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 NF-κB 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.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Ming-Jie
authors.initials: MJ
authors.lastname: Liu
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Shengying
authors.initials: S
authors.lastname: Bao
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Napolitano
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Burris
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America; Department of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Daren L
authors.initials: DL
authors.lastname: Knoell
mesh_terms: D000210:Acute-Phase Reaction / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002432:Cecum / Q000473:pathology; D053263:Gene Regulatory Networks / Q000187:drug effects; D016678:Genome; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism*; D008026:Ligation; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D005810:Multigene Family; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011677:Punctures; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000473:pathology*; D000685:Serum Amyloid A Protein / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology*
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; D053612:Janus Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D015032:Zinc
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