ABSTRACT
Dendritic cells (DCs) play a central role in the maintenance of immune homeostasis, their participation as professional antigen presenting cells is essential to the initiation of the adaptive immune response as well as to the induction of tolerance. The recently described role of the aryl hydrocarbon receptor (AhR) in the immune system, particularly in the modulation of the adaptive immune response has attracted the attention as a potential player in the induction of immune tolerance. However, the effects of AhR activation through endogenous ligands on human DCs have been poorly evaluated. In this study, we investigated the effect of FICZ, a natural AhR ligand, on monocyte-derived dendritic cells (Mo-DCs) from healthy subjects. We found that the activation of AhR through FICZ during DCs differentiation and maturation processes resulted in a decreased expression of CD83, an increased expression of the enzyme IDO and a reduced production of the pro-inflammatory cytokines IL-6 and TNF-α. More importantly, FICZ-treated DCs were able to induce the differentiation of naive T lymphocytes into CD4+ CD25high Foxp3+ T reg-like cells. Our results show that the activation of the AhR on human DCs induces a tolerogenic phenotype with potential implications in immunotherapy.
Subject(s)
Carbazoles/pharmacology , Dendritic Cells/immunology , Immunotherapy/methods , Receptors, Aryl Hydrocarbon/agonists , T-Lymphocytes, Regulatory/immunology , CD4 Antigens/metabolism , Cell Differentiation , Cells, Cultured , Coculture Techniques , Forkhead Transcription Factors/metabolism , Humans , Immune Tolerance , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-6/metabolism , Lymphocyte Activation , Monocytes/immunology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
AIM: Prolactin family hormones include growth hormone, placental lactogen and prolactin, which are able to regulate angiogenesis via NO and prostaglandins. However, their effects on vascular tone are not fully understood. The aim of this study was to evaluate the effects of prolactin family hormones on rat vascular tone in vitro. METHODS: Aortic rings were prepared from adult male rats and precontracted with phenylephrine, then treated with the hormones and drugs. The tension was measured with isometric force displacement transducer connected to a polygraph. NO production and prostacyclin release in physiological solution was determined. Cultured rat aortic endothelial cells (RAECs) were treated with the hormones and drugs, and the phosphorylation of eNOS at serine 1177 was assessed using Western bolt analysis. RESULTS: Administration of growth hormone or placental lactogen (0.01-100 nmol/L) induced endothelium-dependent vasodilation. Both the hormones significantly increased the phosphorylation of eNOS in RAECs and NO level in physiological solution. Preincubation with L-NAME blocked growth hormone- or placental lactogen-induced vasodilation and NO production. Preincubation with an antibody against growth hormone receptors blocked growth hormone- and placental lactogen-induced vasodilation. Addition of a single dose of prolactin (0.01 nmol/L) induced sustained vessel relaxation, whereas multiple doses of prolactin induced a biphasic contraction-relaxation effect. The vascular effects of prolactin depended on endothelium. Prolactin significantly increased the level of prostacyclin I2 in physiological solution. Preincubation with indomethacin or an antibody against prolactin receptors blocked prolactin-induced vasodilation. CONCLUSION: The prolactin family hormones regulate rat vascular tone, selectively promoting either relaxation or contraction of vascular smooth muscle via activation of either growth hormone receptors or prolactin receptors within the endothelium.
Subject(s)
Aorta/drug effects , Epoprostenol/metabolism , Human Growth Hormone/pharmacology , Nitric Oxide/metabolism , Placental Lactogen/pharmacology , Prolactin/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Animals , Aorta/metabolism , Cells, Cultured , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Endothelial Cells/metabolism , In Vitro Techniques , Male , Nitric Oxide Synthase Type III/metabolism , Phosphorylation , Rats, Wistar , Receptors, Somatotropin/drug effects , Receptors, Somatotropin/metabolism , Serine , Signal Transduction/drug effects , Time Factors , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacologyABSTRACT
AgNPs have been used to manufacture nanomaterials with new biophysical properties and functions. However, few experimental approaches have been used to assess their potential toxic or beneficial effects on human health, in association with the size, concentration, and biological target. The aim of this work was to evaluate the effects of the AgNPs on the smooth muscle of rat trachea. A single administration of AgNPs did not modify the smooth muscle tone, but, when the trachea rings were pre-treated with acetylcholine (ACh), AgNPs produced a contractile effect. Simultaneous administration of AgNPs and ACh resulted in a slight increase of smooth muscle contractility induced by ACh. AgNPs pretreatment followed by ACh administration showed that AgNPs exerted an important contraction effect induced by ACh after which muscle tone did not return to the basal level. This effect was associated with an increase in the production of nitric oxide (NO). The contractile response of the AgNPs induced by ACh was completely blocked when the rings were incubated, after the ACh but before the AgNPs administration, with 1400 W (NO blocker). The contractile effect was also abolished by atropine, which suggests that AgNPs alter ACh muscarinic receptor signaling. These data also show that AgNPs modify the contractile action of ACh through NO production and possibly induce hyper-reactivity of tracheal smooth muscle.