IL-15 is produced by a subset of human melanomas, and is involved in the regulation of markers of melanoma progression through juxtacrine loops

Barzegar, Cathy; Meazza, Raffaella; Pereno, Raffaele; Pottin-Clemenceau, Corinne; Scudeletti, Marco; Brouty‐Boyé, Danièle; Doucet, Christelle; Taoufik, Yassine; Ritz, Jérôme; Musselli, Cristina; Mishal, Zohar; Jasmin, C; Indiveri, Francesco; Ferrini, Silvano; Azzarone, Bruno

doi:10.1038/sj.onc.1201775

Cited by 40 publications

(48 citation statements)

References 12 publications

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“…It has been suggested that IL-15 should be considered as a juxtacrine factor secreted and e cient in very low amount undetectable by ELISA or biological assays (Alleva et al, 1997;Barzegar et al, 1998). This hypothesis is supported by recent data showing that CD34 + progenitors NK di erentiation involved IL-15, produced in minute quantities by bone marrow stromal cells and required intimate cell/cell contacts (Carson et al, 1994;Mrozek et al, 1996).…”

Section: Discussionmentioning

confidence: 97%

“…The oligonucleotide primers and conditions used for ampli®cations of IL-15R transcripts and control actin were those previously described (Barzegar et al, 1998). The ampli®ed products were analysed after electrophoresis on ethidium bromide agarose gels.…”

Section: Analysis Of Il-15r Transcripts By Rt ± Pcrmentioning

confidence: 99%

“…The standard isoform, characterized by the longer signal peptide, is localized in the endoplasmic reticulum and may be detected in the Golgi apparatus and early endosomes. It follows therefore a pathway leading to its secretion and/or to its expression as a membrane bound biologically active form (Barzegar et al, 1998;Musso et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

et al. 2000

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IL-15 and SCF fail to induce NK di erentiation and proliferation of CD34 + hematopoietic progenitors from chronic myeloid leukemia patients in contrast to normal stem cells although, both normal and leukemic CD34 + cells display comparable expression of c-kit or IL-15 receptor subunits. Interestingly, confocal microscopy analysis revealed that leukemic and most normal CD34 + cells produce and secrete IL-15, as shown by its tra cking through the Golgi apparatus and early endosomes. However, only leukemic progenitors express the membrane bound IL-15. Colocalization and internalization of IL-15Rb/gc and IL-15Ra/gc complexes indicated that IL-15 was speci®cally uptaken by leukemic progenitors. We also demonstrated that in both normal and leukemic progenitors, the signaling kinase Jak3 is constitutively pre-associated with the gc chain. Anti-IL-15 neutralizing mAb treatment resulted in downregulation of gc chain and disruption of gc/Jak3 interaction in normal but had no e ect in leukemic progenitors. Our results suggest the existence in both normal and leukemic CD34 + cells of a constitutive production of a bioactive IL-15 that does not lead to NK di erentiation and further indicate that membrane bound IL-15 and constitutive activation of gc are hallmarks of leukemic progenitors.

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Section: Discussionmentioning

confidence: 97%

Section: Analysis Of Il-15r Transcripts By Rt ± Pcrmentioning

confidence: 99%

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Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

et al. 2000

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“…The IL-15 transcript is widely expressed, but it is di cult to detect IL-15 protein in the supernatant of cells which display the message for this interleukin (Giri et al, 1994;Bamford et al, 1996;Meazza et al, 1996Meazza et al, , 1997Barzegar et al, 1998). This could be explained by the fact that IL-15 synthesis and secretion are controlled both at transcriptional and post-transcriptional level (Bamford et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…(Barzegar et al, 1998). Thus, natural secreted IL-15 could play a relevant role both in physiological and pathological conditions at concentrations that, to date, were not considered to be biologically meaningful (Waldmann and Tagaya, 1999), by acting either as a pericellular cytokine (Shah et al, 1998) or as a membrane bound cytokine (Musso et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα

et al. 2000

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There are two IL-15 isoforms and eight isoforms for the IL-15Ra chain whose biological role is poorly understood. Here, we have analysed the intracellular tra cking of IL-15 and IL-15Ra and tried to shed some light on their function(s). In IL-15/GFP CHO transfectants both IL-15 isoforms show nuclear localization. Two melanoma cell lines (MELP and MELREO) spontaneously expressing the IL-15 isoforms, display di erent intracellular tra cking of the IL-15/IL-15Ra complex. In MELP cells only IL-15Ra is detected inside the nucleus, whereas IL-15 and IL-15Ra assemble at the cell surface and are internalized. Moreover, the transducing molecule TRAF2 co-immunoprecipitates with IL-15Ra and may be de¯ected to TNFRI using anti-IL-15 blocking mAbs and TNF-a. By contrast, MELREO cells display IL15Ra and IL-15 nuclear localization but only a partial co-localization of these molecules on the cell surface. In these cells, TRAF2 is strongly associated with IL-15Ra and cannot be de¯ected by any treatment. Since TRAF2 activates the transcription factor NF-kB, IL-15 through IL-15Ra, could have a role in the control of this pathway. Indeed, anti-IL-15 MaB inhibit the constitutive nuclear localization of NFkB and the phosphorylation of its inhibitor Ik-Ba. Thus, IL-15Ra controls NF-kB activation, however di erences in the intracellular tra cking of the IL-15 and/or IL-15Ra suggest a di erent biological role for this complex in MELP versus MELREO cells. Oncogene (2000) 19, 5153 ± 5162.

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Differential intracellular trafficking, secretion and endosomal localization of two IL-15 isoforms

et al. 1999

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To analyze the intracellular trafficking of two IL-15 isoforms bearing 48- or 21-amino acid leader peptides (L), we have generated cDNA encoding the two proteins fused at the C terminus with green fluorescent protein (GFP). Confocal microscopy analyses showed that, when transfected in CHO cells, 48L IL-15/GFP was localized in the Golgi apparatus and in early endosomes, while 21L IL-15/GFP was detectable only in the cytosol. The presence of 48L IL-15/GFP in endosomes was confirmed by enzyme-linked immunosorbent assay on endosome-enriched subcellular fractions. Exogenous IL-15 was bound and taken up in endosomes by untransfected CHO cells, indicating that endosomal localization was, at least in part, related to a receptor-mediated uptake. The 48L IL-15/GFP fusion protein was efficiently secreted by COS-7 or CHO cell transfectants, while IL-15 secretion was less efficient in transfectants expressing 21L IL-15/GFP or untagged 48L or 21L IL-15. Treatment with brefeldin A or with inhibitors of N-linked glycosylation further indicated that the 48L IL-15/GFP is secreted through the endoplasmic reticulum/Golgi pathway. Our data suggest a different trafficking of the two IL-15 isoforms and multiple mechanisms controlling IL-15 secretion.

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IL-15 is produced by a subset of human melanomas, and is involved in the regulation of markers of melanoma progression through juxtacrine loops

Cited by 40 publications

References 12 publications

Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα

Differential intracellular trafficking, secretion and endosomal localization of two IL-15 isoforms

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