Specific Inhibition of Glucocorticoid-Induced Thymocyte Apoptosis by Substance P

Abstract

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.

Transformation of breast cells by truncated neurokinin-1 receptor is secondary to activation by preprotachykinin-A peptides

“…Its effectiveness would require detailed pharmacological, biochemical, and molecular studies to determine potential differences between NK1-Tr and NK1-FL recep- tors. It should be noted that the findings reported for NK1-Tr might be similar for other cancers (8,11,24,25). NK1-Tr transfectants and BCCs show similar patterns of cytokine production ( Table 2).…”

“…This could occur by AP-1 inducing rapid cycling of BCCs. Substance P has been shown to protect against cell death (25). Thus, blocking signaling of NK1-Tr with an antagonist might enhance BCC death.…”

The proliferative and antiapoptotic effects of substance P are facilitated by formation of a β-arrestin-dependent scaffolding complex

“…In support of these findings, agonists of the NK1R stimulate proliferation of endothelial cells and protect thymocytes from glucocorticoid-induced apoptosis in vitro and in vivo (33,34). These events may be of importance during neurogenic inflammation, when SP is released from the peripheral endings of primary spinal afferent neurons.…”

TCR signaling inhibits glucocorticoid-induced apoptosis in murine thymocytes depending on the stage of development

“…Recently, it has been shown that upregulation of the GR is associated with cell death induction and failure of upregulation with GC resistance in human leukemic cells [36,37]. Positive autoregulation of the GR has also been reported in GC-sensitive murine T-hybridoma cells [38]. Whether such a mechanism is present in primary murine thymocytes is presently not known.…”