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Faculty of Life Sciences, The Gonda-Goldschmied Center, Bar-Ilan University, Ramat-Gan, Israel
Glucocorticoids (GC) are strong inducers of thymocyte apoptosis. In
the present study we looked into the possibility that the neuropeptide
substance P (SP) might serve as an antagonist to GC-induced apoptosis.
Indeed, SP inhibited hydrocortisone (HC)-induced apoptosis of
CD4+CD8+ thymocytes in mice, both in vivo and
in vitro. It also inhibited HC-induced apoptosis in the T cell
hybridoma line 2B4.11, which is sensitive to GC. The inhibitory effect
was complete if SP was given with HC or within 1 h after it;
partial inhibitory effect could be seen at 2 h and no effect at
3 h. The presence of the SP antagonist nullified SP effect. The
effect was specific to both components of the system (i.e., HC as
apoptosis inducer and SP as its inhibitor), as judged from comparison
to three other apoptosis-inducing means (irradiation, thymic epithelial
cells, or retinoic acid), and to two other neuropeptides (somatostatin
and vasoactive intestinal peptide). SP/HC antagonism was further
demonstrated in two relevant molecular events: 1) HC augmented GC
receptor production in our cell system and this was inhibited by SP;
and 2) HC reduced the expression of the transcription factor NF-
B,
SP increased it and when both were present, SP effect dominated. On the
other hand, the level of IB (NF-B inhibitory molecule) was
decreased by SP, preserved at a relatively high level with HC, and when
both SP and HC were present, SP effect dominated. The intensity of SP
effect, both in vivo and in vitro, its specificity, its inhibition by
SP antagonist, as well as the previously documented presence of SP and
its receptor in the thymus suggest that SP might be a physiological
antagonist of the potent thymocyte apoptosis induced by
GC.
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