Abstract 5162: Inhibition of Interleukin-6 Transsignaling Suppresses Atherosclerotic Lesion Development

Abstract

Introduction: The inflammatory cytokine interleukin-6 (IL-6) is a central mediator in the pathophysiology of various acute and chronic inflammatory disorders e.g. sepsis, Crohn disease or rheumatoid arthritis. Of interest, mainly the IL-6 transsignaling which comprises binding of IL-6 to the soluble IL-6 receptor (sIL-6R) and subsequent signal transduction as an IL-6/sIL-6R complex via ubiquitary expressed gp130 plays a pivotal role in these processes. Since atherosclerosis is likewise characterized by chronic vascular inflammation we here investigated the impact of IL-6 transsignaling on atherosclerotic plaque development in a murine model. For this reason, we used the fusion protein sgp130Fc which competitively binds to the IL-6/sIL-6R complex and thus specifically inhibits the IL-6 transsignaling. Methods and results: Initial in vitro experiments confirmed that recombinant sgp130Fc was able to inhibit the IL-6-induced STAT-3 phosphorylation in primary murine aortic vascular smooth muscle cells and murine monocytic RAW 264.7 cells dose-dependently (VSMC maximal at 10 μ g/ml; RAW maximal at 50 μ g/ml, Western blot, P<0.05). IL-6 induced the migration and proliferation of VSMC in vitro which could be inhibited by sgp130Fc (transwell inserts, BrdU-incorporation, −30%, P<0.05). Migration of RAW cells was likewise suppressed when IL-6 transsignaling was abrogated by sgp130Fc pre-treatment (transwell inserts, −40%, P<0.05). Finally, male atherosclerosis-prone LDLR −/− mice on a cholesterol rich diet were treated with sgp130Fc (0.5 mg/kg/bw i.p., twice-weekly) or the respective vehicle for 8 and 16 weeks. Even though serum lipid levels were unchanged, sgp130Fc administration led to a dramatically decreased atherosclerotic plaque development (thoracoabdominal aorta −65%/aortic root −35%; oil red O staining, P<0.05, n=5–9) as well as a reduced monocyte invasion into the vessel wall (aortic root −35%; MOMA-2 immunostaining, P<0.05, n=5–9). Conclusion: We here demonstrate - for the first time - that inhibition of the IL-6 transsignaling by the pharmacological compound sgp130Fc suppresses pro-atherosclerotic processes and subsequently the development of atherosclerotic plaques.