Diethyldithiocarbamate induction of cytokine release in human long-term
bone marrow cultures
CJ East, CN Abboud and RF Borch
Department of Pharmacology, University of Rochester School of Medicine, NY
14642.
Diethyldithiocarbamate (DDTC) is a biochemical modulating agent that
protects murine bone marrow progenitor cells from the cytotoxicity of a
variety of cancer chemotherapeutic agents. However, the mechanism of this
protection is not well understood. Long-term human bone marrow cultures
(LTBMC) were established and at day 17 treated with 30 mumol/L DDTC for 1
hour, after which DDTC was removed and replaced with complete medium.
Conditioned medium was then collected 6, 12, 24, and 48 hours later and
analyzed for the presence of cytokines. A time- dependent increase in
granulocyte-macrophage colony-stimulating factor (GM-CSF) (12-fold),
granulocyte-CSF (G-CSF) (66-fold), interleukin (IL)- 6, (three-fold), IL-1
beta (161-fold), and tumor necrosis factor (TNF)- alpha (25-fold) was
observed. The maximum increase for the factors other than TNF-alpha was at
24 to 48 hours posttreatment. However, TNF- alpha peaked as early as 6
hours post-DDTC. When conditioned medium from these cultures was tested in
a granulocyte-macrophage progenitor cell (GM-CFC) assay, an increase in
colony formation was observed that correlated with the increased levels of
cytokines in the medium. The specificity of this effect was confirmed by
the fact that the closely related congener bis(hydroxyethyl)dithiocarbamate
was devoid of colony- stimulating activity. The addition of antibodies for
TNF-alpha and/or IL-1 alpha following DDTC treatment did not inhibit the
release of GM- CSF, G-CSF, or IL-6 from the LTBMC. These results suggest
that DDTC accelerates bone marrow recovery following myelotoxic drug
treatment via increased production of cytokines that are known to be
essential for hematopoiesis.
Volume 80,
Issue 5,
pp. 1172-1177,
09/01/1992
Copyright © 1992 by The American Society of Hematology
