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Selective Interleukin-6 trans-signalling antagonism with sgp130Fc reduces infarct size in a rat model of myocardial infarction whereas pan-blockade with an anti-IL-6 antibody does not

M. J. George1, D. Stuckey2, N. H. Jasmin2, V. Taylor2, A. D. Hingorani3, D. Gilroy11Clinical Pharmacology, University College London, London, United Kingdom, 2Centre For Advanced Biological Imaging, University College London, London, United Kingdom, 3Institute of Cardiovascular Science, University College London, London, United Kingdom.

Introduction: Interleukin-6 (IL-6) is elevated during Acute Myocardial Infarction (AMI) particularly after reperfusion and is associated with the development of heart failure and mortality (1). Therefore IL-6 is a potential therapeutic target in AMI. IL-6 has both pro and anti-inflammatory effects; the anti-inflammatory effects are mediated by classic signalling (2), whereas the pro-inflammatory effects are mediated by trans-signalling (3). We hypothesised that selective blockade of IL-6 trans-signalling with the novel sgp130Fc protein during AMI would result in reduced infarct size (IS) whereas pan-IL-6 blockade with an anti-IL-6-Ab would not.

Methods:AMI was induced in male Sprague-Dawley rats by occluding the left-anterior descending artery for 50 minutes prior to reperfusion. The model was characterised by measuring IL-6 and sIL-6R within heart tissue and plasma by ELISA at 6 time-points post reperfusion (2h-7 days, n=3-4/group). In addition, cardiac leukocyte infiltration (flow-cytometry of cells obtained from heart digests) was measured. In therapeutic experiments, rats received either 0.5μg/g of sgp130Fc, 0.1μg/g anti-IL-6-Ab or vehicle alone given intravenously immediately prior to reperfusion. IS (as a percentage of area-at-risk (AAR)) was measured histologically at 24 hours (n=7-8/group). LVEF was measured by cardiac magnetic resonance imaging at 28 days in a group receiving sgp130Fc and compared to age-matched naïve rats and vehicle-controls (n=6-8/group).


Characterisation: IL-6 levels in the heart were biphasic; with peaks at 4 and 72 hours. Only the early peak was associated with elevated circulating IL-6. The early peak was temporally associated with neutrophil influx and the second with mononuclear phagocytes (MPs). Plasma sIL-6R peaked at 24 hours.

Therapeutic studies: IS/AAR was significantly reduced by the administration of sgp130Fc but not by the anti-IL-6-Ab (vehicle: 46.1%, anti-IL6-Ab: 45.6%, sgp130Fc: 26.3%, one-way ANOVA with multiple comparisons: sgp130Fc v vehicle p<0.001). At 28 days sgp130Fc ameliorated the reduction in LVEF associated with AMI (naïve 72.35%, vehicle: 62.58%, sgp130Fc 69.51%, one-way ANOVA with multiple comparisons: naïve vs vehicle p<0.01, naïve vs sgp130Fc ns).

Conclusions:Our results suggest that specific targeting of IL-6 trans-signalling with the novel sgp130Fc protein reduces IS in an animal model of AMI with reperfusion, whereas pan-blockade with an anti-IL-6-Ab does not. Furthermore, administration of sgp130Fc preserves LVEF at 28 days.


1. Fanola CL et al. (2017). J Am Heart Assoc 6:e005637.

2. Luig M et al. (2015). J Am Soc Nephrol 26:1597-607.

3. Tilg H et al. (1994). Blood 83:113-8.