Molecular biology reports · 2025
Upregulation and diagnostic potential of Interleukin-36 cytokine isoforms in dilated cardiomyopathy: evidence from human and murine models.
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Kainat Alishba, Nasim Mubeen Tabish, Mian Fazlul Aziz, Nurulain Syed Muhammad, Awan Hassaan Mehboob, Iqbal Tahir, Hussain Sabir
Аннотация
BACKGROUND: Cardiovascular disease (CVD) is caused by chronic inflammation, however it is yet unknown how interleukin-36 cytokines contribute to coronary artery disease (CAD) and dilated cardiomyopathy (DCM), including how different isoforms affect myocardial remodeling and their possible therapeutic applications.
METHODS: Using a publicly available dataset (GSE97320), we conducted transcriptome analysis to investigate IL-36 expression patterns and associated pathways. To find immunological networks and signaling interactors, functional enrichment and protein-protein interaction studies were performed. RT-qPCR was used to evaluate a validation cohort of 300 patients, and results were further validated in a DCM rat model. The diagnostic performance of interleukin-36 isoforms was assessed using Receiver Operating Characteristic (ROC) curve analysis.
RESULTS: There was a consistent upregulation of interleukin-36 in both DCM and CAD, with IL36G exhibiting the most marked increase (4.9-fold in DCM; p < 0.001). Compared to CAD, expression levels in DCM were noticeably greater. ROC analysis showed good diagnostic accuracy, especially for DCM's IL36A (AUC = 0.98). Interleukin-36 isoform overexpression was verified at the cardiac tissue level in the mouse DCM model. The IL-36R-NF-κB axis is the primary mechanism by which intwerleukin-36 signaling is involved in pro-fibrotic and inflammatory responses, according to pathway and interaction analyses.
CONCLUSION: This study is the first to characterize IL-36 isoforms expression across human and animal models of DCM. Our research provides new insights into the inflammatory landscape of non-ischemic DCM by identifying IL36G as a putative isoform-specific biomarker in myocardial inflammation and remodeling.
METHODS: Using a publicly available dataset (GSE97320), we conducted transcriptome analysis to investigate IL-36 expression patterns and associated pathways. To find immunological networks and signaling interactors, functional enrichment and protein-protein interaction studies were performed. RT-qPCR was used to evaluate a validation cohort of 300 patients, and results were further validated in a DCM rat model. The diagnostic performance of interleukin-36 isoforms was assessed using Receiver Operating Characteristic (ROC) curve analysis.
RESULTS: There was a consistent upregulation of interleukin-36 in both DCM and CAD, with IL36G exhibiting the most marked increase (4.9-fold in DCM; p < 0.001). Compared to CAD, expression levels in DCM were noticeably greater. ROC analysis showed good diagnostic accuracy, especially for DCM's IL36A (AUC = 0.98). Interleukin-36 isoform overexpression was verified at the cardiac tissue level in the mouse DCM model. The IL-36R-NF-κB axis is the primary mechanism by which intwerleukin-36 signaling is involved in pro-fibrotic and inflammatory responses, according to pathway and interaction analyses.
CONCLUSION: This study is the first to characterize IL-36 isoforms expression across human and animal models of DCM. Our research provides new insights into the inflammatory landscape of non-ischemic DCM by identifying IL36G as a putative isoform-specific biomarker in myocardial inflammation and remodeling.