Tumor necrosis factor and human hematopoiesis: I. Kinetics and diversity of human bone marrow cell response to recombinant tumor necrosis factor alpha in short-term suspension cultures in vitro.
The response of normal human bone marrow-derived granulocyte macrophage progenitor cells (GM-CFC) to human recombinant tumor necrosis factor alpha (TNF-alpha) was studied in short-term suspension cultures, in the presence or absence of human placenta-derived colony-stimulating factors (CSF). The effect of rTNF-alpha on GM-CFC was correlated with its influence on more mature progeny, as defined by standard morphological criteria, and was related to both dose of rTNF-alpha and length of exposure. After very short-term exposure (2 h), "inactivation" of a substantial number of GM-CFC was observed only in the presence of very high rTNF-alpha doses (1 x 10(4) ng/ml). When the exposure was prolonged to 16 h, a significant killing of both day 8 (GM-CFC8d) and day 14 (GM-CFC14d) progenitor cells was detected in the presence of 10 ng of rTNF-alpha/ml. Exposure for 5 days resulted in a further increase in the GM-CFC killing. Presence of yet unknown factor(s) in human placenta-conditioned medium sensitized GM-CFC to the action of rTNF-alpha. By morphological analysis of marrow cells, it was found that rTNF-alpha inhibited growth and/or recruitment of granulocytic precursor cells and caused inhibition of their differentiation. This effect was not dose dependent above 1 x 10(1) ng/ml. The presence of rTNF-alpha slightly promoted dose-dependent differentiation along the macrophage pathway. rTNF-alpha appeared to promote eosinophilic differentiation, also in a dose-dependent manner.
Beran
M
M
Department of Hematology/Leukemia, University of Texas M.D. Anderson Hospital, Houston 77030.
O'Brien
S
S
Gutterman
J U
JU
McCredie
K B
KB
D003115:Colony-Stimulating Factors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects*; D010586:Phagocytes / Q000187:drug effects*; D011994:Recombinant Proteins; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics*
D003115:Colony-Stimulating Factors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha