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Research Communications |
-induced apoptosis
* Molecular Pharmacology Lab, University of Milan, 20133-Milan, Italy; and
Department Animal Biology and CNR Center for Study on Histochemistry, University of Pavia, 27100-Pavia, Italy
1Correspondence: MPL, Institute of Pharmacological Sciences, via Balzaretti, 9 Milan-20133 Italy. E-mail: adriana.maggi{at}unimi.it
Induction of apoptosis of mononucleated cells is a physiological process
for regulating the intensity of the immune response. The female steroid
hormones estrogen (E2) and progesterone (Prog) are known to
modulate the reactivity of the immune system; recently it has been
demonstrated that they can regulate induction of apoptosis of
endothelial cells and osteoblasts. TNF-
-mediated induction of
apoptosis has been well characterized in myeloid cells. We investigated
whether E2 and Prog could interfere with TNF--induced
apoptosis of the monoblastoid U937 cell line. Treatment with
E2 or Prog increased survival and prevented apoptosis
induced by TNF- in both undifferentiated and macrophage-like
PMA-differentiated U937 cells, as assessed by trypan blue exclusion
cell counting, thymidine incorporation, AnnexinV labeling, followed by
flow cytometry and DNA fragmentation studies. This effect can be
associated with the activation of specific hormone receptors, since we
observed the expression of the estrogen receptor (ER-), ER-ß,
and progesterone receptor (PR) mRNAs; the ER- protein expression
was confirmed by immunocytochemical analysis. In addition,
hormone-mediated survival against apoptosis was concentration
dependent, reaching the half-maximal effect at 10 nM and blocked by the
ER antagonist ICI 182,780 in undifferentiated cells, further supporting
a receptor-mediated mechanism of cell survival. Other steroid receptor
drugs such as Raloxifene, RU486, or the ICI 182,780 in
PMA-differentiated cells displayed agonist activity by preventing
TNF--induced apoptosis as efficiently as the hormones alone,
providing further evidence to the notion that steroid receptor drugs
may manifest agonist or antagonist activities depending on the cellular
context in which they are studied. Treatment with E2 was
also associated with a time-dependent decrease in the mRNA level of the
proapoptotic Nip-2 protein, supporting the hypothesis that hormone
responsiveness of U937 cells is mediated by target gene transcription.
Together, these results demonstrate that ER and PR can be activated by
endogenous or exogenous ligands to induce a genetic response that
impairs TNF--induced apoptosis in U937 cells. The data presented
here suggest that the female steroid receptors play a role in
regulation of the immune response by preventing apoptosis of
monoblastoid cells; this effect might have important consequences in
the clinical use of steroid receptor drugs.—Vegeto, E., Pollio, G.,
Pellicciari, C., Maggi, A. Estrogen and progesterone induction of
survival of monoblastoid cells undergoing TNF--inuced apoptosis.
Key Words: estrogen receptor • progesterone receptor • U937 cells • TNF- • apoptosis
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