title: IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans.
abstract: 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.
authors.affiliation: Department I of Internal Medicine, University of Kiel, Kiel, Germany.
authors.forename: Nike
authors.initials: N
authors.lastname: Müller
authors.affiliation: Department I of Internal Medicine, University of Kiel, Kiel, Germany Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany.
authors.forename: Dominik M
authors.initials: DM
authors.lastname: Schulte
authors.affiliation: Department I of Internal Medicine, University of Kiel, Kiel, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Türk
authors.affiliation: Institute of Medical Informatics and Statistics, University of Kiel, Kiel, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Freitag-Wolf
authors.affiliation: Department of Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.affiliation: Department I of Internal Medicine, University of Kiel, Kiel, Germany.
authors.forename: Rainald
authors.initials: R
authors.lastname: Zeuner
authors.affiliation: Department I of Internal Medicine, University of Kiel, Kiel, Germany Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany.
authors.forename: Johann O
authors.initials: JO
authors.lastname: Schröder
authors.affiliation: Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Gouni-Berthold
authors.affiliation: Department of Internal Medicine and Geriatrics, Bielefeld Evangelical Hospital, Bielefeld, Germany.
authors.forename: Heiner K
authors.initials: HK
authors.lastname: Berthold
authors.affiliation: Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krone
authors.affiliation: Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Department I of Internal Medicine, University of Kiel, Kiel, Germany Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Department I of Internal Medicine, University of Kiel, Kiel, Germany Cluster of Excellence Inflammation at Interfaces, University of Kiel, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Laudes
mesh_terms: D000068879:Adalimumab / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology; D053241:Apoprotein(a) / Q000097:blood* / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D014176:Protein Biosynthesis / Q000187:drug effects*; D020218:Response Elements; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000068879:Adalimumab; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D053241:Apoprotein(a); D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C494086:STAT3 protein, human; C502936:tocilizumab
keywords: acute phase response; inflammation; interleukin; lipoprotein metabolism; therapy of elevated Lp(a)