title: YB-1 is an early and central mediator of bacterial and sterile inflammation in vivo.
abstract: In vitro studies identified Y-box-binding protein (YB)-1 as a key regulator of inflammatory mediators. In this study, we observed increased levels of secreted YB-1 in sera from sepsis patients. This led us to investigate the in vivo role of YB-1 in murine models of acute peritonitis following LPS injection, in sterile renal inflammation following unilateral ureteral obstruction, and in experimental pyelonephritis. LPS injection enhanced de novo secretion of YB-1 into the urine and the peritoneal fluid of LPS-treated mice. Furthermore, we could demonstrate a significant, transient upregulation and posttranslational modification (phosphorylation at serine 102) of YB-1 in renal and inflammatory cells. Increased renal cytoplasmic YB-1 amounts conferred enhanced expression of proinflammatory chemokines CCL2 and CCL5. Along these lines, heterozygous YB-1 knockout mice (YB-1(+/d)) that display 50% reduced YB-1 levels developed significantly lower responses to both LPS and sterile inflammation induced by unilateral ureteral obstruction. This included diminished immune cell numbers due to impaired migration propensities and reduced chemokine expression. YB-1(+/d) mice were protected from LPS-associated mortality (20% mortality on day 3 versus 80% in wild-type controls); however, immunosuppression in YB-1(+/d) animals resulted in 50% mortality. In conclusion, our findings identify YB-1 as a major, nonredundant mediator in both systemic and local inflammatory responses.
authors.affiliation: Division of Nephrology and Clinical Immunology, University Hospital Rheinisch-Westfaelische Technische Hochschule-Aachen, 52057 Aachen, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Hanssen
authors.forename: Christina
authors.initials: C
authors.lastname: Alidousty
authors.forename: Sonja
authors.initials: S
authors.lastname: Djudjaj
authors.forename: Björn C
authors.initials: BC
authors.lastname: Frye
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
authors.forename: Claudia R
authors.initials: CR
authors.lastname: van Roeyen
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.forename: Felix
authors.initials: F
authors.lastname: Heymann
authors.forename: Andre P
authors.initials: AP
authors.lastname: Tittel
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
authors.forename: Ute
authors.initials: U
authors.lastname: Raffetseder
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009393:Nephritis / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology* / Q000378:metabolism
chemical_list: D014157:Transcription Factors; C541744:Ybx1 protein, mouse