Format

Send to

Choose Destination
Front Immunol. 2018 Sep 12;9:2035. doi: 10.3389/fimmu.2018.02035. eCollection 2018.

IL-6 Receptor Inhibition by Tocilizumab Attenuated Expression of C5a Receptor 1 and 2 in Non-ST-Elevation Myocardial Infarction.

Orrem HL1,2,3, Nilsson PH1,2,4,5, Pischke SE1,2,3, Kleveland O6,7, Yndestad A4,8,9,10,11, Ekholt K1,2, Damås JK12, Espevik T12, Bendz B13, Halvorsen B4,8,9,10,11, Gregersen I8,9, Wiseth R6,7, Andersen GØ11,14,15, Ueland T4,8,9,10,11, Gullestad L10,11,13, Aukrust P4,8,9,16, Barratt-Due A1,2,3, Mollnes TE1,2,4,12,17,18.

Author information

1
Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
2
University of Oslo, Oslo, Norway.
3
Division of Emergencies and Critical Care, Department of Anesthesiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
4
KG Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
5
Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
6
Clinic of Cardiology, St. Olavs Hospital, Trondheim, Norway.
7
Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
8
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
9
Faculty of Medicine, University of Oslo, Oslo, Norway.
10
KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway.
11
Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway.
12
Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
13
Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
14
Center for Clinical Heart Research, Oslo University Hospital, Ullevål, Oslo, Norway.
15
Department of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway.
16
Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway.
17
Research Laboratory, Nordland Hospital, Bodø, Norway.
18
K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway.

Abstract

Background: Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. Materials and Methods: NSTEMI patients were randomized to one dose of tocilizumab (n = 28) or placebo (n = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, n = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, n = 21) and ST-elevation myocardial infarction (STEMI, n = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Results: Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly (p < 0.001) and substantially (>50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients (p < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group (p < 0.05) and C3aR in the NSTE-ACS group (p < 0.05). Conclusion: Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients.

KEYWORDS:

C3a receptor; C5a receptors; IL-6; complement; inflammation; myocardial infarction

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central Icon for Norwegian BIBSYS system
Loading ...
Support Center