Key result
IL-1Ra deficiency drives a ~6-fold increase in hypoxia-induced apoptosis via mitochondria-activated caspases.
Why the study?
The intracellular role of interleukin-1 receptor antagonist (IL-1Ra) in protecting ischemic cardiomyocytes from apoptosis was not fully understood.
Effect estimate: 6-fold increase
Absolute Event Rate: 98% vs 16%
p-value: p=<0.001
Intracellular IL-1Ra provides receptor-independent protection against ischemia-induced apoptosis in cardiomyocytes.
Hypothesis-generating for IL-1Ra cardioprotection; leaves open clinical translation pending human studies.
BACKGROUND: Loss of cardiac myocytes due to apoptosis is a relevant feature of ischemic heart disease. It has been described in infarct and peri-infarct regions of the myocardium in coronary syndromes and in ischemia-linked heart remodeling. Previous studies have provided protection against ischemia-induced cardiomyocyte apoptosis by the anti-inflammatory cytokine interleukin-1 receptor-antagonist (IL-1Ra). Mitochondria triggering of caspases plays a central role in ischemia-induced apoptosis. We examined the production of IL-1Ra in the ischemic heart and, based on dual intra/extracellular function of some other interleukins, we hypothesized that IL-1Ra may also directly inhibit mitochondria-activated caspases and cardiomyocyte apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: Synthesis of IL-1Ra was evidenced in the hearts explanted from patients with ischemic heart disease. In the mouse ischemic heart and in a mouse cardiomyocyte cell line exposed to long-lasting hypoxia, IL-1Ra bound and inhibited mitochondria-activated caspases, whereas inhibition of caspase activation was not observed in the heart of mice lacking IL-1Ra (Il-1ra-/-) or in siRNA to IL-1Ra-interfered cells. An impressive 6-fold increase of hypoxia-induced apoptosis was observed in cells lacking IL-1Ra. IL-1Ra down-regulated cells were not protected against caspase activation and apoptosis by knocking down of the IL-1 receptor, confirming the intracellular, receptor-independent, anti-apoptotic function of IL-1Ra. Notably, the inhibitory effect of IL-1Ra was not influenced by enduring ischemic conditions in which previously described physiologic inhibitors of apoptosis are neutralized. CONCLUSIONS/SIGNIFICANCE: These observations point to intracellular IL-1Ra as a critical mechanism of the cell self-protection against ischemia-induced apoptosis and suggest that this cytokine plays an important role in the remodeling of heart by promoting survival of cardiomyocytes in the ischemic regions.
No takes yet. Share an insight, caveat, or question.
Vecile et al. (2013) studied Ischemic heart disease (n=9). IL-1Ra deficiency (knockout/siRNA) vs. Wild-type / control siRNA was evaluated on Hypoxia-induced apoptosis (TUNEL-positive cardiomyocytes) (6-fold increase, p=<0.001). Deficiency of IL-1Ra resulted in a 6-fold increase in hypoxia-induced apoptosis (98% vs 16% in wild-type, p<0.001), demonstrating that intracellular IL-1Ra protects against ischemia-induced cell death by inhibiting mitochondria-activated caspases.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: