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Biochemistry - Immunology - Oncology - Physiology - Urology

Interleukin-15 Plays a Central Role in Human Kidney Physiology and Cancer through the ?c Signaling Pathway
Published: Tuesday, February 21, 2012
Author: Julien Giron-Michel et al.

by Julien Giron-Michel, Sandy Azzi, Krystel Khawam, Erwan Mortier, Anne Caignard, Aurore Devocelle, Silvano Ferrini, Michela Croce, Hélène François, Lola Lecru, Bernard Charpentier, Salem Chouaib, Bruno Azzarone, Pierre Eid

The ability of Interleukin-15 (IL-15) to activate many immune antitumor mechanisms renders the cytokine a good candidate for the therapy of solid tumors, particularly renal cell carcinoma. Although IL-15 is being currently used in clinical trials, the function of the cytokine on kidney's components has not been extensively studied; we thus investigated the role of IL-15 on normal and tumor renal epithelial cells. Herein, we analyzed the expression and the biological functions of IL-15 in normal renal proximal tubuli (RPTEC) and in their neoplastic counterparts, the renal clear cell carcinomas (RCC). This study shows that RPTEC express a functional heterotrimeric IL-15Raß?c complex whose stimulation with physiologic concentrations of rhIL-15 is sufficient to inhibit epithelial mesenchymal transition (EMT) commitment preserving E-cadherin expression. Indeed, IL-15 is not only a survival factor for epithelial cells, but it can also preserve the renal epithelial phenotype through the ?c-signaling pathway, demonstrating that the cytokine possess a wide range of action in epithelial homeostasis. In contrast, in RCC in vitro and in vivo studies reveal a defect in the expression of ?c-receptor and JAK3 associated kinase, which strongly impacts IL-15 signaling. Indeed, in the absence of the ?c/JAK3 couple we demonstrate the assembly of an unprecedented functional high affinity IL-15Raß heterodimer, that in response to physiologic concentrations of IL-15, triggers an unbalanced signal causing the down-regulation of the tumor suppressor gene E-cadherin, favoring RCC EMT process. Remarkably, the rescue of IL-15/?c-dependent signaling (STAT5), by co-transfecting ?c and JAK3 in RCC, inhibits EMT reversion. In conclusion, these data highlight the central role of IL-15 and ?c-receptor signaling in renal homeostasis through the control of E-cadherin expression and preservation of epithelial phenotype both in RPTEC (up-regulation) and RCC (down-regulation).