Interleukin‐15 and hematopoiesis

Julien Giron‐Michel; Danièle Brouty‐Boyé; M.‐C. Le Bousse‐Kerdilès; Anne Caignard; Salem Chouaib; Bruno Azzarone



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Interleukin‐15 and hematopoiesis
Hématologie. Volume 10, Number 2, 135-45, Mars-Avril 2004, Revue
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Author(s) : Julien Giron‐Michel, Danièle Brouty‐Boyé, M.‐C. Le Bousse‐Kerdilès, Anne Caignard, Salem Chouaib, Bruno Azzarone
Summary : Interleukin‐15 (IL‐15) is a cytokine present under different forms (secreted, membrane‐bound, intracytoplasmic and nuclear) mediating different functions. Its receptor is composed of three chains (IL‐15Rα\\β\\γc) displaying several different functional associations (IL‐15Rα, IL‐15Rα\\β\\γc, IL‐15Rβ\\γc, IL‐15Rα\\γc). IL‐15 is considered the most powerful physiological inducer of the differentiation of human hematopoietic progenitors (HP) into NK cells. It is likely that IL‐15 could display a broader spectrum of regulatory functions on hematopoiesis more important than it has been previously suspected. Unprimed HP CD34 ⁺ cells constitutively secrete an endogenous, IL‐15 (ES‐IL‐15) that controls, through autocrine\\paracrine loops, several transcription factors and molecules playing a central role in the control of hematopoiesis. Nevertheless,ES‐IL‐15 is not competent for triggering HP differentiation into NK cells, likely due to the presence of a novel hybrid receptor composed of the γc and the GM‐CSFRβ able to interfere on the signals of both IL‐15 and GM‐CSF. Finally, a novel type of membrane‐bound IL‐15 (IL‐15mb) is expressed on human stromal spleen (derived myofibroblasts) and retained on the surface by the IL‐15Rβ\\γc complex. Contact with this IL‐15mb: 1) is necessary and sufficient for inducing the differentiation of circulating HP into cytolytic NK cells\; 2) modifies the signalling pathways controlled by the ES‐IL‐15 in CB HP. Furthermore, IL‐15mb signalling is heavily conditioned by the presence on surrounding cells of the IL‐15Rα chain that activates some pathways (NFκB and STAT6), while inhibiting other (STAT3 et STAT5) that play a key role in the control of myelopoiesis. IL‐15, through the cross‐talk between its different forms and the different composition of IL‐15R, could be one of the important regulatory factors of normal hematopoiesis. Alterations of these interactions could generate not only dysmyelopoiesis, but also survival and expansion of some leukemic clones.
Keywords : IL‐15, GM‐CSF, IL‐15R, signal transduction