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.

Since the discovery of the angiotensins a link was sought in vain between these polypeptides and the physiological mechanism that regulates the systemic blood pressure (1). This search, however, was rich in surprises as soon as the amazing diversity of pharmacological actions of angiotensin II was established. Besides being the most powerful vasopressor molecule known, the polypeptide is the hormone for aldosterone release (2) and has several effects on the autonomic nervous system: (a) it inhibits the uptake of catecholamines by sympathetic nerve endings (3); (b) it has a direct action on cholinergic ganglionic cells (4); (c) it accelerates the rate of biosynthesis of norepinephrine (5); and (d) it acts directly or indirectly on central sympathetic structures inducing a prolonged increase in blood pressure and heart rate (6). Even if this versatility shattered the early ideas concerning the function of the polypeptide, the classical scheme that accounted for angiotensin I production was not challenged until very recently. The liberation of the polypeptide was supposed to be restricted to the plasma, where a circulating alpha-2 globulin synthetized by the liver, angiotensinogen, is split by a proteolytic enzyme, renin, synthesized by the granular cells of the juxtaglomerular apparatus of the kidney. This proteolytic step releases a 10-residue long polypeptide from angiotensinogen, denominated angiotensin I, which is itself the substrate for a specific, Cl-activated carboxipeptidase, the converting enzyme, giving rise to the octapeptide angiotensin II. This scheme was first questioned after the finding that isolated rat renal glomeruli, devoid of plasma contamination and incubated in a simple salt medium, were able to secrete angiotensin I in great amounts (7-8). The release of the polypeptide was suppressed with protein-synthesis inhibitors. I The tissue synthesis of angiotensin I was strongly supported by the finding of a polypeptide in several tissues of the rat and the dog with pharmacological and

Serotonin and melatonin inhibit phytohemagglutinin- (PHA) induced interferon-gamma (IFN-gamma) production by lymphocytes. In this paper, it is shown that IFN-gamma-increased tryptophan uptake by lymphocytes and macrophages led to an enhanced production of serotonin. When IFN-gamma and serotonin were added together to a lymphocyte culture, N-acetyl serotonin and melatonin production was increased, whereas the path to 5-hydroxy-indoleacetic acid remained unchanged. Therefore, the stimulated IFN-gamma production of serotonin and melatonin by lymphocytes and macrophages and the inhibition of IFN-gamma synthesis by these indoleamines suggest a hypothesis for an immunoregulatory circuit.

Breast tumors are usually classified according to their response to estrogens as hormone-dependent or -independent. In this work, we investigated the role of the proinflammatory cytokine TNF-a on the estrogen-receptor-positive T47D breast ductal tumor cells. We have found that TNF-a exerts a mitogenic effect, inducing cyclin D1 expression and activation of the transcription factor NF-jB. Importantly, activation of NF-jB was required for estrogen-induced proliferation and cyclin D1 expression. TNF-a enhanced the estrogen response by increasing the levels and availability of NF-jB. Chromatin immunoprecipitation analysis suggested that the action of estrogens is mediated by a protein complex that contains the activated estrogen receptor, the nuclear receptor coactivator RAC3 and a member of the NF-jB family. Finally, our results demonstrate that activation of this transcription factor could be one of the key signals for estrogen-mediated response.