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Nat Med. 2015 Sep;21(9):1076-84. doi: 10.1038/nm.3925. Epub 2015 Aug 17.

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

Author information

Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Helmholtz Group for Cell Biology, German Cancer Research Center, Heidelberg, Germany.
Department of Biology, University of Padova, Padova, Italy.
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
Clinical, Experimental Surgery &Translational Research Center, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Department of Pathology, Onassis Cardiac Surgery Center, Athens, Greece.
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.


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.

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