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-κB, SP increased it and when both were present, SP effect dominated. On the other hand, the level of IκB (NF-κB 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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