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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / prevention & control
  • Desmin / physiology
  • Female
  • Humans
  • Keratin-18 / physiology*
  • Keratin-8 / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / physiology
  • Tumor Necrosis Factor-alpha / physiology*


  • Desmin
  • Keratin-18
  • Keratin-8
  • NF-kappa B
  • Tumor Necrosis Factor-alpha