Interleukin 11 therapy causes acute heart failure and its use in patients should be reconsidered
Background: Interleukin-11 (IL11) was initially identified as a fibroblast secreted factor that supports haematopoietic cell function. This led to its development as a drug to increase platelet counts in patients with thrombocytopenia. However, IL11 was later found redundant for hematopoiesis and its use in humans causes severe and unexplained cardiac side effects. Here we identify and dissect mechanisms underlying previously unappreciated cardiac toxicities associated with IL11 therapy. Methods: We injected recombinant mouse lL11 (rmIl11) at clinically relevant doses to study its effects on myocardial signalling using immunoblotting and genomic variation using qRT-PCR, RNA-seq and ATAC-seq. The physiological impact of Il11 was assessed by echocardiography in vivo and cardiomyocyte contractility assays in vitro. To determine the specific activity of IL11 in cardiomyocytes we generated two distinct cardiomyocyte-specific IL11 receptor knockout (CMKO) mouse models using either AAV9-mediated, Tnnt2-restricted (vCMKO) or mhy6 (m6CMKO) Cre expression in an Il11ra1 floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition following rmIl11 injection to mice.Results: Injection of rmIl11 to mice caused dose-dependent impairment of left ventricular ejection fraction (LVEF: saline, 64.2%±1.62; rmIl11 (50 mg/kg), 31.6±2.0; p<0.0001). RNA-seq of hearts one and three hours following rmIl11 injection revealed strong upregulation of the TNF, NFkB and JAK/STAT pathways as well as increased Nppa and Rrad levels. vCMKO mice were protected from rmIl11-induced STAT3 activation, Rrad upregulation and LV impairment. Similarly, m6CMKO mice of both sexes, were protected from the molecular, cellular and whole organ cardiac toxicities associated with Il11. Administration of JAK inhibitors prevented rmIl11-induced STAT3 activation and preserved cardiac function. Conclusions: Here we show that Il11 injection to mice is strongly proinflammatory in the heart. Furthermore, Il11 has profound negative inotropic effects that are mediated via its on-target activation of JAK/STAT3 signalling  in cardiomyocytes. Our data explain the cardiac side effects associated with IL11 therapy and question its continued use in patients. Overall design: RNA-seq analysis of the hearts of male C57BL6/J mice injected with recombinant mouse IL11 at basline, 1 ,3 and 6 hours after injection.