IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans

Nike Müller; Dominik M. Schulte; Kathrin Türk; Sandra Freitag-Wolf; Jochen Hampe; Rainald Zeuner; Johann O. Schröder; Ioanna Gouni-Berthold; Heiner K. Berthold; Wilhelm Krone; Stefan Rose-John; Stefan Schreiber; Matthias Laudes

Journal of Lipid Research (May 2015)

IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans

Nike Müller,
Dominik M. Schulte,
Kathrin Türk,
Sandra Freitag-Wolf,
Jochen Hampe,
Rainald Zeuner,
Johann O. Schröder,
Ioanna Gouni-Berthold,
Heiner K. Berthold,
Wilhelm Krone,
Stefan Rose-John,
Stefan Schreiber,
Matthias Laudes

Affiliations

Nike Müller: Department I of Internal Medicine, University of Kiel, Kiel, Germany
Dominik M. Schulte: Department I of Internal Medicine, University of Kiel, Kiel, Germany; Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany
Kathrin Türk: Department I of Internal Medicine, University of Kiel, Kiel, Germany
Sandra Freitag-Wolf: Institute of Medical Informatics and Statistics, University of Kiel, Kiel, Germany
Jochen Hampe: Department of Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden, Germany
Rainald Zeuner: Department I of Internal Medicine, University of Kiel, Kiel, Germany
Johann O. Schröder: Department I of Internal Medicine, University of Kiel, Kiel, Germany; Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany
Ioanna Gouni-Berthold: Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany
Heiner K. Berthold: Department of Internal Medicine and Geriatrics, Bielefeld Evangelical Hospital, Bielefeld, Germany
Wilhelm Krone: Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany
Stefan Rose-John: Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany; Institute of Biochemistry, University of Kiel, Kiel, Germany
Stefan Schreiber: Department I of Internal Medicine, University of Kiel, Kiel, Germany; Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany
Matthias Laudes: To whom correspondence should be addressed.; Department I of Internal Medicine, University of Kiel, Kiel, Germany; Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany; To whom correspondence should be addressed.

Journal volume & issue: Vol. 56, no. 5
pp. 1034 – 1042

Abstract

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Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of human subjects (n = 1,153) revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of human liver biopsies (n = 57) revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6-responsive signal transducer and activator of transcription 3 binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments, and electrophoretic mobility shift assay analysis showed that the Lp(a)-lowering effect of TCZ is specifically mediated via a responsive element at −46 to −40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and might be a noninvasive alternative to lipid apheresis in the future.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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