No abstract

Observations of elevated basal cortisol levels in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Consistent with that hypothesis, we show that stress and GC provoke misprocessing of amyloid precursor peptide in the rat hippocampus and prefrontal cortex, resulting in increased levels of the peptide C-terminal fragment 99 (C99), whose further proteolytic cleavage results in the generation of amyloid-b (Ab). We also show that exogenous Ab can reproduce the effects of stress and GC on C99 production and that a history of stress strikingly potentiates the C99-inducing effects of Ab and GC. Previous work has indicated a role for Ab in disruption of synaptic function and cognitive behaviors, and AD patients reportedly show signs of heightened anxiety. Here, behavioral analysis revealed that like stress and GC, Ab administration causes spatial memory deficits that are exacerbated by stress and GC; additionally, Ab, stress and GC induced a state of hyperanxiety. Given that the intrinsic properties of C99 and Ab include neuroendangerment and behavioral impairment, our findings suggest a causal role for stress and GC in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy can have a cumulative impact on the course of AD development and progression.

The online version of this article has a Supplementary Appendix. BackgroundThe immunoregulatory enzyme indoleamine 2,3-dioxygenase, which catalyzes the conversion of tryptophan into kynurenine, is expressed in a significant subset of patients with acute myeloid leukemia, resulting in the inhibition of T-cell proliferation and the induction of regulatory T cells. Acute myeloid leukemia cells can be differentiated into dendritic cells, which have increased immunogenicity and have been proposed as vaccines against leukemia. Design and MethodsLeukemic dendritic cells were generated from acute myeloid leukemia cells and used as stimulators in functional assays, including the induction of regulatory T cells. Indoleamine 2,3-dioxygenase expression in leukemic dendritic cells was evaluated at molecular, protein and enzymatic levels. ResultsWe demonstrate that, after differentiation into dendritic cells, both indoleamine 2,3-dioxygenase-negative and indoleamine 2,3-dioxygenase-positive acute myeloid leukemia samples show induction and up-regulation of indoleamine 2,3-dioxygenase gene and protein, respectively. Indoleamine 2,3-dioxygenase-positive acute myeloid leukemia dendritic cells catabolize tryptophan into kynurenine metabolite and inhibit T-cell proliferation through an indoleamine 2,3-dioxygenase-dependent mechanism. Moreover, indoleamine 2,3-dioxygenase-positive leukemic dendritic cells increase the number of allogeneic and autologous CD4 ConclusionsThese data identify indoleamine 2,3-dioxygenase-mediated catabolism as a tolerogenic mechanism exerted by leukemic dendritic cells and have clinical implications for the use of these cells for active immunotherapy of leukemia.Key words: acute myeloid leukemia, dendritic cells, T regulatory cells, immunotherapy, indoleamine 2,3-dioxygenase.Citation: Curti A, Trabanelli S, Onofri C, Aluigi M, Salvestrini V, Ocadlikova D, Evangelisti C, Rutella S, De Cristofaro R, Ottaviani E, Baccarani M, and Lemoli RM. Indoleamine 2, leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells. Haematologica 2010;95(12):2022-2030. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Indoleamine 2,3-dioxygenase-expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells

As for any solid tumour, pituitary adenoma expansion is dependent on neovascularization through angiogenesis.

TGF-beta isoforms are expressed in the anterior pituitary and modulate the growth and function of endocrine pituitary cells. Recently, TGF-beta has been shown to stimulate growth and basic fibroblast growth factor secretion in nonendocrine folliculostellate (FS) pituitary cells. We therefore studied whether the production of FS cell-derived vascular endothelial growth factor (VEGF), the most important regulator of vascular permeability and angiogenesis, is affected by TGF-beta. We observed by RT-PCR that TtT/GF cells, which are FS mouse pituitary tumor cells, synthesize TGF-beta1, -beta2, and -beta3. They also express TGF-beta receptors types 1 and 2, as well as Smad2, Smad3, and Smad4 proteins, which are essential for TGF-betabinding and signaling. Stimulation of TtT/GF cells with either TGF-beta1 or TGF-beta3 induced a rapid translocation of Smad2 into the cell nuclei. Both TGF-beta isoforms dose dependently stimulated VEGF production in TtT/GF cells, but not in lactosomatotroph GH3 cells. Time-course studies and suppression of TGF-beta-induced VEGF production by cycloheximide suggest that TGF-beta induces de novo synthesis of VEGF in folliculostellate cells, which is completely blocked by dexamethasone. In primary rat pituitary cell cultures, TGF-beta1 and -beta3 stimulated VEGF production. TGF-beta stimulation of VEGF production by folliculostellate cells could modulate intrapituitary vascular permeability and integrity as well as angiogenesis in an auto-/paracrine manner.

Two of the most potent cytokines that regulate anterior pituitary cell function are leukemia inhibitory factor and IL-6. These and others like IL-11 and ciliary neurotrophic factor are referred to as the gp130 cytokines because they share the gp130 glycoprotein as a common receptor initial signal transducer. We and others have shown that gp130 cytokines and their receptors are expressed and functional in normal and tumoral anterior pituitary cells. To study the role of gp130 cytokines in tumorigenic process, we generated gp130 cDNA gp130 sense and gp130 antisense (gp130-AS) transfected stable clones derived from lactosomatotroph GH3 cells. We examined hormone secretion and cell proliferation of these clones as well as their tumorigenic properties in athymic nude mice. Although gp130-AS clones, which have low gp130 levels and impaired signal transducer and activator of transcription 3 activity and suppressor of cytokine signaling-3 expression, showed reduced proliferation and hormone secretion (GH and prolactin) in response to gp130 cytokines, they had a normal response to gp130-independent stimuli. Moreover, gp130-AS clones showed a severely impaired in vivo tumor development. In contrast, the overexpressing gp130 clones (gp130 sense) showed no differences, compared with cells transfected with control vector. Thus, the present study provides new evidence supporting a link between gp130 and pituitary abnormal growth.

After wheat and rice, potato is the third most important staple food worldwide. A collection of ten tetraploid (Solanum tuberosum) and diploid (S. phureja and S. chacoense) genotypes with contrasting carotenoid content was subjected to molecular characterization with respect to candidate carotenoid loci and metabolic profiling using LC-HRMS. Irrespective of ploidy and taxonomy, tubers of these genotypes fell into three groups: yellow-fleshed, characterized by high levels of epoxy-xanthophylls and xanthophyll esters and by the presence of at least one copy of a dominant allele of the β-Carotene Hydroxylase 2 (CHY2) gene; white-fleshed, characterized by low carotenoid levels and by the presence of recessive chy2 alleles; and orange-fleshed, characterized by high levels of zeaxanthin but low levels of xanthophyll esters, and homozygosity for a Zeaxanthin Epoxidase (ZEP) recessive allele. Novel CHY2 and ZEP alleles were identified in the collection. Multivariate analysis identified several groups of co-regulated non-polar compounds, and resulted in the grouping of the genotypes according to flesh color, suggesting that extensive cross-talk exists between the carotenoid pathway and other metabolite pathways in tubers. Postharvest traits like tuber dormancy and weight loss during storage showed little correlation with tuber carotenoid content, with the exception of zeaxanthin and its esters. Other tuber metabolites, such as glucose, monogalactosyldiacyglycerol (a glycolipid), or suberin precursors, showed instead significant correlations with both traits.

Objective: gp130 cytokines are placed as auto-paracrine regulators of pituitary function, since they, as well as their receptors, have been shown to be expressed in and to act in normal and tumoral anterior pituitary cells. The objective of this work was to study their involvement in a model that shows the interaction between different cellular types that participate in a tumorigenic process. Design: The dependence of a pituitary somatotrophic cell line (MtT/S) on a gp130 cytokine-producing folliculostellate (FS) cell line (TtT/GF) for tumorigenesis in vivo has been described. In order to study the participation of gp130 cytokines in the auto-paracrine stimulation of MtT/S growth, we generated MtT/S gp130 sense (gp130-S) and gp130 antisense (gp130-AS) clones stably transfected with pcDNA3/gp130 sense and pcDNA3/gp130 antisense vectors respectively. Methods and results: Functional characterization studies revealed that gp130-AS clones have an inhibited gp130 signalling, and proliferation studies showed that they have an impaired response to gp130 cytokines but respond normally to other independent stimuli. When injected into nude mice, MtT/S clones respond differently depending on cell number; at high concentrations MtT/S clones alone generated tumours equivalent in size to tumours derived from MtT/S plus TtT/GF cells. At low concentrations, MtT/S sense and control clones generated tumours of smaller size than tumours derived from these same clones plus TtT/GF cells, showing a dependence on FS cells. In both cases MtT/S gp130-AS clones had impaired tumour development. Furthermore, vessel density was significantly lower in tumours derived from gp130-AS plus TtT/GF cells. Conclusions: This study underlines the importance of gp130 cytokines in proliferation and establishes its role in auto-paracrine pituitary growth regulation.European Journal of Endocrinology 151 595-604