Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1-dependent mechanism in vitro

Am J Kidney Dis. 2001 Apr;37(4):820-31. doi: 10.1016/s0272-6386(01)80132-3.


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 epithelial-myofibroblast 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-1alpha. 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 alpha-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-beta1 (TGF-beta1) by NRK52E cells. Furthermore, the addition of a neutralizing anti-TGF-beta1 antibody inhibited IL-1-induced TEMT. In conclusion, IL-1 is a profibrogenic cytokine capable of inducing TEMT through a TGF-beta1-dependent mechanism. This may represent a novel mechanism by which IL-1 induces renal fibrosis in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / biosynthesis
  • Actins / metabolism
  • Analysis of Variance
  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Cadherins / biosynthesis
  • Cadherins / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Line
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / physiology
  • Fibrosis / etiology
  • Fibrosis / physiopathology*
  • Immunohistochemistry
  • Interleukin-1 / pharmacology
  • Interleukin-1 / physiology*
  • Kidney Diseases / etiology
  • Kidney Diseases / physiopathology*
  • Kidney Failure, Chronic / etiology
  • Kidney Failure, Chronic / physiopathology
  • Kidney Tubules / cytology
  • Kidney Tubules / physiology*
  • Microscopy, Electron
  • Muscle, Smooth / chemistry
  • Rats


  • Actins
  • Cadherins
  • Interleukin-1