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-kappaB (NF-kappaB) 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 gammac 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. (C) 2003 by The American Society of Hematology.