Neonatal Capsaicin Treatment Affects Rat Thymocyte Proliferation and Cell Death by Modulating Substance P and Neurokinin-1 Receptor Expression

Abstract

Herein we provide evidence that substance P (SP) and its neurokinin-1 receptor (NK-1R) expressed on thymocytes counteract thymus depletion induced by neonatal capsaicin (CPS) treatment by affecting thymocyte proliferation and apoptotic death. SP administration reversed the CPS-mediated inhibitory effects on the total thymocyte number and subset distribution, namely CD4+ and CD4– CD8– cells, through its interaction with NK-1R as shown by concomitant NK-1R (SR140333) antagonist administration. SP-induced enhancement of thymus cellularity parallels its ability of inhibiting the thymocyte apoptotic program. Indeed, exogenously administered SP completely nullified CPS-induced apoptosis, and SR140333 abrogated the SP-mediated protective effect. SP administration also stimulated concanavalin A (Con A)-induced thymocyte proliferation of CPS-treated rats, completely reversing the CPS-induced inhibition. The SP-mediated stimulation of Con A-induced thymocyte proliferation was NK-1R dependent as shown by concomitant administration of SP and SR140333 to CPS-treated rats. Our results also demonstrate that CPS treatment induces a marked decrease of thymocyte PPT-A mRNA level and endogenous SP content as evaluated by quantitative RT-PCR, in situ hybridization and cytofluorimetric analysis. By contrast, NK-1R mRNA levels were increased in thymocytes from CPS-treated rats. Exogenous SP administration augmented PPT-A, SP and NK-1R thymocyte expression in CPS-treated rats, and this enhancement was antagonized by SR140333 administration. Overall, our results strongly suggest that the immunomodulatory effects of neonatal CPS treatment on rat thymocyte functions are dependent on vanilloid-mediated regulation of SP and NK-1R functional expression by neuronal and immune cells.

Distinct thymocyte subsets express the vanilloid receptor VR1 that mediates capsaicin-induced apoptotic cell death

“…We have previously reported that neonatal CPS treatment induces apoptosis of rat thymocytes, 4,6 but evidence on the vanilloid receptor(s) mediating these functional effects are still missing. Thus, in order to directly demonstrate VR1 mRNA expression on rat thymocytes, we initially performed real-time quantitative PCR analysis on Ficoll gradient-purified (499%)…”

“…47 We have previously reported that neonatal CPS treatment in the rats results in a marked reduction of thymus weight and cellularity that is associated with decreased thymocyte proliferation in response to T-cell mitogens and induction of apoptotic cell death. 6 However, the molecular mechanisms underlying the proapoptotic effects of CPS on rat thymus are presently unknown.…”

“…[1][2][3][4][5][6] Many of the acute cellular and physiologic effects associated with CPS exposure are mediated by vanilloid receptors that can act as voltage-independent channels. 7 Vanilloid receptors are expressed mainly by primary sensory neurons involved in nociception and neurogenic inflammation.…”

False positive reactivity of a substance P-antibody in the ectodermal/epithelial plug of the nose, ear, eye and perineum of the human and mouse fetuses

“…Therefore, we hypoth- esized that sc9758 cross-reacted with epithelium-related substances produced by the death process. Actually, SP seems to induce cell death by way of the NK-1 receptor (Castro-Obregón et al 2002;Santoni et al 2004;Meshki et al 2009; see also Introduction). We identified NK-1 receptor in most of the sc9758-positive sites.…”

“…Neuropeptide substance P (SP) and its receptor, neurokinin-1 receptor, were first identified by an in vitro study using cultures of rat embryonic nerve cells, and mediate an alternative, non-apoptotic form of programmed cell death (Castro-Obregón et al 2002). SP has killing activity against proliferating non-neuronal cells (Meshki et al 2009;D'Souza et al 2007;Santoni et al 2004). This type of cell death requires gene expression, displays non-apoptotic morphology, and is independent of caspase activation.…”