Membrane-bound interleukin (IL)-15 on renal tumor cells rescues natural killer cells from IL-2 starvation-induced apoptosis.
Renal cell carcinoma primary tumors and lung metastases are infiltrated by activated natural killer (NK) cells. Interleukin (IL)-15, a major cytokine involved in cross-talk between accessory cells (dendritic cells and macrophages) and NK cells, is produced by epithelial renal cells. We show that renal cell carcinoma cells and normal renal cells express IL-15 mRNA and membrane-bound IL-15 (MbIL-15). These cells also express IL-15 receptor alpha (IL-15Ralpha). Silencing of IL-15Ralpha by specific small interfering RNA in renal cell carcinoma had no effect on MbIL-15 production, indicating that the cytokine is not cross-presented by IL-15Ralpha in renal cell carcinoma cells but anchored to the membrane. Furthermore, we show that MbIL-15 from renal cell carcinoma cells is functional and involved in rapid nuclear translocation of phosphorylated signal transducers and activators of transcription 3 in IL-2-starved NK cells. MbIL-15 on the target did not interfere with resting NK cell activation and target cell cytolysis but rescued NK cells from IL-2 starvation-induced apoptosis through contact-dependent interaction. Masking of MbIL-15 with soluble IL-15Ralpha molecules restored NK cell apoptosis. These findings suggest that IL-15 produced by renal tumor cells is involved in the maintenance of active NK cells at the tumor site.
Wittnebel
Sebastian
S
Institut National de la Santé et de la Recherche Médicale U753, France.
Da Rocha
Sylvie
S
Giron-Michel
Julien
J
Jalil
Abdelali
A
Opolon
Paule
P
Escudier
Bernard
B
Validire
Pierre
P
Khawam
Krystel
K
Chouaib
Salem
S
Azzarone
Bruno
B
Caignard
Anne
A
D017209:Apoptosis / Q000502:physiology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D002462:Cell Membrane / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D019409:Interleukin-15 / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007694:Killer Cells, Natural / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D034741:RNA, Small Interfering; D020239:Receptor Cross-Talk / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D007376:Interleukin-2; D034741:RNA, Small Interfering