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.

METHODS AND 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: Harald Schuett, René Oestreich, Georg H Waetzig, Wijtske Annema, Maren Luchtefeld, Anja Hillmer, Udo Bavendiek, Johann von Felden, Dimitar Divchev, Tibor Kempf, Kai C Wollert, Dirk Seegert, Stefan Rose-John, Uwe J F Tietge, Bernhard Schieffer, Karsten Grote
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 2 Pg. 281-90 (Feb 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22075248 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Lipids
• Receptors, LDL
• Recombinant Fusion Proteins
• Cytokine Receptor gp130
• olamkicept

Topics

• Aged
• Animals
• Atherosclerosis (physiopathology, prevention & control)
• Coronary Artery Disease (blood, physiopathology, prevention & control)
• Cytokine Receptor gp130 (blood, pharmacology, therapeutic use)
• Disease Models, Animal
• Disease Progression
• Female
• Humans
• Hypercholesterolemia (blood, physiopathology)
• Interleukin-6 (physiology)
• Lipids (blood)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Receptors, LDL (deficiency, genetics)
• Recombinant Fusion Proteins (pharmacology, therapeutic use)
• Signal Transduction (drug effects, physiology)