220 research outputs found
The immunostimulatory effect of IL-1β in vivo is blocked by antisense peptides complementary to the loop sequence 163–171
No full textAbstractAntisense (AS) peptides complementary to the β-bulge surface loop VQGEESNDK (Boraschi loop) of the cytokine interleukin-1β (IL-1β) have been shown to bind IL-1β at the Boraschi loop position, and to inhibit some of the IL-1β-mediated biological effects in vitro. Here we show that primary AS peptide FVITFFSLY inhibits IL-1β-mediated immunostimulation in vivo in a dose-dependent fashion, while inactive on IL-1β-induced inflammation, an effect that takes place independently of the Boraschi loop. To the best of our knowledge, this is the first time that an AS peptide has been used successfully in vivo
Corporate Scandals and Capital Structure
No full textcorporate scandals, security offerings, capital structure, contagion effect, market timing, G32, G33, K41,
Balance between autocrine interleukin-1b and caspases defines life versus death of polymorphonuclear cells.
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Eur Cytokine Netw. 2001 Mar;12(1):177-86.
Balance between autocrine interleukin-1beta and caspases defines life versus death of polymorphonuclear cells.
Bossù P, del Grosso E, Cesaroni MP, Maurizi G, Balestro N, Stoppacciaro A, del Giudice E, Ruggiero P, Boraschi D.
Source
Research Center Dompé S.p.A., Via Campo di Pile, I-67100 L'Aquila, Italy. [email protected]
Abstract
The role of endogenous IL-1beta in regulating spontaneous and Fas-triggered apoptosis of human PMN has been studied in relation to the activity of the IL-1beta-generating enzyme ICE (caspase-1), an enzyme also involved in the mechanism of cell death. Upon in vitro culture, PMN undergo spontaneous apoptosis and express increasing levels of IL-1beta, caspase-1- and caspase-3-like enzymes. Endogenous IL-1beta protects PMN from apoptosis, since inhibition of either IL-1beta or caspase-1 activity can accelerate PMN apoptotic death. Thus, in spontaneous PMN apoptosis caspase-1 essentially plays an anti-apoptotic role by inducing maturation of protective IL-1beta, whereas other molecules are responsible of driving apoptosis. Upon Fas triggering, PMN apoptosis is greatly accelerated, in correlation with increased caspase activity, whereas IL-1beta production is not augmented. Inhibition of IL-1beta activity can increase Fas-induced apoptosis, whereas caspase-1 inhibitors are without significant effect. It is hypothesized that in Fas-induced PMN apoptosis caspase-1 has a double role: it can protect from apoptosis through generation of protective IL-1beta, as in spontaneous apoptosis, and it can also exert pro-apoptotic activity which counterbalances the protective effect and allows accelerated apoptosis
Modulation of macrophage suppressive activity and prostaglandin release by lymphokines and interferon: comparison of alveolar, pleural and peritoneal macrophages
No full textIn order to better characterize the mechanisms which regulate the immune response at the pulmonary level, the effects of beta-interferon (IFN-beta) and lymphokines (LK) on prostaglandin E (PGE) release and the suppressive capacity of mouse resident alveolar (AM phi) and pleural macrophages (PlM phi) were investigated in comparison with peritoneal macrophages (PM phi). After in vitro exposure to IFN-beta, PlM phi and PM phi showed a significant decrease of suppressive capacity and PGE release, whereas LK treatment did not affect such activities. In contrast, pre-treatment of AM phi with LK caused a strong impairment of their suppressive capacity. This effect was optimal after an incubation time of 20 h, was evident also at very low doses of LK and was not paralleled by any change of PGE release. Again in contrast with PlM phi and PM phi, suppressive capacity of AM phi was decreased only by very high doses of IFN-beta, whereas lower doses caused either an increase or no change of this activity. Furthermore, PGE release by AM phi was markedly increased after treatment with IFN-beta. Thus, suppressive capacity of AM phi appears to be controlled by different mechanisms from those of PlM phi and PM phi. In addition, a dissociation is evident between suppressive capacity and PGE release by AM phi
Interaction of nanoparticles with immunocompetent cells: nanosafety considerations.
No full textThe article deals with the interaction of nanoparticulate drug carriers with the immune system of the bod
Challenges in the design of clinically useful brain-targeted drug nanocarriers
No full textAbstract: Nowadays, the delivery of drugs by means of intravenously administered nanosized drug carriers - polymer-drug conjugates, liposomes and micelles, is technically possible. These delivery systems are mainly designed for tumour therapy, and accumulate passively into tumours by means of the well known EPR effect. Targeted nanocarriers, that additionally contain ligands for receptors expressed on cell surfaces, are also widely studied but products of this kind are not marketed, and only a few are in clinical trial. Polymeric nanoparticles (Np) able to deliver drugs to the CNS were pioneered in 1995; a number of papers have been published dealing with brain-targeted drug delivery using polymeric Np able to cross the BBB, mainly for the treatment of brain tumours. At present, however, the translation potential of these Np seems to have been exceeded by targeted liposomes, a platform based on a well-known technology. This drug delivery system entered clinical trials soon after its discovery, while the challenges in formulation, characterization and manufacturing of brain-targeted polymeric Np and the cost/benefit ratio could be the factors that have prevented their development. A key issue is that it is virtually impossible to define the in vivo fate of polymers and especially in the brain, which is a regulatory requirement, and perhaps this is why no progress has been made. The most advanced Np for brain tumours treatment will be compared here with the published data available for those in clinical trial for tumours outside the CNS, to highlight the knowledge gaps that still penalise these delivery systems. At present, new approaches for brain tumour treatment are emerging, such as lipid Np or the use of monoclonal antibody (mAb)-drug conjugates, which avoid polymers. The possibility of success or failure in the approval of the polymeric Np currently in clinical trial will certainly affect the fate of brain-targeted Np. At present, the chances of their approval appear to be very low
The causes and financial consequences of corporate frauds
No full textAnother wave of corporate scandals has hit the market in the last decade, reviving attention to the effect of these events on shareholder value, corporate governance and stock market reactions. Given this evidence a growing body of research has investigated the determinants of frauds, the effects of frauds on investors and stakeholders wealth and tried to identify channels and tools to early detect frauds and therefore reduce the loss in social welfare. This chapter provides a comprehensive view on the state of the current research on these issues and provides suggestions for future research
Model of ligand/receptor complex formation by the IL-1-like cytokines IL-18 and IL-1F7 with IL-18RRα and with the accessory protein IL-18RRβ.
No full textIL-18 is an immunomodulatory/inflammatory protein belonging to the IL-1 family of innate cytokines. IL-18 activates target cells following interaction with IL-18RRα, an Ig-like protein belonging to the IL-1R family. As for IL-11β, after interaction of IL-18 with IL-18RRα, a second accessory receptor chain (IL-18RRβ, another member of the IL-1R family) is recruited to the complex and allows signal transduction. The complex of IL-11β with its receptor IL-1RI has been crystallised and its structure resolved. A subsequent modelling study has allowed to describe the interaction of the accessory chain IL-1RAcP with the IL-11β/IL-1RI complex. Nothing is known about the interaction between IL-18, IL-18RRα, and IL-18RRβ.
In this study, the interaction of IL-18 with IL-18RRα and the subsequent interaction of the complex with IL-18RRβ has been studied in silico by molecular modelling, on the basis of the structural data of the IL-11β/IL-1RI/IL-1RAcP complex. First, IL-18RRα and IL-18RRβ have been modelled on the crystal structure of IL-1RI, PDB code 1ITB. The alignment was generated with ClustalW, the 3D structure prediction was made with MODELLER9 and validated with PROSA/PROCHECK. Then, the IL-18 NMR structure (PDB code 1J0S) has been docked to IL-18RRα using AutoDock 3.05 on the basis of mutagenesis data. At last, IL-18RRβ has been docked to the predicted IL-18/IL-18RRα model.
Another IL-1-like molecule, IL-1F7, can bind to IL-18RRα, but allegedly does not recruit IL-18RRβ into an activating complex. Modelling and docking of IL-1F7 to the IL-18RRα model and subsequent docking of the IL-18RRβ model to the modelled IL-1F7/IL-18RRα complex is in progress
Ifn-beta-induced reduction of superoxide anion generation by macrophages.
No full text: Resident mouse peritoneal macrophages (M phi) produced significant amounts of superoxide anion (O2-) in response to phagocytic stimuli. When M phi were exposed in vitro for 20 hr to fibroblast interferon (IFN-beta), their capacity to release O2- was significantly reduced, such reduction being more evident with increasing IFN-beta concentrations. In contrast, O2- production by M phi exposed for 20 hr to the lymphokine macrophage activating factor (MAF) or treated with either MAF or IFN-beta for 4 hr was not significantly different from that of control cells. This pattern of activity closely followed that of M phi-mediated suppression of lymphocyte proliferation, which was dramatically reduced by 20 hr exposure of M phi to IFN-beta, but unchanged by treatment with MAF. No correlation was however found between superoxide anion generation and enhancement of tumoricidal capacity in IFN-beta-treated M phi. We thus concluded that O2- does not play a relevant role in IFN-beta-induced M phi cytolysis, whereas the reduction of O2- production could be of major importance in the decrease of M phi suppression induced by IFN-beta
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