Expression of Substance P and Its Neurokinin-1 Receptor on Thymocytes: Functional Relevance in the Regulation of Thymocyte Apoptosis and Proliferation

Santoni, Giorgio; Amantini, Consuelo; Lucciarini, Roberta; Pompei, Pierluigi; Perfumi, Marina; Nabissi, Massimo; Morrone, Stefania; Piccoli, Mario

doi:10.1159/000068327

Cited by 25 publications

(36 citation statements)

References 43 publications

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“…D, thymocytes were stained with FITC-conjugated anti-rat CD4, PE-conjugated anti-rat CD8 mAb, and rabbit anti-rat NEP/CD10 polyclonal Ab, followed by biotin GAR IgG and tricolor-conjugated streptavidin. The expression of CD4 and CD8 antigens was analyzed by flow cytometry on R1-gated CD10 SP levels in an autocrine fashion upon interaction with its receptor NK 1 R (Bae et al, 2002;Santoni et al, 2002). Thus, to assess whether inhibition of SP degradation by in vivo thiorphan administration could affect SP expression on CD5 ϩ rat thymocytes, we determined both the expression of SP precursor PPT-A at the mRNA level and SP protein levels.…”

Section: Resultsmentioning

confidence: 99%

“…SP in the rat thymus not only derives from sensory nerve fiber-mediated axonal transport and release in the thymic microenvironment (Jurjus et al, 1998), but it is also synthesized and spontaneously released by thymocytes (Santoni et al, 2002). In this regard, we have provided evidence for the expression of the SP precursor preprotachykinin-A (PPT-A) mRNA, mature SP, and its NK 1 R by CD4 ϩ and CD4 ϩ CD8 ϩ (double positive; DP) rat thymocytes.…”

mentioning

confidence: 84%

“…In addition, these mice showed subtle differences in lymphoid development (Lu et al, 1995). SP can also modulate thymocyte survival pathways (Santoni et al, 2002), although the signaling pathways by which SP affects cell survival are still poorly elucidated.…”

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confidence: 99%

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

Amantini

Mosca²,

Lucciarini³

et al. 2008

J Pharmacol Exp Ther

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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 ϩ thymocytes, namely on the CD4 ϩ CD8 ϩ (double positive; DP) and CD4 ϩ 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 ϩ CD4 ϩ and CD10 ϩ DP thymocyte numbers, and an NK 1 R antagonist,, 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 ϩ 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.Development of T lymphocytes is a complex process that depends on both stromal cell interactions and the production of soluble factors such as cytokines, peptide hormones, and neuropeptides locally synthesized or released in the thymic microenvironment (Blalock and Smith, 1985). In the thymus, the concentration of biologically active peptides is maintained by a specialized family of enzymes, the endopeptidases (Naquet and Pierres, 1991).The neutral endopeptidase (NEP)-24.11 (EC 3.4.24.11), also known as enkephalinase, neprilysin, common acute lymphoblastic leukemia antigen, or CD10 (Turner and Tanzawa, 1997), is the prototype of a family of membrane-bound zincdependent endopeptidases that regulate the physiological action of a variety of peptides by lowering their extracellular concentration available for receptor binding. Molecular cloning of NEP/CD10 revealed that it is a type II integral membrane protein consisting of a short NH 2 -terminal cytoplasmic domain and a large extracellular domain that contains the active site of the enzyme. It was first isolated as a major 90 to 100-kDa glycoprotein from the renal brush border membrane of rabbits (Kerr and Kenny, 1974).NEP/CD10 is expressed on early normal T-and B-cell progenitors (Shipp and Look, 1993) and on the majority of acute lymphoblastic leukemias and lymphoid malignancies with immature phenotypes (Ritz et al., 1981). Unfracti...

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Section: Resultsmentioning

confidence: 99%

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confidence: 84%

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

Amantini

Mosca²,

Lucciarini³

et al. 2008

J Pharmacol Exp Ther

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“…Hepatocytes (10 6 ), isolated by the two-step collagenase perfusion method of Seglen (1973) were fixed and permeabilized using CytoFix/CytoPerm Plus (BD Biosciences, Heidelberg, Germany) according to Santoni et al (2002), rinsed with the washing buffer of the CytoFix/CytoPerm Plus kit, and blocked for 1 h…”

Section: Methodsmentioning

confidence: 99%

“…In cells originating from the bone marrow, for example, in thymocytes and granulocytes, SP seems to exert antiapoptotic effects, whereas NK-1R antagonists act proapoptotic (Dimri et al, 2000;Bockmann et al, 2001;Santoni et al, 2002). Likewise, SP also promotes proliferation and prevents apoptosis in cancer cells (Heasley, 2001;DeFea et al, 2000;Friess et al, 2003).…”

Section: Nk-1 Receptor Antagonists Protect Against Hepatic Apoptosis mentioning

confidence: 99%

Neurokinin-1 Receptor Antagonists Protect Mice from CD95- and Tumor Necrosis Factor-α-Mediated Apoptotic Liver Damage

Bang¹,

Biburger²,

Neuhuber³

et al. 2003

J Pharmacol Exp Ther

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Previously, we have shown that primary afferent neurons are necessary for disease activity in immune-mediated liver injury in mice. These nerve fibers are detectable by substance P (SP) immunocytochemistry in the portal tract of rodent liver. Antagonists of the neurokinin-1 receptor (NK-1R), which is the prime receptor of SP, prevented liver damage by suppressing the synthesis of proinflammatory cytokines. Here, we investigated the influence of primary afferent nerve fibers, SP, and NK-1 receptor antagonists on hepatocyte apoptosis in vivo induced by administration of activating anti-CD95 monoclonal antibody (mAb) to mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment prevented CD95-mediated activation of caspase-3, measured as enzymatic activity in liver homogenates or by demonstration of hepatocellular immunoreactivity for active caspase-3 in liver slices, and liver damage. This effect was reversed by administration of SP to anti-CD95 mAb-treated mice In conclusion, SP, probably by binding to its receptor on hepatocytes, might aggravate apoptotic signals in these cells. Because NK-1 receptor antagonists not only suppress the proinflammatory cytokine response in the liver but also prevent liver cell apoptosis in vivo, they might be suitable drugs for treatment of immunemediated liver disease.

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Towards Neuroimmunotherapy for Cancer: the Neurotransmitters Glutamate, Dopamine and GnRH-II augment substantially the ability of T cells of few Head and Neck cancer patients to perform spontaneous migration, chemotactic migration and migration towards the autologous tumor, and also elevate markedly the expression of CD3zeta and CD3epsilon TCR-associated chains

Saussez

Laumbacher²,

Chantrain

et al. 2014

J Neural Transm

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In previous studies we found that several Neurotransmitters and Neuropeptides among them: Glutamate, Dopamine, Gonadotropin-releasing-hormone (GnRH) I and II, Somatostatin, CGRP and Neuropeptide Y, can each by itself, at low physiological concentration (~10 nM) bind its receptors in human T cells and trigger several key T cell functions. These findings showed that the nervous system, via Neurotransmitters and Neuropeptides, can 'talk' directly to the immune system, and stimulate what we coined 'Nerve-Driven Immunity': immune responses dictated by the nervous system. In various human cancers, the immune system of the patients, and their T cells in particular, are not functioning well enough against the cancer due to several reasons, among them the suppressive effects on the immune system induced by: (1) the cancer itself, (2) the chemotherapy and radiotherapy, (3) the ongoing/chronic stress, anxiety, depression and pain felt by the cancer patients. In Head and Neck Cancer (HNC), 5-year survival rate remains below 50%, primarily because of local recurrences or second primary tumors. Two-thirds of HNC patients are diagnosed at advanced clinical stage and have significantly poorer prognosis. Most HNC patients have multiple severe immunological defects especially in their T cells. A major defect in T cells of patients with HNC or other types of cancer is low CD3zeta expression that correlates with poor prognosis, decreased proliferation, apoptotic profile, abnormal cytokine secretion and poor abilities of destructing cancer cells. T cells of cancer patients are often also unable to migrate properly towards the tumor. In this study we asked if Glutamate, Dopamine or GnRH-II can augment the spontaneous migration, chemotactic migration and towards autologous HNC migration, and also increase CD3zeta and CD3epsilon expression, of peripheral T cells purified from the blood of five HNC patients. These HNC patients had either primary tumor or recurrence, and have been already treated by surgery and/or radiotherapy and/or chemotherapy without satisfactory outcomes. We found that Glutamate, Dopamine and GnRH-II, each by itself, at 10 nM, and during 30 min incubation only with the peripheral T cells of the HNC patients increased substantially their: (1) spontaneous migration (up to 4.4 fold increase), (2) chemotactic migration towards the key chemokine SDF-1 (up to 2.3 fold increase), (3) migration towards the autologous HNC tumor removed surgically ~48 h earlier in a pre-planned operation (up to 3.5 fold increase). Each of the Neurotransmitters even 'allowed' the T cells of one HNC patient to overcome completely the suppressive anti-migration effect of his autologous tumor, (4) cell surface CD3zeta expression (up to 4.3 fold increase), (5) cell surface CD3epsilon expression (up to 1.9 fold increase). If the absolutely essential larger scale subsequent studies would validate our present findings, Glutamate, Dopamine and GnRH-II could be used for a completely novel indication: adoptive T cell immunotherapy for some patients with ...

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Expression of Substance P and Its Neurokinin-1 Receptor on Thymocytes: Functional Relevance in the Regulation of Thymocyte Apoptosis and Proliferation

Cited by 25 publications

References 43 publications

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

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

Neurokinin-1 Receptor Antagonists Protect Mice from CD95- and Tumor Necrosis Factor-α-Mediated Apoptotic Liver Damage

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