Differential STAT3, STAT5, and NF-kappaB activation in human hematopoietic progenitors by endogenous interleukin-15: implications in the expression of functional molecules.
Different forms of interleukin-15 (IL-15) have been identified and shown to elicit different transduction pathways whose impact on hematopoiesis is poorly understood. We demonstrated herein that hematopoietic CD34+ cells constitutively produced endogenous secreted IL-15 (ES-IL-15) that activated different transcription factors and controlled the expression of several functional proteins, depending on the progenitor source. Thus, nuclear factor-kappa B (NF-kappa B) was activated in bone marrow (BM) and cord blood (CB) progenitors, whereas signal transducer and activator of transcription 3 (STAT3) and STAT5 activation was restricted to peripheral granulocyte-colony-stimulating factor (G-CSF)-mobilized and BM progenitors, respectively. ES-IL-15 acts through autocrine/paracrine loops controlled by high-affinity receptors involving IL-15 receptor alpha (IL-15Ralpha). Furthermore, ES-IL-15 was found to differentially control the expression of several functional molecules important for hematopoietic differentiation. Indeed, in BM precursors, neutralizing anti-IL-15 monoclonal antibody (mAb) inhibits the expression of the gamma c chain and of the chemokine stromal derived factor-1 (SDF-1) but had no effect on vascular cell adhesion molecule 1 (VCAM-1) and beta1 integrin adhesion molecule expression. Conversely, in CB progenitors, anti-IL-15 mAb inhibited VCAM-1 and beta1 integrin expression without affecting gammac chain expression and, most important, up-regulated SDF-1 expression. In conclusion, unprimed human hematopoietic CD34+ cells secrete cell-unbound IL-15, which activates through autocrine/paracrine loop distinct signaling pathways, depending on the progenitor source, thereby influencing the expression of several molecules important in the control of hematopoiesis.
Giron-Michel
Julien
J
U 506 INSERM, Bâtiment Lavoisier, Hôpital Paul Brousse, 94807 Villejuif, France.
Caignard
Anne
A
Fogli
Manuela
M
Brouty-Boyé
Daniele
D
Briard
Diane
D
van Dijk
Marc
M
Meazza
Raffaella
R
Ferrini
Silvano
S
Lebousse-Kerdilès
Caroline
C
Clay
Denis
D
Bompais
Heidi
H
Chouaib
Salem
S
Péault
Bruno
B
Azzarone
Bruno
B
D000328:Adult; D018952:Antigens, CD34; D001854:Bone Marrow Cells; D002450:Cell Communication; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005312:Fetal Blood; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology*; D008894:Milk Proteins; D016328:NF-kappa B / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D019012:Integrin beta1; D019409:Interleukin-15; D008894:Milk Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor