RT Journal Article
SR Electronic
T1 Thiorphan-Induced Survival and Proliferation of Rat Thymocytes by Activation of Akt/Survivin Pathway and Inhibition of Caspase-3 Activity
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 215
OP 225
DO 10.1124/jpet.108.138719
VO 327
IS 1
A1 Consuelo Amantini
A1 Michela Mosca
A1 Roberta Lucciarini
A1 Marina Cecilia Perfumi
A1 Giorgio Santoni
YR 2008
UL http://jpet.aspetjournals.org/content/327/1/215.abstract
AB The activity of substance P (SP) in the rat thymus seems to be tightly controlled by its bioavailability. In this study, we provide evidence for the expression of the SP-degrading enzyme, neutral endopeptidase (NEP)/CD10, by rat thymocyte subsets, and we illustrate its involvement in the in vivo SP/neurokinin-1 receptor (NK1R)-mediated regulation of thymocyte survival and proliferation. NEP/CD10 was expressed at both mRNA and protein levels on a substantial portion (45.5%) of CD5+ thymocytes, namely on the CD4+CD8+ (double positive; DP) and CD4+ subsets. Continuous administration of thiorphan, a specific NEP/CD10 inhibitor, by means of miniosmotic pumps, enhanced rat thymocyte preprotachykinin-A (PPT-A) and NK1R mRNA expression as well as SP and NK1R protein levels in an NK1R-dependent manner. Thiorphan increased CD10+CD4+ and CD10+DP thymocyte numbers, and an NK1R antagonist, (S)1-{2-[3(3-4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)-piperidine-3-yl]ethyl}-4-pheny-1-azoniabicyclo[2.2.2]octane, chloride (SR140333), abrogated these stimulatory effects. In addition, the NEP/CD10 inhibitor stimulated interleukin (IL)-2 production, IL-2 receptor α chain expression, and concanavalin A-induced proliferation of CD5+ thymocytes, and it inhibited spontaneous and NK1R-dependent thymocyte apoptosis. The thiorphan-protective antiapoptotic and proliferative effects involved the activation of Akt serine-threonine kinase, subsequent up-regulation of survivin mRNA, down-regulation of procaspase-3 mRNA levels, and suppression of caspase-3 activity, which were inhibited by SR140333 and mimicked by exogenous SP administration. Overall, our findings suggest that by controlling SP availability, NEP/CD10 negatively regulates thymocyte homeostasis and development. The American Society for Pharmacology and Experimental Therapeutics