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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Thiorphan-Induced Survival and Proliferation of Rat Thymocytes by Activation of Akt/Survivin Pathway and Inhibition of Caspase-3 Activity

Department of Experimental Medicine and Public Health, University of Camerino, Camerino, Italy

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 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.

Address correspondence to: Dr. Giorgio Santoni, Department of Experimental Medicine and Public Health, University of Camerino, Via Madonna delle Carceri 9, 62032, Camerino, Italy. E-mail: giorgio.santoni{at}unicam.it

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