Tumor necrosis factor alpha cooperates with interleukin 3 in the recruitment of a primitive subset of human CD34+ progenitors.

Abstract

SummaryWe have recently demonstrated that tumor necrosis factor ol (TNF-ot) potentiates interleukin 3 (IL-3)-and granulocyte/macrophage colony-stimulating factor-induced growth of CD34 + hematopoietic progenitor cells (HPC), and favors the generation of dendritic/Langerhans cells. The stimulatory effect of TNF-ot was detailed in the present study. Thus, CD34 + HPC entering in cycle (S/G2M) after a 48-h pulse with IL-3 expressed the transferrin receptor (TfR), and fluorescence-activated cell sorter-separated TfR + HPC, but not TIP,-HPC, showed a high proliferative response to IL-3. In contrast, TfR-HPC were found to undergo strong proliferation in response to IL-3 + TNF-cz. Limiting dilution experiments indicated that TNF-cz increased both the frequency and the average size of clones generated from TfR-HPC as a result of the development of a higher number of large clones. In contrast, TNF-ot did not enhance the IL-3-dependent proliferation of TfR + HPC. Preculturing CD34 + HPC for 48 h with TNF-ot enhanced the subsequent generation of IL-3-dependent colony-forming units. Precultures with TNF-a or cultures with suboptimal doses of TNF-cz allowed the recruitment of cells with both granulocytic and monocytic differentiation potential. Taken together, our results indicate that TNF-ot recruits a subpopulation of CD34 § HPC hyposensitive to IL-3, with high proliferative capacity and some features of multipotential progenitors, that are likely to be more primitive than those responding to IL-3 alone.

IL-3 in dendritic cell development and function: a comparison with GM-CSF and IL-4

“…IL-3 has been described as a myeloid growth factor (Ihle, 1992). Comparing the generation of DC from human CD34 pos cord blood cells in vitro, IL-3 is similarly potent in raising human myeloid DC when compared with GM-CSF (Caux et al, 1993). Human and murine thymic DC precursor cells seem to be especially unresponsive to GM-CSF but readily expand in culture with a cytokine cocktail containing IL-3 (Kelly et al, 2001;Saunders et al, 1996), possibly indicating that IL-3 but not GM-CSF is required for thymic DC progeny in vivo.…”

An intrinsic thyrotropin-mediated pathway of TNF-α production by bone marrow cells

“…This has been demonstrated with regard to BM-derived Langerhans cells, 23 and for the development of DCs from early progenitor-stage cells. 24 Moreover, that effect may be the consequence of TNF-␣-mediated up-regulation of GM-CSF receptors on DC precursors. 25 Other studies have demonstrated that TNF-␣ plus IL-3 in the absence of GM-CSF can mediate DC development from human cord blood, 26 implying that TNF-␣ can act synergistically with several growth-promoting factors, or possibly that it induces the secretion of other growth-promoting factors, but nonetheless further defining an important role for TNF-␣ in the process of DC development within primary hematopoietic tissues.…”

CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha.

“…rhGM-CSF (specific activity: 2 • 10 a U/rag; Schering-Plough Research Institute, Kenilworth, NJ) was used at a saturating concentration of 100 ng/ml (200 U/ml). rhTNFct (specific activity: 2 • 107 U/rag; Genzyme, Boston, MA) was used at an optimal concentration of 2.5 ng/ml (50 U/ml) (20) rhSCF (specific activity 4 • 105 U/mg; R&D, Abington, UK) and rhM-CSF (specific activity: 2 • 106 U/mg; R&D) were used at optimal concentrations of 25 ng/ml. Umbil-ical cord blood samples were obtained according to institutional guidelines.…”