Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-β1-dependent mechanism in vitro

Jun Ming Fan, Xiao Ru Huang, Yee Yung Ng, David J. Nikolic-Paterson, Wei Mu, Robert C. Atkins, Hui Y. Lan

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Abstract

Interleukin-1 (IL-1) has been shown to exert profibrotic activity in a number of disease models, including crescentic glomerulonephritis and pulmonary fibrosis, but the mechanisms by which this operates are poorly understood. Recent studies have identified a novel mechanism promoting renal fibrosis: tubular epithelialmyofibrolast transdifferentiation (TEMT). The present study examined whether IL-1 can stimulate TEMT in vitro. Cells of the normal rat kidney tubular epithelial cell line (NRK52E) were grown to confluence on collagen-coated plates and cultured for 5 days in the presence 1 to 20 ng/mL of IL-1α. Doses of 10 to 20 ng/mL of IL-1 caused transdifferentiation of NRK52E cells into myofibroblast-like cells. Scanning electron microscopy identified IL-1-induced morphological changes as a loss of apical-basal polarity and microvilli, cell hypertrophy, and the development of an elongated and invasive appearance. Phenotypically, IL-1-induced TEMT was characterized by de novo messenger RNA and protein expression of the mesenchymal marker (α-smooth muscle actin, shown by Northern blotting, immunohistochemistry, and Western blotting. This was accompanied by loss of the epithelial marker E-cadherin. The addition of an excess of IL-1-receptor antagonist completely inhibited IL-1-induced TEMT. IL-1 was shown to stimulate the secretion of active transforming growth factor-β1 (TGF-β1) by NRK52E cells. Furthermore, the addition of a neutralizing anti-TGF-β1 antibody inhibited IL-1-induced TEMT. In conclusion, IL-1 is a profibrogenic cytokine capable of inducing TEMT through a TGF-β1-dependent mechanism. This may represent a novel mechanism by which IL-1 induces renal fibrosis in vivo.

Original languageEnglish
Pages (from-to)820-831
Number of pages12
JournalAmerican Journal of Kidney Diseases
Volume37
Issue number4
DOIs
Publication statusPublished - 1 Jan 2001

Keywords

  • E-cadherin
  • Epithelial
  • Interleukin-1 (IL-1)
  • Mesenchymal
  • Transdifferentiation
  • Transforming growth factor-β (TGF-β)
  • α-smooth muscle actin (α-SMA)

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