Membrane-bound and soluble IL-15/IL-15Ralpha complexes display differential signaling and functions on human hematopoietic progenitors.
Membrane-bound and soluble interleukin-15 (IL-15)/IL-15 receptor alpha (Ralpha) complexes trigger differential transcription factor activation and functions on human hematopoietic progenitors. Indeed, human spleen myofibroblasts (SMFs) are characterized by a novel mechanism of IL-15 trans-presentation (SMFmb [membrane-bound]-IL-15), based on the association of an endogenous IL-15/IL-15Ralpha complex with the IL-15Rbetagamma c chains. SMFmb-IL-15 (1) induces lineage-specific signaling pathways that differ from those controlled by soluble IL-15 in unprimed and committed normal progenitors; (2) triggers survival and proliferation of leukemic progenitors expressing low-affinity IL-15R (M07Sb cells); (3) causes only an antiapoptotic effect on leukemic cells expressing high-affinity receptors (TF1beta cells). This behavior is likely due to the IL-15Ralpha chain present on these cells that interact with the SMFmb-IL-15, inhibiting signal transducer and transcriptional activator 5 (STAT5) activation. On the other hand, the soluble IL-15/IL-15Ralpha complex (hyper IL-15) displays a dominant pattern of action, activating only those cells expressing low-affinity IL-15R (IL-15Rbetagamma c). Thus, hyper IL-15 induces antiapoptotic effects on M075b cells and the up-regulation of STAT6 activation on adult peripheral blood (PB) pre-natural killer (NK) committed progenitors. The latter effect using 100-fold concentrations of recombinant (r)-IL-15. In conclusion, SMFmb-IL-15 and soluble IL-15Ralpha/IL-15 complexes seem to play a pivotal role in the control of the survival, proliferation and differentiation of both normal and leukemic circulating progenitors, highlighting new functions of IL-15 and of IL-15Ralpha.
Medicina Istituto Gaslini and the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Julien
J
Giron-Michel
Massimo
M
Giuliani
Manuela
M
Fogli
Danièle
D
Brouty-Boyé
Silvano
S
Ferrini
Florence
F
Baychelier
Pierre
P
Eid
Caroline
C
Lebousse-Kerdilès
Deniz
D
Durali
Roberto
R
Biassoni
Bernard
B
Charpentier
Aimé
A
Vasquez
Salem
S
Chouaib
Anne
A
Caignard
Lorenzo
L
Moretta
Bruno
B
Azzarone
D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D019409:Interleukin-15 / Q000378:metabolism*; D018613:Microscopy, Confocal; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors
D018952:Antigens, CD34; D016207:Cytokines; C508024:IL15RA protein, human; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors