The interleukin-6/glycoprotein 130 pathway in cardiomyocytes contributes to the pathogenesis of sepsis-induced cardiomyopathy

Abstract Background Sepsis remains a leading cause of death, with sepsis-induced cardiomyopathy (SICM) contributing to this devastating outcome. Despite its clinical importance, targeted therapies for SICM are lacking. Interleukin-6 (IL-6) is a key proinflammatory cytokine elevated in septic patients, strongly associated with disease severity and SICM pathogenesis. However, the specific effects of IL-6 via its receptor glycoprotein 130 (gp130, il6st) on cardiomyocyte function and mitochondrial integrity are not well understood but mitochondrial dysfunction is discussed. Purpose We hypothesized that IL-6 signaling via gp130 contributes to SICM by mitochondrial dysfunction and impairing cardiomyocyte function. Methods The effects of IL-6 on cardiomyocytes were investigated in HL-1 cells. SiRNA-mediated reduction of gp130 was employed to assess if the IL-6 effects on HL-1 cells were gp130 dependent. qRT-PCR was performed to quantitate IL-6 effects on cardiac stress markers (Nppb, Myh6, Myh7, Socs3) and mitochondrial biogenesis (Ppargc1a) genes. Functional assessment of adult rat ventricular myocytes (ARVM) were conducted using contractility measurements. To investigate the role of gp130 in SICM, we used male mice with cardiomyocyte-specific deletion of gp130 (il6st cKO). Sepsis was induced by cecal ligation and puncture (CLP) surgery, with sham-operated controls. Cardiac function was quantitated by transthoracic echocardiography 24 hours post-surgery. Gene expression of cardiac stress markers (Nppb, Myh6, Myh7, Socs3) and mitochondrial genes (Ppargc1a, Drp-1) was quantitated, and mitochondrial function was assessed using high-resolution respirometry (HRR). Results IL-6 treatment of HL-1 cells induced Nppb expression, which was attenuated by gp130 knockdown, indicating gp130 dependence. Functional analysis revealed that IL-6 caused a dose-dependent reduction in ARVM contractility and relaxation. In vivo, WT mice subjected to CLP developed SICM, exhibiting deterioration of cardiac function. In contrast, Il6st cKO mice were protected from SICM, displaying preserved cardiac function and attenuated transcriptional stress response (Nppb) compared to septic WT mice. Sepsis reduced the expression of mitochondrial genes (Ppargc1a/Drp-1) in WT but not in Il6st cKO mouse hearts. HRR revealed an increase in oxygen flow rates in heart tissues of both septic WT and septic Il6st cKO mice, with no genotype-dependent differences. Conclusion Our findings demonstrate that IL-6 signaling via gp130 promotes SICM by inducing cardiac stress responses and impairing contractile function in vitro and in vivo. However, sepsis-induced mitochondrial dysfunction appears to be independent of the IL-6/gp130 axis, suggesting alternative pathways contribute to mitochondrial dysregulation in SICM. These insights highlight IL-6/gp130 as a potential therapeutic target for SICM while emphasizing the need to explore additional mechanisms underlying sepsis-induced mitochondrial dysfunction.