RGD Reference Report - Thiorphan-induced survival and proliferation of rat thymocytes by activation of Akt/survivin pathway and inhibition of caspase-3 activity. - Rat Genome Database

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Thiorphan-induced survival and proliferation of rat thymocytes by activation of Akt/survivin pathway and inhibition of caspase-3 activity.

Authors: Amantini, C  Mosca, M  Lucciarini, R  Perfumi, MC  Santoni, G 
Citation: Amantini C, etal., J Pharmacol Exp Ther. 2008 Oct;327(1):215-25. Epub 2008 Jul 11.
RGD ID: 2304262
Pubmed: PMID:18621988   (View Abstract at PubMed)
DOI: DOI:10.1124/jpet.108.138719   (Journal Full-text)

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 (NK(1)R)-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 NK(1)R mRNA expression as well as SP and NK(1)R protein levels in an NK(1)R-dependent manner. Thiorphan increased CD10(+)CD4(+) and CD10(+)DP thymocyte numbers, and an NK(1)R 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 alpha chain expression, and concanavalin A-induced proliferation of CD5(+) thymocytes, and it inhibited spontaneous and NK(1)R-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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of lymphocyte proliferation  IMP 2304262; 2304262 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Tac1  (tachykinin, precursor 1)
Tacr1  (tachykinin receptor 1)


Additional Information