Frontiers in Immunology (Sep 2018)
IL-6 Receptor Inhibition by Tocilizumab Attenuated Expression of C5a Receptor 1 and 2 in Non-ST-Elevation Myocardial Infarction
- Hilde L. Orrem,
- Hilde L. Orrem,
- Hilde L. Orrem,
- Per H. Nilsson,
- Per H. Nilsson,
- Per H. Nilsson,
- Per H. Nilsson,
- Søren E. Pischke,
- Søren E. Pischke,
- Søren E. Pischke,
- Ola Kleveland,
- Ola Kleveland,
- Arne Yndestad,
- Arne Yndestad,
- Arne Yndestad,
- Arne Yndestad,
- Arne Yndestad,
- Karin Ekholt,
- Karin Ekholt,
- Jan K. Damås,
- Terje Espevik,
- Bjørn Bendz,
- Bente Halvorsen,
- Bente Halvorsen,
- Bente Halvorsen,
- Bente Halvorsen,
- Bente Halvorsen,
- Ida Gregersen,
- Ida Gregersen,
- Rune Wiseth,
- Rune Wiseth,
- Geir Ø. Andersen,
- Geir Ø. Andersen,
- Geir Ø. Andersen,
- Thor Ueland,
- Thor Ueland,
- Thor Ueland,
- Thor Ueland,
- Thor Ueland,
- Lars Gullestad,
- Lars Gullestad,
- Lars Gullestad,
- Pål Aukrust,
- Pål Aukrust,
- Pål Aukrust,
- Pål Aukrust,
- Andreas Barratt-Due,
- Andreas Barratt-Due,
- Andreas Barratt-Due,
- Tom E. Mollnes,
- Tom E. Mollnes,
- Tom E. Mollnes,
- Tom E. Mollnes,
- Tom E. Mollnes,
- Tom E. Mollnes
Affiliations
- Hilde L. Orrem
- Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Hilde L. Orrem
- University of Oslo, Oslo, Norway
- Hilde L. Orrem
- Division of Emergencies and Critical Care, Department of Anesthesiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Per H. Nilsson
- Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Per H. Nilsson
- University of Oslo, Oslo, Norway
- Per H. Nilsson
- KG Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
- Per H. Nilsson
- Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
- Søren E. Pischke
- Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Søren E. Pischke
- University of Oslo, Oslo, Norway
- Søren E. Pischke
- Division of Emergencies and Critical Care, Department of Anesthesiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Ola Kleveland
- Clinic of Cardiology, St. Olavs Hospital, Trondheim, Norway
- Ola Kleveland
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Arne Yndestad
- KG Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
- Arne Yndestad
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Arne Yndestad
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Arne Yndestad
- 0KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
- Arne Yndestad
- 1Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Karin Ekholt
- Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Karin Ekholt
- University of Oslo, Oslo, Norway
- Jan K. Damås
- 2Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Terje Espevik
- 2Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Bjørn Bendz
- 3Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Bente Halvorsen
- KG Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
- Bente Halvorsen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Bente Halvorsen
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Bente Halvorsen
- 0KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
- Bente Halvorsen
- 1Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Ida Gregersen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Ida Gregersen
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Rune Wiseth
- Clinic of Cardiology, St. Olavs Hospital, Trondheim, Norway
- Rune Wiseth
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Geir Ø. Andersen
- 1Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Geir Ø. Andersen
- 4Center for Clinical Heart Research, Oslo University Hospital, Ullevål, Oslo, Norway
- Geir Ø. Andersen
- 5Department of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway
- Thor Ueland
- KG Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
- Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Thor Ueland
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Thor Ueland
- 0KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
- Thor Ueland
- 1Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Lars Gullestad
- 0KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
- Lars Gullestad
- 1Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway
- Lars Gullestad
- 3Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Pål Aukrust
- KG Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
- Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Pål Aukrust
- Faculty of Medicine, University of Oslo, Oslo, Norway
- Pål Aukrust
- 6Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway
- Andreas Barratt-Due
- Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Andreas Barratt-Due
- University of Oslo, Oslo, Norway
- Andreas Barratt-Due
- Division of Emergencies and Critical Care, Department of Anesthesiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Tom E. Mollnes
- Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Tom E. Mollnes
- University of Oslo, Oslo, Norway
- Tom E. Mollnes
- KG Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
- Tom E. Mollnes
- 2Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Tom E. Mollnes
- 7Research Laboratory, Nordland Hospital, Bodø, Norway
- Tom E. Mollnes
- 8K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway
- DOI
- https://doi.org/10.3389/fimmu.2018.02035
- Journal volume & issue
-
Vol. 9
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.
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