Victor E. Nahmod

Control of dendritic cell differentiation by angiotensin II

Here we analyze the role of the angiotensinergic system in the differentiation of dendritic cells (DC). We found that human monocytes produce angiotensin II (AII) and express AT1 and AT2 receptors for AII. DC differentiated from human monocytes in the presence of AT1 receptor antagonists losartan or candesartan show very low levels of CD1a expression and poor endocytic and allostimulatory activities. By contrast, DC differentiation in the presence of either the AT2 receptor antagonist PD 123319 or exogenous AII results in the development of nonadherent cells with CD1a expression and endocytic and allostimulatory activities higher than control DC. Similar contrasting effects were observed in mouse DC obtained from bone marrow cultures supplemented with granulocyte‐monocyte colony‐stimulating factor. DC differentiated in the presence of the AT1 receptor antagonist losartan express lower levels of CD11c, CD40, and Ia and display a lower ability to endocyte horseradish peroxidase (HRP) and to induce antibody responses in vivo, compared with controls. By contrast, DC differentiation in the presence of either the AT2 receptor antagonist PD 123319 or exogenous AII results in cells with high levels of CD11c, CD40, and Ia, as well as high ability to endocyte HRP and to induce antibody responses in vivo. Our results support the notion that the differentiation of DC is regulated by AII.

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.

Serotonin inhibition of tumor necrosis factor-α synthesis by human monocytes

Abstract Serotonin inhibited in a concentration dependent way (10 −3 M to 10 −10 M) the LPS induced Tumor Necrosis Factor-α synthesis both, when added to the monocyte cultures from the beginning and when added together with the activating stimulus 8 hours before the end of the culture. The inhibitory effect was specifically blocked by the 5-HT 1 and 5-HT 2 serotonin antagonist methysergide and the 5-HT 2 receptor antagonist ketanserin. This indicates that only the 5-HT 2 receptor family (5-HT 2 or 5-HT 1C ) may be involved in the inhibitory effect. Serotonin seems to play an important immunomodulatory role in macrophage functions.

Low lymphocyte interferon-gamma production and variable proliferative response in anorexia nervosa patients

Interferon-gamma (IFN-γ) production by peripheral blood mononuclear cells (PBMC) in 14 patients with anorexia nervosa (AN) was significantly lower than in 14 age-matched healthy controls. Follow-up samples in four patients displayed low levels, except in two when they recovered the IFN-γ production as the hormonal cycles were restored. A large interindividual variation for the lymphocyte proliferative response was observed in 30 AN patients. DNA synthesis of PBMC was normal in 8 patients (27%), significantly increased in 6 (20%) (P<0.001), and significantly decreased in 16 (53%) (P<0.001). IFN-γ inhibition was reversed by culturing a control lymphocyte population with monocytes from patients with AN. This was not observed in cultures of control monocytes and AN lymphocytes. IL-2 receptor (TAC subunit) was assessed and no difference was found in the number of TAC-positive cells between patients and controls. These results point out impaired production of the immunomodulator cytokine IFN-γ as a major functional defect of AN peripheral lymphocytes.

Angiotensin II enhances long-term memory in the crab Chasmagnathus

An opaque screen moving overhead provokes an escape response in the crab Chasmagnathus granulatus that habituates after a few presentations of the eliciting stimulus. Fifteen trials with a 180-s intertrial interval or 30 trials with a 90-s interval (strong training protocol) ensures long-term habituation (LTH) of the response for 24 h, whereas 10 trials (weak training protocol) fail to induce it. However, robust LTH is obtained when crabs are injected with human angiotensin (All; 50 pmol) immediately after a weak training protocol. This memory-enhancing effect of All is dose-dependent, reversible by saralasin (5 pmol), and vanishes either when the weak training protocol is reduced to only five trials, or when the peptide is given before training or 1 h after. LTH is impaired by saralasin (5 pmol) administered before or after the strong training protocol, but no amnestic effect is disclosed when the antagonist is given 1 h after. On the other hand, both All-like immunoreactivity and angiotensin-converting enzyme-like activity are described in diverse tissues of Chasmagnathus, namely, in gills and in both thoracic and supraesophageal ganglia. Results support the view that some components of the renin-angiotensin system and their influence on memory might have emerged early in evolution.

Neurogenic hypertension after depletion of norepinephrine in anterior hypothalamus induced by 6-hydroxydopamine administration into the ventral pons: Role of serotonin

Destruction of the ventral noradrenergic pathway elicited by administration of 6-hydroxydopamine (6-OHDA, 5 micrograms into each side of the ventral pons) reduced the content of norepinephrine (NE) in the anterior hypothalamus (-80%) and induced an increase in arterial blood pressure (ABP) and in heart rate. These hypertensive rats, showed hypersensitivity to the hypotensive effect of NE (0.5-2 micrograms) and clonidine (0.75-1.5 micrograms) administered into the anterior hypothalamic preoptic (AH/PO) region. Methysergide (1-2 micrograms) and, to a lesser extent, ketanserin (1-2 micrograms) administered into the anterior hypothalamic preoptic region also reduced the arterial blood pressure in these rats treated with 6-OHDA. Bilateral administration of 5,7-dihydroxytryptamine (5,7-DHT, 8 micrograms) into the median forebrain bundle decreased the content of serotonin (5-HT) in the hypothalamus (-85%) without change in arterial blood pressure but largely prevented the development of hypertension after treatment with 6-OHDA in the ventral pons. These results suggest that neurogenic hypertension is produced after the removal of NE tonic depressor activity in the anterior hypothalamus and that serotonergic mechanisms play a major role in the development of the increased arterial blood pressure in this preparation.

Angiotensin II (3–8) induces long-term memory improvement in the crab Chasmagnathus

A shadow moving overhead acts as a danger stimulus and elicits an escape response in the crab Chasmagnathus that habituates after 15 trials and for a long period of time. Previous work showed that angiotensin II enhances this long-term memory. Present results indicate: (1) that the facilitatory effect of angiotensin II is not blocked by either losartan, DUP 753 or the Parke Davis compound PD 123177; (2) that the angiotensin II (3-8) fragment has an enhancing effect on crabs memory stronger than that reported for the integer octopeptide; (3) that the hypermnestic effect of angiotensin II (3-8) is dose-dependent and saralasin reversible. The possibility that the action of angiotensin II on crabs memory were not due to its own action but to that of the degradation fragment angiotensin II (3-8) is discussed.

Thyrotropin-releasing hormone increases the number of muscarinic receptors in the lateral septal area of the rat brain

Stereotactic injection of acetylcholine (0.5-2 micrograms) into the lateral septal region of the rat brain produces a long-lasting sympathetic-mediated increase of the arterial blood pressure. This effect is mediated by muscarinic receptors since 1 microgram atropine abolishes this response. In this same brain region, TRH (0.5-4 micrograms) did not elicit any significant change in the arterial blood pressure, but potentiated the effect of acetylcholine. This phenomenon is apparently due to an increase of the number of muscarinic receptors in the lateral septal area of the rat brain.

Serotonin mediates cardiovascular responses to acetylcholine, bradykinin, angiotensin II and norepinephrine in the lateral septal area of the rat brain

The infusion of acetylcholine, bradykinin, angiotensin II, norepinephrine and serotonin into the lateral septal area produced a dose-dependent increase of arterial blood pressure and heart rate. A pattern of inhibition of these cardiovascular responses, produced by pretreatment of the lateral septal area with phentolamine, 6-hydroxydopamine, methysergide and 5,7-dihydroxytryptamine was disclosed. These results suggest that the effects of acetylcholine, bradykinin and partially of angiotensin II, depend on the release of norepinephrine and the actions of this neurotransmitter in turn depend on the integrity of the serotonergic system in the lateral septal area.

Angiotensin II and the transcription factor Rel/NF-κB link environmental water shortage with memory improvement

One of the essential requirements even in the most ancient life forms is to be able to preserve body fluid medium. In line with such requirement, animals need to perform different behaviors to cope with water shortages. As angiotensin II (ANGII) is involved on a widespread range of functions in vertebrates, including memory modulation, an integrative role, in response to an environmental water shortage, has been envisioned. Previous work on the semi-terrestrial and brackish-water crab Chasmagnathus granulatus showed that endogenous ANGII enhanced an associative long-term memory and, in addition, that high salinity environment induces both an increase of brain ANGII levels and memory improvement. Here, we show that in the crab Chasmagnathus air exposure transiently increases blood sodium concentration, significantly increases brain ANGII immunoreactivity, and has a facilitatory effect on memory that is abolished by a non-selective ANGII receptor antagonist, saralasin. Furthermore, Rel/NF-kappaB, a transcription factor activated by ANGII in mammals and during memory consolidation in Chasmagnathus brain, is induced in the crabs brain by air exposure. Moreover, nuclear brain NF-kappaB is activated by ANGII, and this effect is reversed by saralasin. Our results constitute the first demonstration in an invertebrate that cognitive functions are modulated by an environmental stimulus through a neuropeptide and give evolutionary support to the role of angiotensins in memory processes. Moreover, these results suggest that angiotensinergic system is preserved across evolution not only in its structure and molecular mechanisms, but also in its capability of coordinating specific adaptative responses.