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Potentiation of early hematopoiesis by tumor necrosis factor-alpha is
followed by inhibition of granulopoietic differentiation and proliferation
C Caux, C Favre, S Saeland, V Duvert, I Durand, P Mannoni and J Banchereau
Laboratory for Immunological Research, Schering-Plough, Dardilly, France.
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.
Volume 78,
Issue 3,
pp. 635-644,
08/01/1991
Copyright © 1991 by The American Society of Hematology
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