title: Interleukin-6 receptor inhibition modulates the immune reaction and restores titin phosphorylation in experimental myocarditis.
abstract: Increased levels of interleukin-6 (IL-6) have been observed in patients with acute myocarditis and are associated with poor prognosis. This study was designed to examine whether treatment with anti-IL-6 receptor antibody improves cardiac dysfunction and left ventricular (LV) remodeling in experimental Coxsackie virus B3 (CVB3)-induced myocarditis. C57BL6/J mice were subjected to acute CVB3 infection. One day after viral infection mice were treated with a single injection of an anti-IL-6 receptor antibody (MR16-1, tocilizumab) or control IgG. Seven days after viral infection, LV function was examined by conductance catheter technique, cardiac remodeling assessed by estimation of titin phosphorylation, cardiac fibrosis, and inflammatory and antiviral response by immunohistochemistry, RT-PCR and cell culture experiments. Compared to controls, infected mice displayed an impaired systolic and diastolic LV function associated with an increase in cardiac inflammation, fibrosis and impaired titin phosphorylation. IL-6 receptor blockade led to a shift of the immune response to a Th1 direction and significant reduction of viral load. In addition, cardiac immune response, extracellular matrix regulation and titin function improved, resulting in a preserved LV function. IL-6 receptor blockade exerts cardiac beneficial effects by antiviral and immunomodulatory actions after induction of an acute murine CVB3 virus myocarditis.
authors.affiliation: Department of Cardiology and Pneumology, Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany, ksavvatis@gmail.com.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Savvatis
authors.forename: Irene
authors.initials: I
authors.lastname: Müller
authors.forename: Matthias
authors.initials: M
authors.lastname: Fröhlich
authors.forename: Kathleen
authors.initials: K
authors.lastname: Pappritz
authors.forename: Christin
authors.initials: C
authors.lastname: Zietsch
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.forename: Karsten
authors.initials: K
authors.lastname: Grote
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Linthout
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use*; D064211:Connectin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology*; D010766:Phosphorylation; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D064211:Connectin; D019947:Receptors, Interleukin-6; C502936:tocilizumab