title: Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis.
abstract: Deregulated Toll-like receptor (TLR)-triggered inflammatory responses that depend on NF-κB are detrimental to the host via excessive production of proinflammatory cytokines, including TNF-α. Stat2 is a critical component of type I IFN signaling, but it is not thought to participate in TLR signaling. Our study shows that LPS-induced lethality in Stat2(-/-) mice is accelerated as a result of increased cellular transmigration. Blocking intercellular adhesion molecule-1 prevents cellular egress and confers survival of Stat2(-/-) mice. The main determinant of cellular egress in Stat2(-/-) mice is the genotype of the host and not the circulating leukocyte. Surprisingly, lethality and cellular egress observed on Stat2(-/-) mice are not associated with excessive increases in classical sepsis cytokines or chemokines. Indeed, in the absence of Stat2, cytokine production in response to multiple TLR agonists is reduced. We find that Stat2 loss leads to reduced expression of NF-κB target genes by affecting nuclear translocation of NF-κB. Thus, our data reveal the existence of a different mechanism of LPS-induced lethality that is independent of NF-κB triggered cytokine storm but dependent on cellular egress.
authors: The Blizard Institute, Barts and the London School of Medicine, Queen Mary, University of London, London E1 2AT, United Kingdom.
authors: William
authors: W
authors: Alazawi
authors: Helen
authors: H
authors: Heath
authors: Jennifer A
authors: JA
authors: Waters
authors: Abigail
authors: A
authors: Woodfin
authors: Alastair J
authors: AJ
authors: O'Brien
authors: Anthony J
authors: AJ
authors: Scarzello
authors: Bin
authors: B
authors: Ma
authors: Yolanda
authors: Y
authors: Lopez-Otalora
authors: Michael
authors: M
authors: Jacobs
authors: Gemma
authors: G
authors: Petts
authors: Robert D
authors: RD
authors: Goldin
authors: Sussan
authors: S
authors: Nourshargh
authors: Ana M
authors: AM
authors: Gamero
authors: Graham R
authors: GR
authors: Foster
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D050795:STAT2 Transcription Factor; D018805:Sepsis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; C090509:Icam1 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050795:STAT2 Transcription Factor; C494085:Stat2 protein, mouse; D051193:Toll-Like Receptors; D018799:Intercellular Adhesion Molecule-1
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