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

Abstract

We have previously shown that tumor necrosis factor-α (TNFα) 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 TNFα displays inhibitory effects. Thus, TNFα 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. TIMFα was demonstrated to reversibly block granulocytic differentiation at the level of uncommitted CD13- , CD15- blast cells that accumulate in IL-3 + TNFα cultures. Furthermore, growth of committed granulocytes(CD15+) from IL-3 cultures was also inhibited by TNFα through an arrest of cell cycle in G0/G1. Finally, the use of neutralizing anti-TIMFα monoclonal antibody and limiting dilution studies indicate that the inhibitory effects of TNFα are direct. Taken together, our data demonstrate that, following a phase of potentiation of proliferation of early HPC, TNFα displays direct inhibitory effects due to negative interference with both granulocytic differentiation and proliferation of granulocytic cells. © 1991 by The American Society of Hematology.