengying Bao, Jessica R. Napolitano, Dara L. Burris, Lianbo Yu, Susheela Tridandapani, Daren L. Knoell

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Sepsis rapidly activates the host inflammatory response and acute phase response. Severe sepsis, complicated by multiple organ failure, is associated with overwhelming inflammation and high mortality. We previously observed that zinc (Zn) deficiency significantly increases mortality in a mouse model of polymicrobial sepsis due to over-activation of the inflammatory response. In order to identify potential mechanisms that account for Zn-responsive effects, we generated whole exome expression profiles from the lung tissue of septic mice that were maintained on Zn modified diets. Based on systems analysis, we observed that Zn deficiency enhances the acute phase response and particularly the JAK-STAT3 pathway, resulting in increased serum amyloid A production. In vitro studies of primary hepatocytes and HepG2 cells substantiated that Zn-deficiency augments serum amyloid A production through up-regulation of the JAK-STAT3 and NFkB pathways. In contrast, Zn inhibited STAT3 activation through the up-regulation of SHP1 activity. Collectively, these findings demonstrate that Zn deficiency enhances the acute phase response through up-regulation of the JAK-STAT3 pathway, thereby perpetuating increased inflammation that may lead to increased morbidity and mortality in response to sepsis.

Original languageEnglish (US)
Article numbere94934
JournalPloS one
Volume9
Issue number4
DOIs
StatePublished - Apr 14 2014

Fingerprint

Acute-Phase Reaction
amyloid
Amyloid
Zinc
Sepsis
zinc
Serum
inflammation
Serum Amyloid A Protein
Up-Regulation
Mortality
Chemical activation
Inflammation
Exome
Multiple Organ Failure
systems analysis
Hep G2 Cells
Nutrition
Systems Analysis
in vitro studies

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Zinc regulates the acute phase response and serum amyloid a production in response to sepsis through JAK-STAT3 signaling. / Liu, Ming Jie; Bao, Shengying; Napolitano, Jessica R.; Burris, Dara L.; Yu, Lianbo; Tridandapani, Susheela; Knoell, Daren L.

In: PloS one, Vol. 9, No. 4, e94934, 14.04.2014.

Research output: Contribution to journalArticle

Liu, Ming Jie ; Bao, Shengying ; Napolitano, Jessica R. ; Burris, Dara L. ; Yu, Lianbo ; Tridandapani, Susheela ; Knoell, Daren L. / Zinc regulates the acute phase response and serum amyloid a production in response to sepsis through JAK-STAT3 signaling. In: PloS one. 2014 ; Vol. 9, No. 4.
@article{6469739a59504d76a62d37eb2828c88f,
title = "Zinc regulates the acute phase response and serum amyloid a production in response to sepsis through JAK-STAT3 signaling",
abstract = "Sepsis rapidly activates the host inflammatory response and acute phase response. Severe sepsis, complicated by multiple organ failure, is associated with overwhelming inflammation and high mortality. We previously observed that zinc (Zn) deficiency significantly increases mortality in a mouse model of polymicrobial sepsis due to over-activation of the inflammatory response. In order to identify potential mechanisms that account for Zn-responsive effects, we generated whole exome expression profiles from the lung tissue of septic mice that were maintained on Zn modified diets. Based on systems analysis, we observed that Zn deficiency enhances the acute phase response and particularly the JAK-STAT3 pathway, resulting in increased serum amyloid A production. In vitro studies of primary hepatocytes and HepG2 cells substantiated that Zn-deficiency augments serum amyloid A production through up-regulation of the JAK-STAT3 and NFkB pathways. In contrast, Zn inhibited STAT3 activation through the up-regulation of SHP1 activity. Collectively, these findings demonstrate that Zn deficiency enhances the acute phase response through up-regulation of the JAK-STAT3 pathway, thereby perpetuating increased inflammation that may lead to increased morbidity and mortality in response to sepsis.",
author = "Liu, {Ming Jie} and Shengying Bao and Napolitano, {Jessica R.} and Burris, {Dara L.} and Lianbo Yu and Susheela Tridandapani and Knoell, {Daren L.}",
year = "2014",
month = "4",
day = "14",
doi = "10.1371/journal.pone.0094934",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - Zinc regulates the acute phase response and serum amyloid a production in response to sepsis through JAK-STAT3 signaling

AU - Liu, Ming Jie

AU - Bao, Shengying

AU - Napolitano, Jessica R.

AU - Burris, Dara L.

AU - Yu, Lianbo

AU - Tridandapani, Susheela

AU - Knoell, Daren L.

PY - 2014/4/14

Y1 - 2014/4/14

N2 - Sepsis rapidly activates the host inflammatory response and acute phase response. Severe sepsis, complicated by multiple organ failure, is associated with overwhelming inflammation and high mortality. We previously observed that zinc (Zn) deficiency significantly increases mortality in a mouse model of polymicrobial sepsis due to over-activation of the inflammatory response. In order to identify potential mechanisms that account for Zn-responsive effects, we generated whole exome expression profiles from the lung tissue of septic mice that were maintained on Zn modified diets. Based on systems analysis, we observed that Zn deficiency enhances the acute phase response and particularly the JAK-STAT3 pathway, resulting in increased serum amyloid A production. In vitro studies of primary hepatocytes and HepG2 cells substantiated that Zn-deficiency augments serum amyloid A production through up-regulation of the JAK-STAT3 and NFkB pathways. In contrast, Zn inhibited STAT3 activation through the up-regulation of SHP1 activity. Collectively, these findings demonstrate that Zn deficiency enhances the acute phase response through up-regulation of the JAK-STAT3 pathway, thereby perpetuating increased inflammation that may lead to increased morbidity and mortality in response to sepsis.

AB - Sepsis rapidly activates the host inflammatory response and acute phase response. Severe sepsis, complicated by multiple organ failure, is associated with overwhelming inflammation and high mortality. We previously observed that zinc (Zn) deficiency significantly increases mortality in a mouse model of polymicrobial sepsis due to over-activation of the inflammatory response. In order to identify potential mechanisms that account for Zn-responsive effects, we generated whole exome expression profiles from the lung tissue of septic mice that were maintained on Zn modified diets. Based on systems analysis, we observed that Zn deficiency enhances the acute phase response and particularly the JAK-STAT3 pathway, resulting in increased serum amyloid A production. In vitro studies of primary hepatocytes and HepG2 cells substantiated that Zn-deficiency augments serum amyloid A production through up-regulation of the JAK-STAT3 and NFkB pathways. In contrast, Zn inhibited STAT3 activation through the up-regulation of SHP1 activity. Collectively, these findings demonstrate that Zn deficiency enhances the acute phase response through up-regulation of the JAK-STAT3 pathway, thereby perpetuating increased inflammation that may lead to increased morbidity and mortality in response to sepsis.

UR - http://www.scopus.com/inward/record.url?scp=84899624093&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899624093&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0094934

DO - 10.1371/journal.pone.0094934

M3 - Article

C2 - 24732911

AN - SCOPUS:84899624093

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e94934

ER -