Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy

Glucocorticoid-induced tumor necrosis factor receptor (GITR) on T cells and its natural ligand, GITRL, on accessory cells contribute to the control of immune homeostasis. Here we show that reverse signaling through GITRL after engagement by soluble GITR initiates the immunoregulatory pathway of tryptophan catabolism in mouse plasmacytoid dendritic cells, by means of noncanonical NF-kappaB-dependent induction of indoleamine 2,3-dioxygenase (IDO). The synthetic glucocorticoid dexamethasone administered in vivo activated IDO through the symmetric induction of GITR in CD4(+) T cells and GITRL in plasmacytoid dendritic cells. The drug exerted IDO-dependent protection in a model of allergic airway inflammation. Modulation of tryptophan catabolism via the GITR-GITRL coreceptor system might represent an effective therapeutic target in immune regulation. Induction of IDO could be an important mechanism underlying the anti-inflammatory action of corticosteroids.     

The Lepidopteran KAAT1 and CAATCH1: Orthologs to Understand Structure–Function Relationships in Mammalian SLC6 Transporters

To the SLC6 family belong 20 human transporters that utilize the sodium electrochemical gradient to move biogenic amines, osmolytes, amino acids and related compounds into cells. They are classified into two functional groups, the Neurotransmitter transporters (NTT) and Nutrient amino acid transporters (NAT). Here we summarize how since their first cloning in 1998, the insect (Lepidopteran) Orthologs of the SLC6 family transporters have represented very important tools for investigating functional–structural relationships, mechanism of transport, ion and pH dependence and substate interaction of the mammalian (and human) counterparts.

     

The Q-soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor (Q-SNARE) SNAP-47 Regulates Trafficking of Selected Vesicle-associated Membrane Proteins (VAMPs)

SNAREs constitute the core machinery of intracellular membrane fusion, but vesicular SNAREs localize to specific compartments via largely unknown mechanisms. Here, we identified an interaction between VAMP7 and SNAP-47 using a proteomics approach. We found that SNAP-47 mainly localized to cytoplasm, the endoplasmic reticulum (ER), and ERGIC and could also shuttle between the cytoplasm and the nucleus. SNAP-47 preferentially interacted with the trans-Golgi network VAMP4 and post-Golgi VAMP7 and -8. SNAP-47 also interacted with ER and Golgi syntaxin 5 and with syntaxin 1 in the absence of Munc18a, when syntaxin 1 is retained in the ER. A C-terminally truncated SNAP-47 was impaired in interaction with VAMPs and affected their subcellular distribution. SNAP-47 silencing further shifted the subcellular localization of VAMP4 from the Golgi apparatus to the ER. WT and mutant SNAP-47 overexpression impaired VAMP7 exocytic activity. We conclude that SNAP-47 plays a role in the proper localization and function of a subset of VAMPs likely via regulation of their transport through the early secretory pathway.     

Role of endothelial progenitor cells in cancer progression

Tumor-associated neovasculature is a critical therapeutic target; however, despite significant progress made in the clinical efficacy of anti-vessel drugs, the effect of these agents remains transient: over time, most patients develop resistance, which inevitably leads to tumor progression. To develop more effective treatments, it is imperative that we better understand the mechanisms involved in tumor vessel formation, how they participate to the tumor progression and metastasis, and the best way to target them.     

Cutting edge: Autocrine TGF-beta sustains default tolerogenesis by IDO-competent dendritic cells

CD8(-) and CD8(+) dendritic cells (DCs) are distinct subsets of mouse splenic accessory cells with opposite but flexible programs of Ag presentation, leading to immunogenic and tolerogenic responses, respectively. In this study, we show that the default tolerogenic function of CD8(+) DCs relies on autocrine TGF-beta, which sustains the activation of IDO in response to environmental stimuli. CD8(-) DCs do not produce TGF-beta, yet externally added TGF-beta induces IDO and turns those cells from immunogenic into tolerogenic cells. The acquisition of a suppressive phenotype by CD8(-) DCs correlates with activation of the PI3K/Akt and noncanonical NF-kappaB pathways. These data are the first to link TGF-beta signaling with IDO in controlling spontaneous tolerogenesis by DCs.     

Leptin-leptin receptor are involved in angiogenesis in human hepatocellular carcinoma

Recent evidence in vitro and in vivo indicates that leptin, an adipose tissue-secreted hormone which is involved in the regulation of satiety, metabolic rate and thermogenesis, is implicated in angiogenesis. However, the role of leptin-mediated angiogenesis in hepatic carcinogenesis has not yet been completely elucidated. In this study, we have correlated microvascular density and leptin/leptin receptor (Ob-R) expression in endothelial and tumor cells with the histopathological type in human hepatocellular carcinoma (HCC). For this purpose, specimens of 40 primary HCC were submitted to immunohistochemical investigation using anti-CD31, anti-leptin and anti-Ob-R antibodies. Poorly-differentiated HCC had a higher degree of vascularization than other stages and leptin/Ob-R expression in both tumor and endothelial cells increased in parallel with the grade of malignancy and was highly correlated with the degree of angiogenesis. In the chick embryo chorioallantoic membrane in vivo assay, HCC biopsy specimens induced a strong angiogenic response, which was counteracted by an anti-leptin antibody. Taken together, these findings indicate that leptin/Ob-R correlate with angiogenesis and tumor progression in patients with HCC and that an anti-leptin antibody exerts an angiostatic activity in HCC.     

Phylogenetic diversity of stress signalling pathways in fungi

Background  

Microbes must sense environmental stresses, transduce these signals and mount protective responses to survive in hostile environments. In this study we have tested the hypothesis that fungal stress signalling pathways have evolved rapidly in a niche-specific fashion that is independent of phylogeny. To test this hypothesis we have compared the conservation of stress signalling molecules in diverse fungal species with their stress resistance. These fungi, which include ascomycetes, basidiomycetes and microsporidia, occupy highly divergent niches from saline environments to plant or mammalian hosts.     

An updated 18S rRNA phylogeny of tunicates based on mixture and secondary structure models

Background  

Tunicates have been recently revealed to be the closest living relatives of vertebrates. Yet, with more than 2500 described species, details of their evolutionary history are still obscure. From a molecular point of view, tunicate phylogenetic relationships have been mostly studied based on analyses of 18S rRNA sequences, which indicate several major clades at odds with the traditional class-level arrangements. Nonetheless, substantial uncertainty remains about the phylogenetic relationships and taxonomic status of key groups such as the Aplousobranchia, Appendicularia, and Thaliacea.     

Comparative,double-blind,controlled study of intra-articular hyaluronic acid (Hyalubrix?) injections versus local anesthetic in osteoarthritis of the hip

Introduction

Comparison of intra-articular bacterial-derived hyaluronic acid (Hyalubrix^®) (HA) with local analgesia (mepivacaine) for osteoarthritis (OA) of the hip.

Methods

A pilot prospective, double-blind, 6-month randomized trial of 42 patients with hip OA. HA or mepivacaine was administered twice (once a month) under ultrasound guidance. Efficacy measurements included the Lequesne''s algofunctional index, a visual analog scale for pain, concomitant use of analgesia, patient and physician global measurement, and safety.

Results

Patients in the HA group exhibited a significantly reduced Lequesne''s algofunctional index 3 and 6 months after treatment (P < 0.001) and significantly reduced visual analog scale pain scores 3 and 6 months after treatment (P < 0.05) compared with the local anesthetic group. All primary and secondary measures were significantly improved versus baseline, but other than the above were not different from each other at 3 or 6 months. Adverse effects were minimal.

Conclusions

This comparative study suggests a beneficial effect and safety of intra-articular HA in the management of hip OA.

Trial registration number

ISRCTN39397064.     

Design and synthesis of substituted 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides, novel HIV-1 integrase inhibitors

A series of 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides was synthesized and tested for their inhibition of HIV-1 integrase catalytic activity and HIV-1 replication in cells. Structure-activity studies around lead compound 5 indicated that a coplanar relationship of metal-binding heteroatoms provides optimal binding to the integrase active site. Identification of potency-enhancing substituents and adjustments in lipophilicity provided 17b which inhibits integrase-catalyzed strand transfer with an IC(50) value of 74 nM and inhibits HIV-1 replication in cell culture in the presence of 50% normal human serum with an IC(95) value of 63 nM.