Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis

T. Namba, K. I. Tanaka, Y. Ito, T. Hoshino, M. Matoyama, N. Yamakawa, Y. Isohama, A. Azuma, T. Mizushima

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is a serious clinical concern and myofibroblasts have been suggested to have a major role, with it recently being revealed that some of these myofibroblasts are derived from lung epithelial cells through epithelial-mesenchymal transition (EMT). In this study, we examined the EMT-inducing abilities of drugs known to induce ILD clinically. EMT-like phenotypes were induced by A771726, an active metabolite of leflunomide having an inhibitory effect on dihydroorotate dehydrogenase (DHODH). Smad-interacting protein 1 (a transcription factor regulating EMT) and the Notch-signaling pathway but not transforming growth factor-Β was shown to be involved in A771726-induced EMT-like phenotypes. When the cultures were supplemented with exogenous uridine, the A771726-induced EMT-like phenotypes and activation of the Notch-signaling pathway disappeared. Similarly, an A771726 analog without inhibitory activity on DHODH produced no induction, suggesting that this process is mediated through the inhibition of DHODH. In vivo, administration of leflunomide stimulated bleomycin-induced EMT-like phenomenon in pulmonary tissue, and exacerbated bleomycin-induced pulmonary fibrosis, both of which were suppressed by coadministration of uridine. Taken together, these findings suggest that leflunomide-dependent exacerbation of bleomycin-induced pulmonary fibrosis is mediated by stimulation of EMT of lung epithelial cells, providing the first evidence that drug-induced pulmonary fibrosis involves EMT of these cells.

Original languageEnglish
Pages (from-to)1882-1895
Number of pages14
JournalCell Death and Differentiation
Volume17
Issue number12
DOIs
Publication statusPublished - 2010 Dec
Externally publishedYes

Fingerprint

leflunomide
Epithelial-Mesenchymal Transition
Pulmonary Fibrosis
A 771726
Phenotype
Bleomycin
Myofibroblasts
Uridine
Interstitial Lung Diseases
Lung
Epithelial Cells
Smad Proteins
Pharmaceutical Preparations
Transforming Growth Factors

Keywords

  • EMT
  • leflunomide
  • pulmonary fibrosis

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Namba, T., Tanaka, K. I., Ito, Y., Hoshino, T., Matoyama, M., Yamakawa, N., ... Mizushima, T. (2010). Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis. Cell Death and Differentiation, 17(12), 1882-1895. https://doi.org/10.1038/cdd.2010.64

Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis. / Namba, T.; Tanaka, K. I.; Ito, Y.; Hoshino, T.; Matoyama, M.; Yamakawa, N.; Isohama, Y.; Azuma, A.; Mizushima, T.

In: Cell Death and Differentiation, Vol. 17, No. 12, 12.2010, p. 1882-1895.

Research output: Contribution to journalArticle

Namba, T, Tanaka, KI, Ito, Y, Hoshino, T, Matoyama, M, Yamakawa, N, Isohama, Y, Azuma, A & Mizushima, T 2010, 'Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis', Cell Death and Differentiation, vol. 17, no. 12, pp. 1882-1895. https://doi.org/10.1038/cdd.2010.64
Namba, T. ; Tanaka, K. I. ; Ito, Y. ; Hoshino, T. ; Matoyama, M. ; Yamakawa, N. ; Isohama, Y. ; Azuma, A. ; Mizushima, T. / Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis. In: Cell Death and Differentiation. 2010 ; Vol. 17, No. 12. pp. 1882-1895.
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