Inhibition of TGF-β1 Signaling by IL-15

A Novel Role for IL-15 in the Control of Renal Epithelial-Mesenchymal Transition: IL-15 Counteracts TGF-β1-Induced EMT in Renal Fibrosis

Aurore Devocelle, Lola Lecru, Hélène François, Christophe Desterke, Cindy Gallerne, Pierre Eid, Oberlin Estelle, Bruno Azzarone, Julien Giron-Michel

Research output: Contribution to journalArticle

Abstract

Renal tubulointerstitial fibrosis is the final common pathway in end-stage renal disease and is characterized by aberrant accumulation of extracellular matrix (ECM) components secreted by myofibroblasts. Tubular type 2 EMT, induced by TGF-β, plays an important role in renal fibrosis, by participating directly or indirectly in myofibroblasts generation. TGF-β1-induced apoptosis and fibrosis in experimental chronic murine kidney diseases are concomitantly associated with an intrarenal decreased expression of the IL-15 survival factor. Since IL-15 counteracts TGF-β1 effects in different cell models, we analyzed whether (1) human chronic inflammatory nephropathies evolving towards fibrosis could be also characterized by a weak intrarenal IL-15 expression and (2) IL-15 could inhibit epithelial-mesenchymal transition (EMT) and excess matrix deposition in human renal proximal tubular epithelial cells (RPTEC). Our data show that different human chronic kidney diseases are characterized by a strong decreased expression of intrarenal IL-15, which is particularly relevant in diabetic nephropathy, in which type 2 tubular EMT plays an important role in fibrosis. Moreover, primary epithelial tubular cultures deprived of growth supplements rapidly produce active TGF-β1 inducing a "spontaneous" EMT process characterized by the loss of membrane-bound IL-15 (mbIL-15) expression. Both "spontaneous" EMT and recombinant human (rh) TGF-β1-induced EMT models can be inhibited by treating RPTEC and HK2 cells with rhIL-15. Through a long-lasting phospho-c-jun activation, IL-15 inhibits rhTGF-β1-induced Snail1 expression, the master inducer of EMT, and blocks TGF-β1-induced tubular EMT and downstream collagen synthesis. In conclusion, our data suggest that intrarenal IL-15 could be a natural inhibitor of TGF-β in human kidney able to guarantee epithelial homeostasis and to prevent EMT process. Thus, both in vivo and in vitro an unbalance in intrarenal IL-15 and TGF-β1 levels could render RPTEC cells more prone to undergo EMT process. Exogenous IL-15 treatment could be beneficial in some human nephropathies such as diabetic nephropathy.

Original languageEnglish
Pages (from-to)9151394
JournalInternational Journal of Cell Biology
Volume2019
DOIs
Publication statusPublished - 2019

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Interleukin-15
Epithelial-Mesenchymal Transition
Fibrosis
Kidney
Myofibroblasts
Epithelial Cells
Diabetic Nephropathies
Chronic Renal Insufficiency
Chronic Kidney Failure
Extracellular Matrix
Homeostasis
Collagen
Apoptosis

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Inhibition of TGF-β1 Signaling by IL-15 : A Novel Role for IL-15 in the Control of Renal Epithelial-Mesenchymal Transition: IL-15 Counteracts TGF-β1-Induced EMT in Renal Fibrosis. / Devocelle, Aurore; Lecru, Lola; François, Hélène; Desterke, Christophe; Gallerne, Cindy; Eid, Pierre; Estelle, Oberlin; Azzarone, Bruno; Giron-Michel, Julien.

In: International Journal of Cell Biology, Vol. 2019, 2019, p. 9151394.

Research output: Contribution to journalArticle

Devocelle, Aurore ; Lecru, Lola ; François, Hélène ; Desterke, Christophe ; Gallerne, Cindy ; Eid, Pierre ; Estelle, Oberlin ; Azzarone, Bruno ; Giron-Michel, Julien. / Inhibition of TGF-β1 Signaling by IL-15 : A Novel Role for IL-15 in the Control of Renal Epithelial-Mesenchymal Transition: IL-15 Counteracts TGF-β1-Induced EMT in Renal Fibrosis. In: International Journal of Cell Biology. 2019 ; Vol. 2019. pp. 9151394.
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T2 - A Novel Role for IL-15 in the Control of Renal Epithelial-Mesenchymal Transition: IL-15 Counteracts TGF-β1-Induced EMT in Renal Fibrosis

AU - Devocelle, Aurore

AU - Lecru, Lola

AU - François, Hélène

AU - Desterke, Christophe

AU - Gallerne, Cindy

AU - Eid, Pierre

AU - Estelle, Oberlin

AU - Azzarone, Bruno

AU - Giron-Michel, Julien

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AB - Renal tubulointerstitial fibrosis is the final common pathway in end-stage renal disease and is characterized by aberrant accumulation of extracellular matrix (ECM) components secreted by myofibroblasts. Tubular type 2 EMT, induced by TGF-β, plays an important role in renal fibrosis, by participating directly or indirectly in myofibroblasts generation. TGF-β1-induced apoptosis and fibrosis in experimental chronic murine kidney diseases are concomitantly associated with an intrarenal decreased expression of the IL-15 survival factor. Since IL-15 counteracts TGF-β1 effects in different cell models, we analyzed whether (1) human chronic inflammatory nephropathies evolving towards fibrosis could be also characterized by a weak intrarenal IL-15 expression and (2) IL-15 could inhibit epithelial-mesenchymal transition (EMT) and excess matrix deposition in human renal proximal tubular epithelial cells (RPTEC). Our data show that different human chronic kidney diseases are characterized by a strong decreased expression of intrarenal IL-15, which is particularly relevant in diabetic nephropathy, in which type 2 tubular EMT plays an important role in fibrosis. Moreover, primary epithelial tubular cultures deprived of growth supplements rapidly produce active TGF-β1 inducing a "spontaneous" EMT process characterized by the loss of membrane-bound IL-15 (mbIL-15) expression. Both "spontaneous" EMT and recombinant human (rh) TGF-β1-induced EMT models can be inhibited by treating RPTEC and HK2 cells with rhIL-15. Through a long-lasting phospho-c-jun activation, IL-15 inhibits rhTGF-β1-induced Snail1 expression, the master inducer of EMT, and blocks TGF-β1-induced tubular EMT and downstream collagen synthesis. In conclusion, our data suggest that intrarenal IL-15 could be a natural inhibitor of TGF-β in human kidney able to guarantee epithelial homeostasis and to prevent EMT process. Thus, both in vivo and in vitro an unbalance in intrarenal IL-15 and TGF-β1 levels could render RPTEC cells more prone to undergo EMT process. Exogenous IL-15 treatment could be beneficial in some human nephropathies such as diabetic nephropathy.

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