title: Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice.
abstract: The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. Although thought to be involved in immune defense, the net biological effect of the acute phase response remains unknown. As the acute phase response is stimulated by diverse cytokines that activate either NF-κB or STAT3, we hypothesized that it could be eliminated by hepatocyte-specific interruption of both transcription factors. Here, we report that the elimination in mice of both NF-κB p65 (RelA) and STAT3, but neither alone, abrogated all acute phase responses measured. The failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli, including pneumococcal pneumonia. When the effects of infection were analyzed in detail, pneumococcal pneumonia was found to alter the expression of over a thousand transcripts in the liver. This outcome was inhibited by the combined loss of RelA and STAT3. Moreover, this interruption of the acute phase response increased mortality and exacerbated bacterial dissemination during pneumonia, possibly as a result of acute humoral enhancement of macrophage opsonophagocytosis, which was impaired in the mutant mice. Thus, we conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection.
authors.affiliation: The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA. lquinton@bu.edu
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Quinton
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Blahna
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Jones
authors.forename: Eri
authors.initials: E
authors.lastname: Allen
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ferrari
authors.forename: Kristie L
authors.initials: KL
authors.lastname: Hilliard
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.forename: Vishakha
authors.initials: V
authors.lastname: Sabharwal
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Pelton
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
mesh_terms: D000210:Acute-Phase Reaction / Q000097:blood / Q000235:genetics / Q000382:microbiology*; D000818:Animals; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000378:metabolism*; D007113:Immunity, Innate; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011018:Pneumonia, Pneumococcal / Q000097:blood / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000378:metabolism; D013296:Streptococcus pneumoniae; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: C498144:Rela protein, mouse; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; D000683:Serum Amyloid P-Component; C494087:Stat3 protein, mouse; D051996:Transcription Factor RelA