1,721,064 research outputs found
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
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
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
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
Enhancement of in vivo immune response by tumor necrosis factor
No full text: Interleukin 1 (IL-1) has been shown to regulate several immunologic functions. Since tumor necrosis factor (TNF) shares many biologic properties with IL-1, we have investigated here the role of TNF in the modulation of the immune response. We have thus tested low doses of human recombinant TNF-alpha (hu rTNF-alpha) for its capacity to enhance the in vivo antibody responses evaluated at the cellular level in the hemolytic plaque assay. It was found that hu rTNF-alpha, like human IL-1 beta, is able to enhance the immune response to a T cell-dependent antigen (sheep red blood cells). Interestingly, at variance with human recombinant IL-1 beta, hu rTNF-alpha was not able to enhance the in vivo antibody response to a T cell-independent antigen (type III pneumococcal polysaccharide). These results suggest that low levels of TNF may have a role in the modulation of the immune response in vivo and shed new light on the biologic significance of this mediator
Cytokines and soluble receptors of the interleukin-1 family in Schnitzler syndrome
No full textOBJECTIVES: Schnitzler syndrome (SchS) is an autoinflammatory disorder characterized by chronic urticaria, fever, and monoclonal gammopathy. The success of interleukin-1 (IL-1) blocking therapies suggests a crucial role for IL-1 in disease induction. The aim of this study is to perform a comprehensive analysis of IL-1 family cytokines and soluble receptors in a group of SchS patients. METHOD: Three patients fulfilling the criteria for the diagnosis of SchS were recruited; 80 blood donors formed the control group. IL-1 family cytokines (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, sIL-1R4), and antagonists [IL-1Ra, IL-18 binding protein (IL-18BP)] were measured by a multiarray enzyme-linked immunosorbent assay. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Cytokine levels were compared by the Mann-Whitney test. RESULTS: IL-18 and free IL-18 were increased in patients compared with controls (p = 0.005 and p = 0.0082, respectively), while IL-18BP levels were not different. IL-1α, IL-1β, and IL-33 were undetectable in both patients and controls. The soluble receptors sIL-1R1, sIL-1R2, and ST2/sIL-1R4, and the IL-1 antagonist IL-1Ra were all within normal ranges; sIL-1R3 was significantly lower in patients than in controls (p = 0.039). CONCLUSIONS: The data indicate that SchS is characterized by increased circulating levels of free IL-18, possibly leading to a higher activation of innate/inflammatory effector cells. At variance with other inflammatory diseases, the lack of increase in sIL-1R1 and sIL-1R2 and the decreased levels of sIL-R3 imply a failure in the counterbalancing mechanism aimed at inhibiting excessive IL-1β in tissues
IgA-driven antibacterial activity against Streptococcus pneumoniae by mouse lung lymphocytes
No full textTo investigate the role of lung lymphocytes (LL) in the local defense mechanisms, we studied the natural antibacterial (NA) activity of mouse LL with an in vitro assay using S. pneumoniae type 3 as target. In parallel, natural killer (NK) activity against YAC-1 tumor cells was investigated. Lung cells obtained by enzymatic digestion were found to exert detectable NA and NK activities, which were further increased after purification of LL (greater than 90\% lymphocytes) by carbonyl iron and magnet treatment. Depletion experiments with antibodies and complement indicated that the effector cell of NA activity was a Thy 1.2+, L3T4+, aGM1+ lymphocyte, whereas the effector of NK activity was found to have a Thy 1.2-, aGM1+ phenotype. Preincubation of LL with anti-IgA antibodies, but not with anti-IgG, completely inhibited NA activity, suggesting that it was mediated by preexisting IgA bound to the LL surface. Furthermore, purified IgA from S107 plasmacytoma with specificity for phosphorylcholine, a component of the outer wall of S. pneumoniae, was able to enhance the antibacterial activity of LL and to restore their activity after treatment with anti-IgA. In addition, S107 antibodies were found to specifically induce antibacterial activity against S. pneumoniae in resident alveolar macrophages (AM) and peritoneal exudate cells, which did not express NA activity. We conclude that mouse LL include a subset of IgA-bearing lymphocytes with the phenotype of helper-T cells, which are able to exert NA activity against pneumococcus through an IgA-driven mechanism.(ABSTRACT TRUNCATED AT 250 WORDS
Free circulating interleukin-18 is increased in Schnitzler syndrome: a new autoinflammatory disease?
No full textSchnitzler syndrome is a rare disease characterised by chronic urticaria and arthralgia. The recent evidence that the IL-1 receptor antagonist IL-1Ra could induce rapid and complete remission of Schnitzler symptoms has pointed to IL-1 as a major pathological factor in this disease. To examine the possibility that Schnitzler syndrome may be considered to be an autoinflammatory disease, in this study we measured the serum levels of IL-18, another cytokine of the IL-1 family that is cleaved by caspase-1, in two recently diagnosed Schnitzler patients before and after treatment with IL-1Ra. In parallel, mRNA expression of IL-1 family cytokines and caspase-1 were assessed in isolated blood monocytes. Treatment with IL-1Ra significantly inhibited IL-1beta gene expression, indicating that IL-1beta activity in Schnitzler syndrome is central to IL-1beta gene upregulation in a type of auto-amplification loop. While no IL-1beta was detected in serum, free circulating IL-18 was increased in patients with Schnitzler syndrome, despite low IL-18 gene expression in monocytes. This suggests constitutive activation of the IL-1beta/IL-18-producing inflammasome, and supports the hypothesis that Schnitzler's syndrome is a new autoinflammatory disease
A short synthetic peptide fragment of human interleukin-1 beta increases both human and murine natural killer activity
No full textThe effect of a short synthetic fragment of human interleukin-1 beta (hu IL-1 beta) on natural killer (NK) activity was examined. Peripheral-blood mononuclear cells (PBMC) from normal donors showed a significant increase in NK activity against K562 leukemia cells after preincubation for 18 h with the IL-1 peptide. A similar augmentation was not observed after culturing the cells in the presence of hu IL-1 beta. The increase in tumor cell lysis could not be ascribed to a cytolytic activity of the synthetic fragment on target cells, since the peptide caused no direct lysis of various tumor cell lines. Although the peptide enhanced NK cytotoxicity of PBMC, highly purified large granular lymphocytes were not susceptible to its stimulatory effect. The addition to the cultures of antibodies to human interleukin-2 (hu IL-2) completely blocked the peptide-induced boost of NK cytotoxicity, suggesting that IL-2 is mainly involved in the activation process. The ability of the IL-1 peptide to increase NK activity was further confirmed in vivo in the mouse. Cytotoxicity against YAC-1 lymphoma cells, which was very low in the spleen of untreated BALB/c mice, was in fact significantly increased after a single inoculation of the peptide. These data thus indicate that a short synthetic peptide fragment of hu IL-1 beta is able to increase both human and murine NK activity
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
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