title: Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice.
abstract: OBJECTIVE
  Transsignaling of interleukin (IL)-6 is a central pathway in the pathogenesis of disorders associated with chronic inflammation, such as Crohn disease, rheumatoid arthritis, and inflammatory colon cancer. Notably, IL-6 also represents an independent risk factor for coronary artery disease (CAD) in humans and is crucially involved in vascular inflammatory processes.
  
  
  RESULTS
  In the present study, we showed that treatment with a fusion protein of the natural IL-6 transsignaling inhibitor soluble glycoprotein 130 (sgp130) and IgG1-Fc (sgp130Fc) dramatically reduced atherosclerosis in hypercholesterolemic Ldlr(-/-) mice without affecting weight gain and serum lipid levels. Moreover, sgp130Fc treatment even led to a significant regression of advanced atherosclerosis. Mechanistically, endothelial activation and intimal smooth muscle cell infiltration were decreased in sgp130Fc-treated mice, resulting in a marked reduction of monocyte recruitment and subsequent atherosclerotic plaque progression. Of note, patients with CAD exhibited significantly lower plasma levels of endogenous sgp130, suggesting that a compromised counterbalancing of IL-6 transsignaling may contribute to atherogenesis in humans.
  
  
  CONCLUSIONS
  These data clarify, for the first time, the critical involvement of, in particular, the transsignaling of IL-6 in CAD and warrant further investigation of sgp130Fc as a novel therapeutic for the treatment of CAD and related diseases.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schuett
authors.forename: René
authors.initials: R
authors.lastname: Oestreich
authors.forename: Georg H
authors.initials: GH
authors.lastname: Waetzig
authors.forename: Wijtske
authors.initials: W
authors.lastname: Annema
authors.forename: Maren
authors.initials: M
authors.lastname: Luchtefeld
authors.forename: Anja
authors.initials: A
authors.lastname: Hillmer
authors.forename: Udo
authors.initials: U
authors.lastname: Bavendiek
authors.forename: Johann
authors.initials: J
authors.lastname: von Felden
authors.forename: Dimitar
authors.initials: D
authors.lastname: Divchev
authors.forename: Tibor
authors.initials: T
authors.lastname: Kempf
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
authors.forename: Dirk
authors.initials: D
authors.lastname: Seegert
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
authors.forename: Karsten
authors.initials: K
authors.lastname: Grote
mesh_terms: D000368:Aged; D000818:Animals; D050197:Atherosclerosis / Q000503:physiopathology* / Q000517:prevention & control; D003324:Coronary Artery Disease / Q000097:blood / Q000503:physiopathology* / Q000517:prevention & control; D050822:Cytokine Receptor gp130 / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000503:physiopathology; D015850:Interleukin-6 / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D008055:Lipids; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D050822:Cytokine Receptor gp130; C519852:olamkicept