Eduardo Arzt

Immunomodulation by indoleamines: Serotonin and melatonin action on DNA and interferon-γ synthesis by human peripheral blood mononuclear cells

Different concentrations of indoleamines, serotonin and melatonin, inhibited phytohemagglutinin stimulated DNA synthesis. Thus, 10−3 to 10−4 M of either indoleamine acted at the optimal phytohemagglutinin concentration, while 10−3 to 10−7 M acted at suboptimal phytohemagglutinin levels. The serotonin effect was reversed by the serotonergic S1-S2 receptor antagonist methysergide but not by the S2 antagonist ketanserin. This indicates that only the S1 receptor is involved in the inhibitory effect. Inhibition of lymphoproliferation by indoleamines was also exerted on pokeweed mitogen and protein A fromStaphylococcus aureus stimulations. Serotonin and melatonin also inhibited phytohemagglutinin and protein A from Staphylococcus aureus induction of interferon-γ synthesis. The initial uptake of Ca2+ was not affected by indoleamines, suggesting that it is not the mechanism of their inhibitory effects. As interferon-γ induced tryptophan uptake by T lymphocyte- and macrophage-depleted populations, and tryptophan is the metabolic precursor of serotonin and melatonin, a new immunoregulatory circuit is postulated.

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

Cushing’s disease is a severe clinical condition caused by hypersecretion of corticosteroids due to excessive ACTH secretion from a pituitary adenoma. This complex endocrine disorder still represents a major challenge for the physician in terms of efficient treatment. In the last years there was only little progress in elucidating the molecular mechanisms responsible for the constitutive and autonomous ACTH secretion of pituitary corticotrophinomas. As a consequence, no effective drug therapy is currently available, particularly if surgical excision is not successful. In the present article we examine recent studies that have investigated the therapeutic potential of retinoic acid receptors as nuclear receptor targets for the treatment of Cushing’s disease. Retinoic acid is an efficient drug used for the treatment of different types of cancers and it proved to act in animal models of Cushing’s disease. The efficiency of this treatment in patients with this disorder still needs to be tested in clinical trials.

The muscarinic agonist pilocarpine inhibits DNA and interferon-γ synthesis in peripheral blood mononuclear cells

Lymphocyte basal DNA synthesis and proliferative responses to phytohemagglutinin (PHA) showed a dose-dependent (5 X 10(-5)-5 X 10(-3) M) inhibition by the muscarinic agonist pilocarpine, in contrast to the basal enhancing effect produced by the M2 muscarinic-nicotinic agonist carbachol. The effect of pilocarpine was reversed by both atropine (1 X 10(-6) M) and pirenzepine (1 X 10(-7)-1 X 10(-8) M), M1-M2 and M1 muscarinic antagonists, respectively. The effect of pilocarpine may thus be specific for the M1 muscarinic receptor. Pilocarpine also inhibited interferon-gamma (IFN-gamma)-PHA induced production, but was unable to reverse the pokeweed mitogen (PWM)-induced DNA synthesis. Distinct immunoregulatory activities are suggested for cholinergic muscarinic receptors M1 and M2.

Alpha-Interferon Induces Cortisol Release by Human Adrenals in vitro

It is at present not clear whether alpha interferon (INF-alpha) can participate in the control of glucocorticoid blood levels through direct action on the adrenal gland. In this study, the possible action of INF-alpha on cortisol release by adrenal tissue was tested in vitro. Slices of normal human adrenals were incubated with INF-alpha for 3 h at 37 degrees C in 95% air and 5% CO2. Cortisol release by adrenal tissue was stimulated by INF-alpha, showing a dose-response curve from 20 IU/ml, the lowest dose that gave a response, to a maximal dose of 60 IU/ml when the response reached a plateau. The effect of INF-alpha on cortisol liberation by adrenal tissue in vitro may be implied in neuroimmune regulatory interactions.

The Inhibitory Effect of the Muscarinic Agonist Pilocarpine on Lymphocyte Activation Involves the IL-2 Pathway and the Increase in Suppressor Cell Function

The inhibition of lymphocyte DNA synthesis by the cholinergic muscarinic agonist pilocarpine (5 x 10(-4) M) was not reversed by addition of exogenous recombinant Interleukin-2 (100-1000 IU/ml). Pilocarpine did not inhibit Interleukin-2 (IL-2) production by human peripheral blood mononuclear cells but decreased the number of interleukin-2 receptor bearing cells (TAC positive cells). Furthermore, pilocarpine increased the CD8:CD4 T lymphocyte ratio enhancing the suppressor cell function. All these effects were blocked by the muscarinic antagonist atropine (1 x 10(-6) M). As described for the specific lymphocyte nicotinic stimulation, the pure cholinergic muscarinic stimulation inhibits lymphocyte proliferation by enhancing suppressor activity.