Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma

Abstract

Human B lymphocytes and derived lines from a spectrum of B cell malignancy were studied for expression of dopaminergic pathway components and for their cytostatic response to the catecholamine and related, potentially therapeutic compounds. Proliferating normal lymphocytes and dividing malignant clones rapidly arrested on exposure to dopamine in the low (<10 M) micromolar range. The antiparkinsonian drugs L-DOPA and apomorphine (particularly) were similarly antiproliferative. With the exception of D4, dopamine receptors D1-D5 were variably expressed among normal and neoplastic B cell populations, as was the dopamine transporter. Transcripts for D1 and D2 were frequently found, whereas D3 and D5 revealed restricted expression; dopamine transporter was detected in most cases. Nevertheless, pharmacological analysis disclosed that dopamine targeted cycling B cells independent of these structures. Rather, oxidative stress constituted the primary mechanism: the catecholamine's actions being mimicked by hydrogen peroxide and reversed by exogenous catalase, and evidence for the intracellular redox protein thioredoxin contributing protection. Among proliferating clones, growth arrest was accompanied by cell death in populations deplete in antiapoptotic Bcl-2: resting lymphocytes escaping low micromolar dopamine toxicity. Dysregulated bcl-2 expression, although preventing oxidative-induced caspase-dependent apoptosis, by itself conferred only minor protection against dopamine cytostasis. The selective impact of dopamine on lymphocytes that are in active cycle indicates an axis for therapeutic intervention not only in B cell neoplasia but also in lymphoproliferative disturbances generally. Rational tailoring of drug delivery systems already in development for Parkinson's disease could provide ideal vehicles for carrying the oxidative hit directly to the target populations.apoptosis ͉ oxidative stress ͉ Parkinson's disease ͉ Bcl-2 ͉ monoamines

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

“…EAE is mediated mainly by T cells, but B cells also contribute to the initiation and development of the disease (43,45,46). Type I DARs as well as serotonin receptors have been found to be expressed on many types of immune cells including DCs (47), T cells (23,48,49), and B cells (50,51). Therefore, systemic treatment with SCH could affect several types of immune cells.…”

Inhibition of proliferation of small intestinal and bronchopulmonary neuroendocrine cell lines by using peptide analogs targeting receptors

“…22 Apoptotic pathway activation after treatment with the IC 50 concentrations of each agent was evaluated by PCR analysis of caspase 3 transcript and measurement of caspase 3 activity using the PhiPhiLux assay. 23,24 Finally, flow cytometric analysis was performed and cell cycle alterations were examined in response to IC 50 concentrations of each compound over a 72-hour period (2 population doubling times for each cell line 20,21 ). The requirement for trypsin digest with the associated cell death in the adherent NCI-H727 cell line precluded flow cytometric analysis.…”

“…Cas-pase-3 activity was evaluated using the PhiPhiLux G1D2 kit (MBL, Nagoya, Japan) as described. 23,24 A substrate of PhiPhiLux G1D2, which can penetrate into the cell nucleus, is converted to the fluorescent form when cleaved by the protease activity of caspase-3. The assessment was performed according to the manufacturer's recommendations.…”

Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

“…[32][33][34][35] Similarly, neuropeptides and neurotransmitters that have key functions in the central and peripheral nervous systems can exert immune modulatory effects. 2,5,36 Indeed, emerging data demonstrate that these molecules can be transported or expressed by hematopoietic cells. 24,37,38 In our previous study, we demonstrated that DCs take up and sequester 5-HT in lysosomal vesicles for subsequent release via Ca 2ϩ -triggered exocytosis.…”