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

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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 epithelial-myofibroblast transdifferentaation (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.

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    Supported in part by grant no. G13N/18 from the Australian Kidney Foundation and CRCG grant no. 98/33704 from The Hong Kong University.

    Presented in part at the 36th Annual Meeting of the Australian and New Zealand Society of Nephrology, Melbourne, Australia, March 13–16, 2000.

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