IL-15 is produced by a subset of human melanomas, and is involved in the regulation of markers of melanoma progression through juxtacrine loops.
IL-15 is a novel cytokine active through the IL-2R/betagamma. Since several human melanoma cell lines display functional IL-2Rs, we studied the IL-15/melanoma cells interactions. Ten out of 17 melanoma cell lines express the IL-15 transcript and four of them express levels of IL-15 mRNA similar to those detected in control activated monocytes. Nine out of ten cell lines also express two transcripts for the IL-15R alpha originated by the alternative splicing of exon'3'. Two melanoma cell lines, MELP and MELREO, derived from patients with rapidly progressive primary melanomas, co-express the two IL-15 transcripts, originated by alternative splicing of exon 'A'. Intracellular IL-15 protein was only detected in these two cells lines and it is mainly retained in the Endoplasmic Reticulum (ER). However, a small amount of IL-15 is also found in the Golgi apparatus and in the early endosomes, suggesting production and intercellular trafficking of endogenous IL-15 protein. Nevertheless, no biologically active IL-15 could be detected in the supernatant of all melanoma cells. The anti IL-15 blocking mAb M111 causes the up regulation of HLA Class I in dense MELP and MELREO cultures. These data suggest that IL-15 is probably active through juxtacrine loops negatively controlling HLA Class I molecules expression. These data offer, for the first time, a likely explanation to the controversial issue of IL-15 secretion and constitute a natural model for understanding IL-15 routing. Moreover, we identify a subset of melanoma cells producing IL-15, possibly involved in tumor escape mechanisms.
Barzegar
C
C
U268 INSERM Hôpital Paul Brousse, Villejuif, France.
Meazza
R
R
Pereno
R
R
Pottin-Clemenceau
C
C
Scudeletti
M
M
Brouty-Boyé
D
D
Doucet
C
C
Taoufik
Y
Y
Ritz
J
J
Musselli
C
C
Mishal
Z
Z
Jasmin
C
C
Indiveri
F
F
Ferrini
S
S
Azzarone
B
B
D014408:Biomarkers, Tumor; D003470:Culture Media; D018450:Disease Progression; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction / Q000379:methods; D012313:RNA; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000235:genetics; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D003470:Culture Media; D015395:Histocompatibility Antigens Class I; C508024:IL15RA protein, human; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D012313:RNA