Enhanced IL-17 signalling following myocardial ischaemia/reperfusion injury.
IL-17A and IL-17F are pro-inflammatory cytokines which induce the expression of several cytokines, chemokines and matrix metalloproteinases (MMPs) in target cells. IL-17 cytokines have recently attracted huge interest due to their pathogenic role in diseases such as arthritis and inflammatory bowel disease although a role for IL-17 cytokines in myocardial infarction (MI) has not previously been described.



In vivo MI was performed by coronary artery occlusion in the absence or presence of a neutralizing IL-17 antibody for blocking IL-17 actions in vivo. IL-17 signaling was also assessed in isolated primary cardiomyocytes by Western blot, mRNA expression and immunostaining.



Expression of IL-17A, IL-17F and the IL-17 receptor (IL-17RA) were all increased following MI. Expression of several IL-17 target genes, including Cxcl1, Cxcl2, IL-1β, iNOS and IL-6 was also upregulated following MI. In addition, IL-17A promoted the expression of Cxcl1 and IL-6 in isolated cardiomyocytes in a MAPK and PI(3)K-dependent manner. IL-17A and ischaemia/reperfusion (I/R) injury were found to have an additive effect on Cxcl1 expression, suggesting that IL-17 may enhance myocardial neutrophil recruitment during MI. Moreover, protein levels of both IL-17R and IL-17A were enhanced following in vivo MI. Finally, blocking IL-17 signaling in vivo reduced the levels of apoptotic cell death markers following in vivo MI.



These data imply that the expression of IL-17 cytokines and their receptor are elevated during myocardial I/R injury and may play a fundamental role in post infarct inflammatory and apoptotic responses.
Institute of Molecular Medicine, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.
Seán P
SP
Barry
Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
Samir
S
Ounzain
Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
James
J
McCormick
Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, 22201 Moross Road, Detroit, USA.
Tiziano M
TM
Scarabelli
Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, 22201 Moross Road, Detroit, USA.
Carol
C
Chen-Scarabelli
Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, 22201 Moross Road, Detroit, USA.
Louis I I
LII
Saravolatz
Division of Cardiac Surgery, University of Verona, Verona, Italy.
Giuseppe
G
Faggian
Division of Cardiac Surgery, University of Verona, Verona, Italy.
Alessandro
A
Mazzucco
Sezione di Chimica Biologica, Dipartimento di Scienze Morfologico-Biomediche, Università di Verona, Strada Le Grazie, 8, I-37134 Verona, Italy.
Hisanori
H
Suzuki
Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, St Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Christoph
C
Thiemermann
Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
Richard A
RA
Knight
Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
David S
DS
Latchman
Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK. Electronic address: a.stephanou@ich.ucl.ac.uk.
Anastasis
A
Stephanou
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D018836:Inflammation Mediators / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
D015415:Biomarkers; D018836:Inflammation Mediators; D020381:Interleukin-17