Potentiation of early hematopoiesis by tumor necrosis factor-alpha is followed by inhibition of granulopoietic differentiation and proliferation

Abstract

We have previously shown that tumor necrosis factor-alpha (TNF alpha) strongly potentiates interleukin-3 (IL-3)-induced short-term proliferation of human CD34+ hematopoietic progenitor cells (HPC). Using longer term cultures of CD34+ HPC, we demonstrate here that this initial potentiation ceases after 10 to 12 days; whereupon TNF alpha displays inhibitory effects. Thus, TNF alpha was found to inhibit cells of granulocytic affiliation while it potentiates the development of maturing cells of the monocytic lineage both in liquid and semi-solid (day 14 colony-forming unit) cultures. TNF alpha was demonstrated to reversibly block granulocytic differentiation at the level of uncommitted CD13-, CD15- blast cells that accumulate in IL-3 + TNF alpha cultures. Furthermore, growth of committed granulocytes (CD15+) from IL-3 cultures was also inhibited by TNF alpha through an arrest of cell cycle in G0/G1. Finally, the use of neutralizing anti-TNF alpha monoclonal antibody and limiting dilution studies indicate that the inhibitory effects of TNF alpha are direct. Taken together, our data demonstrate that, following a phase of potentiation of proliferation of early HPC, TNF alpha displays direct inhibitory effects due to negative interference with both granulocytic differentiation and proliferation of granulocytic cells.

The purification of CD34+ cells from human cord blood: comparison of separation techniques and cytokine requirements for optimal growth of clonogenic progenitors

“…The stimulating role of TNF on CFU-GEMM growth was unexpected. For CFU-GEMM from CD34 cord blood cells Caux et al (1991) found TNF had an inhibitory effect, although with higher concentrations of TNF than in our assay. TNF is a pleiotrophic cytokine and its effect might depend on dose and growth factor combination.…”

Innate immune stimuli modulate bone marrow‐derived dendritic cell production in vitro by toll‐like receptor‐dependent and ‐independent mechanisms

“…39 This proliferative effect was revealed to be short term; after initial proliferation, TNF-a inhibited the in vivo differentiation of granulocytic cells while driving the development of maturing monocytic cells. 40 More recently, Welner et al 28 demonstrated that reduced in vivo B-cell production from lymphoid precursors in response to TLR9 ligation was suppressed by TNF-a, while DC production observed under the same conditions was independent of TNF-a. Taken together, this evidence suggests that although TNF-a can affect the generation of BMDCs, other growth and differentiation factors may be required to generate all the effects observed in this study.…”

Incidence of apoptosis in HIV‐myelopathy, myelodysplastic syndromes and non‐specific inflammatory lesions of the bone marrow

“…Such a hypothetical mechanism could be mediated by the secretion of TNF-a 30,31 by activated macrophages. This cytokine is primarily synthesized by macrophages 32 and known to induce programmed cell death in a variety of target cells 33 , especially haemopoietic progenitor cells [34][35][36][37] . Interestingly, raised serum levels of TNF-a have been described in various inflammatory conditions 30 , in particular rheumatoid arthritis 38 , MDS [39][40][41][42][43][44] and AIDS [45][46][47][48][49][50] .…”