Inhibition of phorbol ester-induced monocytic differentiation and c-fms
gene expression by dexamethasone: potential involvement of arachidonic acid
metabolites
RM Stone, K Imamura, R Datta, ML Sherman and DW Kufe
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, MA 02115.
The treatment of human U-937 leukemia cells with 12-O-
tetradecanoylphorbol-13-acetate (TPA) is associated with induction of
monocytic differentiation. However, the signaling pathways responsible for
induction of the differentiated monocytic phenotype remain unclear. The
present studies demonstrate that dexamethasone blocks TPA-induced U- 937
cell growth inhibition, adherence, and alpha-naphthyl acetate esterase
staining. The results also demonstrate that dexamethasone inhibits the
appearance of c-fms transcripts associated with TPA treatment. Run-on
transcription assays demonstrated that the c-fms gene is transcriptionally
active in uninduced U-937 cells and that the rate of transcription is
unchanged after dexamethasone and/or TPA treatment. These findings
indicated that TPA increases c-fms expression by a dexamethasone-sensitive
posttranscriptional mechanism. Treatment of U- 937 cells with TPA was also
associated with stimulation of arachidonic acid metabolism. Furthermore,
dexamethasone, an inhibitor of phospholipase A2 activity, blocked
TPA-induced increases in arachidonic acid release. These findings suggested
that TPA may regulate certain features of monocytic differentiation, such
as c-fms gene expression, through the formation of arachidonic acid
metabolites. Indomethacin, an inhibitor of cyclooxygenase, had no
detectable effect on c-fms gene expression. However, the cyclooxygenase
metabolite, prostaglandin E2, inhibited the TPA-induced increases in c-fms
mRNA levels. Taken together, the results indicate that TPA regulates c-fms
gene expression by a dexamethasone-sensitive mechanism and that c-fms mRNA
levels are controlled by metabolites of the arachidonic acid pathway.
Volume 76,
Issue 6,
pp. 1225-1232,
09/15/1990
Copyright © 1990 by The American Society of Hematology
