Involvement of c-Jun N-Terminal Kinase in TNF-alpha-Driven Remodeling

Irene M. J. Eurlings, Niki L. Reynaert, Cheryl van de Wetering, Scott W. Aesif, Evi M. Mercken, Rafael de Cabo, Jos L. van der Velden, Yvonne M. Janssen-Heininger, Emiel F. M. Wouters, Mieke A. Dentener*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Web of Science)


Lung tissue remodeling in chronic obstructive pulmonary disease (COPD) is characterized by airway wall thickening and/or emphysema. Although the bronchial and alveolar compartments are functionally independent entities, we recently showed comparable alterations in matrix composition comprised of decreased elastin content and increased collagen and hyaluronan contents of alveolar and small airway walls. Out of several animal models tested, surfactant protein C (SPC)-TNF-alpha mice showed remodeling in alveolar and airway walls similar to what we observed in patients with COPD. Epithelial cells are able to undergo a phenotypic shift, gaining mesenchymal properties, a process in which c-Jun N-terminal kinase (JNK) signaling is involved. Therefore, we hypothesized that TNF-alpha induces JNK-dependent epithelial plasticity, which contributes to lung matrix remodeling. To this end, the ability of TNF-alpha to induce a phenotypic shift was assessed in A549, BEAS2B, and primary bronchial epithelial cells, and phenotypic markers were studied in SPC-TNF-alpha mice. Phenotypic markers of mesenchymal cells were elevated both in vitro and in vivo, as shown by the expression of vimentin, plasminogen activator inhibitor-1, collagen, and matrix metalloproteinases. Concurrently, the expression of the epithelial markers, E-cadherin and keratin 7 and 18, was attenuated. A pharmacological inhibitor of JNK attenuated this phenotypic shift in vitro, demonstrating involvement of JNK signaling in this process. Interestingly, activation of JNK signaling was also clearly present in lungs of SPC-TNF-alpha mice and patients with COPD. Together, these data show a role for TNF-alpha in the induction of a phenotypic shift in vitro, resulting in increased collagen production and the expression of elastin-degrading matrix metalloproteinases, and provide evidence for involvement of the TNF-alpha-JNK axis in extracellular matrix remodeling.

Original languageEnglish
Pages (from-to)393-401
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number3
Publication statusPublished - Mar 2017


  • c-Jun N-terminal kinase
  • TNF-alpha
  • matrix remodeling
  • lung
  • TGF-BETA-1

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