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-Selective Compounds in Mouse Thymocytes through a Novel Apoptosis
Pathway
Departments of
Biochemistry (Z.S., R.T., L.F.) and
Clinical
Chemistry (E.A.), University Medical School of Debrecen, Hungary,
H-4012, and
Centre International de Recherches Dermatologiques
Galderma, 06902 Sophia Antipolis Cedex, France (U.R., J.-M.B., S.M.,
P.A.)
Retinoic acids are morphogenic signaling molecules that are derived
from vitamin A and involved in a variety of tissue functions. Two
groups of their nuclear receptors have been identified: retinoic acid
receptors (RARs) and retinoic acid X receptors (RXRs).
All-trans retinoic acid is the high affinity ligand for
RARs, and 9-cis retinoic acid also binds to RXRs with
high affinity. In cells at high concentrations,
all-trans retinoic acid can be converted to
9-cis retinoic acid via unknown mechanisms. It was
previously shown that retinoic acids prevents activation-induced death
of thymocytes. Here, we report that both all-trans and
9-cis retinoic acid induce apoptosis of mouse thymocytes
and purified CD4+CD8+ cells in ex
vivo cultures, with 9-cis retinoic acid being 50 times more effective. The induction of apoptosis by retinoic acids is
mediated by RAR
because (a) the phenomenon can be reproduced only by
RAR-selective retinoic acid analogs, (b) the cell death induced by
either retinoic acids or RAR analogs can be inhibited by
RAR-specific antagonists, and (c) CD4+CD8+
thymocytes express RAR. In vivo administration of an
RAR analog resulted in thymus involution with the concomitant
activation of the apoptosis-related endonuclease and induction of
tissue transglutaminase. The RAR pathway of apoptosis is RNA and
protein synthesis dependent, affects the
CD4+CD8+ double positive thymocytes, and can be
inhibited by the addition of either Ca2+ chelators or
protease inhibitors. Using various RAR- and RXR-specific analogs and
antagonists, it was demonstrated that stimulation of RAR
inhibits
the RAR-specific death pathway (which explains the lack of apoptosis
stimulatory effects of all-trans retinoic acid at
physiological concentrations) and that costimulation of the RXR
receptors (in the case of 9-cis retinoic acid) can
neutralize this inhibitory effect. It is suggested that formation of
9-cis retinoic acid may be a critical element in
regulating both the positive selection and the "default cell death
pathway" of thymocytes.
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