Interleukin 11 Therapy Causes Acute Left Ventricular Dysfunction
Academic Background
Interleukin 11 (IL-11) is a member of the IL-6 cytokine family and was initially thought to play an important role in platelet production, leading to its development as a drug for treating thrombocytopenia. However, subsequent research found that IL-11 is not essential for hematopoiesis, and its use in patients is associated with severe, unexplained cardiac side effects. Previously, IL-11 was believed to have cardioprotective effects, but recent studies have challenged this view. In particular, the specific mechanisms of IL-11 in the heart and its direct toxicity to cardiomyocytes remain unclear. Therefore, this study aims to reveal, for the first time, the direct toxic effects of IL-11 on cardiomyocytes and explain its cardiac side effects in clinical applications.
Source of the Paper
This paper was authored by Mark Sweeney and colleagues, with the research team hailing from several renowned institutions, including the MRC Laboratory of Medical Sciences, Imperial College London, and the Max Delbrück Center for Molecular Medicine, among others. The paper was published online on October 9, 2024, in the journal Cardiovascular Research, with the DOI 10.1093/cvr/cvae224.
Research Process and Results
1. Experimental Design and Methods
The research team injected recombinant mouse IL-11 (rmIL-11) into mice and used various molecular biology techniques (such as immunoblotting, qRT-PCR, RNA sequencing, single-nucleus RNA sequencing, and ATAC sequencing) to study its effects on the heart. Additionally, the physiological impact of IL-11 was assessed using echocardiography, and cardiomyocyte contractility experiments were conducted in vitro. To determine the specific role of IL-11 in cardiomyocytes, the team constructed two cardiomyocyte-specific IL-11 receptor alpha 1 (IL-11RA1) knockout mouse models, using AAV9-mediated Tnnt2-restricted expression and Myh6-driven Cre expression, respectively.
2. Effects of IL-11 on Left Ventricular Function
The study found that injection of rmIL-11 caused acute, dose-dependent reductions in left ventricular ejection fraction (LVEF). Specifically, after rmIL-11 injection, the LVEF in mice significantly decreased from 62.4% to 32.6%. Additionally, phosphorylation levels of STAT3 and JNK in the myocardium increased significantly, and RNA sequencing results showed upregulation of pro-inflammatory pathways (such as TNFα, NFκB, and JAK/STAT) and disturbances in calcium handling. Single-nucleus RNA sequencing revealed that rmIL-11 induced the expression of stress factors (such as ANKRD1, ANKRD23, and XIRP2) and AP-1 transcription factor genes in cardiomyocytes.
3. Cardiomyocyte-Specific IL-11RA1 Knockout Experiments
To further validate the direct toxic effects of IL-11 on cardiomyocytes, the research team successfully constructed cardiomyocyte-specific IL-11RA1 knockout mice (vCMKO) using AAV9-mediated Tnnt2-restricted Cre expression. Experiments showed that vCMKO mice did not exhibit left ventricular dysfunction after rmIL-11 injection, and STAT3 phosphorylation levels in cardiomyocytes were significantly reduced. This indicates that the toxic effects of IL-11 are mediated through its receptor IL-11RA1 in cardiomyocytes.
4. Inhibition of the JAK/STAT Signaling Pathway
The study also found that IL-11 induces cardiac dysfunction by activating the JAK/STAT signaling pathway. By pretreating mice with JAK inhibitors (such as ruxolitinib and tofacitinib), the research team successfully prevented rmIL-11-induced cardiac damage. This suggests that the JAK/STAT signaling pathway plays a key role in IL-11-induced cardiac toxicity.
Conclusions and Significance
This study is the first to reveal the direct toxic effects of IL-11 on cardiomyocytes and explain the mechanisms behind its severe cardiac side effects in clinical applications. The results demonstrate that IL-11 causes acute heart failure by activating the IL-11RA1/JAK/STAT3 signaling pathway. This finding overturns the previously held view that IL-11 has cardioprotective effects and raises concerns about its clinical use.
Research Highlights
- First to Reveal IL-11’s Direct Toxicity to Cardiomyocytes: This study is the first to clarify the direct toxic effects of IL-11 on cardiomyocytes, filling a gap in this field of research.
- Key Role of the JAK/STAT Signaling Pathway: The study highlights the central role of the JAK/STAT signaling pathway in IL-11-induced cardiac toxicity, providing a theoretical basis for developing new treatment strategies.
- Successful Construction of Cardiomyocyte-Specific Knockout Models: By constructing cardiomyocyte-specific IL-11RA1 knockout mouse models, the research team successfully validated that IL-11’s toxic effects are mediated through its receptor in cardiomyocytes.
Application Value
The findings of this study have significant implications for the clinical use of IL-11. Given the widespread use of IL-11 in treating thrombocytopenia and its severe cardiac side effects, the results suggest that the clinical use of IL-11 should be re-evaluated, and safer alternative treatments should be explored. Additionally, the study provides new insights for further exploring the role of IL-11 in other diseases.
Other Valuable Information
The research team also revealed the stress responses and transcriptional regulation mechanisms induced by IL-11 in cardiomyocytes through single-nucleus RNA sequencing and ATAC sequencing. These findings offer new perspectives for understanding the molecular mechanisms of IL-11 in the heart and lay the groundwork for further research into the pathological mechanisms of heart diseases.
Through this study, we have gained a deeper understanding of the mechanisms of IL-11 and provided important reference points for clinical treatment. In the future, based on these findings, safer and more effective treatment options may be developed to mitigate the side effects of IL-11 in clinical applications.