Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18

Stamatis Papathanasiou, Steffen Rickelt, Maria Eugenia Soriano, Tobias G. Schips, Harald J. Maier, Constantinos H. Davos, Aimilia Varela, Loukas Kaklamanis, Douglas L. Mann, Yassemi Capetanaki

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Tumor necrosis factor-α (TNF-α), one of the major stress-induced proinflammatory cytokines, is upregulated in the heart after tissue injury, and its sustained expression can contribute to the development of heart failure. Whether TNF-α also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-α in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-α are a consequence of nuclear factor-κB (NF-κB)-mediated ectopic expression in cardiomyocytes of keratin 8 (K8) and keratin 18 (K18), two epithelial-specific intermediate filament proteins. In cardiomyocytes, K8 and K18 (K8/K18) formed an alternative cytoskeletal network that localized mainly at intercalated discs (IDs) and conferred cardioprotection by maintaining normal ID structure and mitochondrial integrity and function. Ectopic induction of K8/K18 expression in cardiomyocytes also occurred in other genetic and experimental models of heart failure. Loss of the K8/K18 network resulted in a maladaptive cardiac phenotype following transverse aortic constriction. In human failing myocardium, where TNF-α expression is upregulated, K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-α- and NF-κB-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans.

Original languageEnglish
Pages (from-to)1076-1084
Number of pages9
JournalNature medicine
Volume21
Issue number9
DOIs
StatePublished - Sep 8 2015

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