Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal homeostasis.

Experiments in IL-15(-/-) and IL-15Rα(-/-) mice show that intra-renal IL-15, through IL-15Rα behaves as an epithelial survival factor. Recent data highlight new functions of IL-15 in renal homeostasis mediated by IL-15Rγ (CD132). Indeed, in CD132+ renal epithelial tubular cells IL-15 preserves E-cadherin expression inhibiting epithelial-mesenchymal transition (EMT). By contrast, during allograft rejection, the increased intra-graft IL-15 expression favors tubular destruction facilitating the intraepithelial recruitment of CD8 T cells expressing the E-cadherin ligand CD103. In renal cancer, loss of CD132 by epithelial cells defines a tumoral microenvironment where IL-15 triggers E-cadherin down-regulation and EMT. Finally, in CD132+ renal cancer stem cells IL-15 induces the generation of non-tumorigenic epithelial cells sensitive to cytotoxic drugs. These findings are discussed in the light of IL-15-based immunotherapy for renal cancer.

Giron-Michel J ，Azzi S ，Ferrini S ，Chouaib S ，Camussi G ，Eid P ，Azzarone B ... -  《-》

Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal cancer.

Giron-Michel J ，Azzi S ，Khawam K ，Caignard A ，Devocelle A ，Perrier A ，Chouaib S ，Eid P ，Azzarone B ... -  《-》

Tubulitis in renal allograft rejection: role of transforming growth factor-beta and interleukin-15 in development and maintenance of CD103+ intraepithelial T cells.

Wong WK ，Robertson H ，Carroll HP ，Ali S ，Kirby JA ... -  《TRANSPLANTATION》

Human renal cancer cells express a novel membrane-bound interleukin-15 that induces, in response to the soluble interleukin-15 receptor alpha chain, epithelial-to-mesenchymal transition.

Khawam K ，Giron-Michel J ，Gu Y ，Perier A ，Giuliani M ，Caignard A ，Devocelle A ，Ferrini S ，Fabbi M ，Charpentier B ，Ludwig A ，Chouaib S ，Azzarone B ，Eid P ... -  《-》

Human Renal Normal, Tumoral, and Cancer Stem Cells Express Membrane-Bound Interleukin-15 Isoforms Displaying Different Functions.

Intrarenal interleukin-15 (IL-15) participates to renal pathophysiology, but the role of its different membrane-bound isoforms remains to be elucidated. In this study, we reassess the biology of membrane-bound IL-15 (mb-IL-15) isoforms by comparing primary cultures of human renal proximal tubular epithelial cells (RPTEC) to peritumoral (ptumTEC), tumoral (RCC), and cancer stem cells (CSC/CD105(+)). RPTEC express a 14 to 16 kDa mb-IL-15, whose existence has been assumed but never formally demonstrated and likely represents the isoform anchored at the cell membrane through the IL-15 receptor α (IL-15Rα) chain, because it is sensitive to acidic treatment and is not competent to deliver a reverse signal. By contrast, ptumTEC, RCC, and CSC express a novel N-hyperglycosylated, short-lived transmembrane mb-IL-15 (tmb-IL-15) isoform around 27 kDa, resistant to acidic shock, delivering a reverse signal in response to its soluble receptor (sIL-15Rα). This reverse signal triggers the down-regulation of the tumor suppressor gene E-cadherin in ptumTEC and RCC but not in CSC/CD105(+), where it promotes survival. Indeed, through the AKT pathway, tmb-IL-15 protects CSC/CD105(+) from non-programmed cell death induced by serum starvation. Finally, both mb-IL-15 and tmb-IL-15 are sensitive to metalloproteases, and the cleaved tmb-IL-15 (25 kDa) displays a powerful anti-apoptotic effect on human hematopoietic cells. Overall, our data indicate that both mb-IL-15 and tmb-IL-15 isoforms play a complex role in renal pathophysiology downregulating E-cadherin and favoring cell survival. Moreover, "apparently normal" ptumTEC cells, sharing different properties with RCC, could contribute to organize an enlarged peritumoral "preneoplastic" environment committed to favor tumor progression.

Azzi S ，Gallerne C ，Romei C ，Le Coz V ，Gangemi R ，Khawam K ，Devocelle A ，Gu Y ，Bruno S ，Ferrini S ，Chouaib S ，Eid P ，Azzarone B ，Giron-Michel J ... -  《NEOPLASIA》