title: LPS resistance of SPRET/Ei mice is mediated by Gilz, encoded by the Tsc22d3 gene on the X chromosome.
abstract: Natural variation for LPS-induced lethal inflammation in mice is useful for identifying new genes that regulate sepsis, which could form the basis for novel therapies for systemic inflammation in humans. Here we report that LPS resistance of the inbred mouse strain SPRET/Ei, previously reported to depend on the glucocorticoid receptor (GR), maps to the distal region of the X-chromosome. The GR-inducible gene Tsc22d3, encoding the protein Gilz and located in the critical region on the X-chromosome, showed a higher expressed SPRET/Ei allele, regulated in cis. Higher Gilz levels were causally related to reduced inflammation, as shown with knockdown and overexpression studies in macrophages. Transient overexpression of Gilz by hydrodynamic plasmid injection confirmed that Gilz protects mice against endotoxemia Our data strongly suggest that Gilz is responsible for the LPS resistance of SPRET/Ei mice and that it could become a treatment option for sepsis.
authors.affiliation: Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
authors.forename: Iris
authors.initials: I
authors.lastname: Pinheiro
authors.forename: Lien
authors.initials: L
authors.lastname: Dejager
authors.forename: Ioanna
authors.initials: I
authors.lastname: Petta
authors.forename: Sofie
authors.initials: S
authors.lastname: Vandevyver
authors.forename: Leen
authors.initials: L
authors.lastname: Puimège
authors.forename: Tina
authors.initials: T
authors.lastname: Mahieu
authors.forename: Marlies
authors.initials: M
authors.lastname: Ballegeer
authors.forename: Filip
authors.initials: F
authors.lastname: Van Hauwermeiren
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.forename: Marnik
authors.initials: M
authors.lastname: Vuylsteke
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009919:Orchiectomy; D010052:Ovariectomy; D010641:Phenotype; D040641:Quantitative Trait Loci; D034622:RNA Interference; D012737:Sex Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014960:X Chromosome
chemical_list: C498608:Dsip1 protein, mouse; D008070:Lipopolysaccharides; D014157:Transcription Factors