title: Interleukin-15 plays a central role in human kidney physiology and cancer through the γc signaling pathway.
abstract: 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-15Rαβγc 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 γc-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 γc-receptor and JAK3 associated kinase, which strongly impacts IL-15 signaling. Indeed, in the absence of the γc/JAK3 couple we demonstrate the assembly of an unprecedented functional high affinity IL-15Rαβ 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/γc-dependent signaling (STAT5), by co-transfecting γc and JAK3 in RCC, inhibits EMT reversion. In conclusion, these data highlight the central role of IL-15 and γc-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).
authors.affiliation: INSERM UMR 1014, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Giron-Michel
authors.forename: Sandy
authors.initials: S
authors.lastname: Azzi
authors.forename: Krystel
authors.initials: K
authors.lastname: Khawam
authors.forename: Erwan
authors.initials: E
authors.lastname: Mortier
authors.forename: Anne
authors.initials: A
authors.lastname: Caignard
authors.forename: Aurore
authors.initials: A
authors.lastname: Devocelle
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Michela
authors.initials: M
authors.lastname: Croce
authors.forename: Hélène
authors.initials: H
authors.lastname: François
authors.forename: Lola
authors.initials: L
authors.lastname: Lecru
authors.forename: Bernard
authors.initials: B
authors.lastname: Charpentier
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.forename: Bruno
authors.initials: B
authors.lastname: Azzarone
authors.forename: Pierre
authors.initials: P
authors.lastname: Eid
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D053631:Interleukin Receptor Common gamma Subunit / Q000378:metabolism*; D019409:Interleukin-15 / Q000378:metabolism* / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015820:Cadherins; C569274:IL15 protein, human; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15