Molecular immunology
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Molecular immunology · Jul 2015
Exploiting ovine immunology to improve the relevance of biomedical models.
Animal models of human disease are important tools in many areas of biomedicine; for example, in infectious disease research and in the development of novel drugs and medical devices. Most studies involving animals use rodents, in particular congenic mice, due to the availability of a wide number of strains and the ease with which they can be genetically manipulated. ⋯ It is increasingly becoming recognised that in many circumstances mice do not provide the best model and that alternative species may be more appropriate. Here, we describe the relative merits of sheep as biomedical models for human physiology and disease in comparison to mice, with a particular focus on reproductive and respiratory pathogens.
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Molecular immunology · May 2015
Lipoprotein in the cell wall of Staphylococcus aureus is a major inducer of nitric oxide production in murine macrophages.
Staphylococcus aureus is a Gram-positive bacterium that causes inflammation at infection sites by inducing various inflammatory mediators such as nitric oxide (NO). To identify the staphylococcal virulence factors contributing to NO production, we compared the ability of ethanol-killed wild-type S. aureus and mutant strains lacking lipoteichoic acid (ΔltaS), lipoproteins (Δlgt), or d-alanine (ΔdltA) to stimulate NO production in a murine macrophage cell line, RAW 264.7, and the primary macrophages derived from C57BL/6 mice. Wild-type, ΔltaS, and ΔdltA strains induced NO production in a dose-dependent manner but this response was not observed when the cells were stimulated with the Δlgt strain. ⋯ Transient transfection followed by a reporter gene assay and Western blotting experiments demonstrated that wild-type, ΔltaS, and ΔdltA strains, but not the Δlgt strain, induced substantial activation of NF-κB and STAT1 phosphorylation, both of which are known to be crucial for iNOS expression. Moreover, wild-type, ΔltaS, and ΔdltA strains increased Toll-like receptor 2 (TLR2) activation, which is known to mediate S. aureus-induced innate immunity, whereas the Δlgt strain did not. Collectively, these results suggest that lipoproteins in the cell wall of S. aureus play a major role in the induction of NO production in murine macrophages through activation of the TLR2 receptor.
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Molecular immunology · Feb 2015
The effect of the decoy molecule PA401 on CXCL8 levels in bronchoalveolar lavage fluid of patients with cystic fibrosis.
The chemokine interleukin-8 (CXCL8) is a key mediator of inflammation in airways of patients with cystic fibrosis (CF). Glycosaminoglycans (GAGs) possess the ability to influence the chemokine profile of the CF lung by binding CXCL8 and protecting it from proteolytic degradation. CXCL8 is maintained in an active state by this glycan interaction thus increasing infiltration of immune cells such as neutrophils into the lungs. As the CXCL8-based decoy PA401 displays no chemotactic activity, yet demonstrates glycan binding affinity, the aim of this study was to investigate the anti-inflammatory effect of PA401 on CXCL8 levels, and activity, in CF airway samples in vitro. ⋯ PA401 can disrupt CXCL8:GAG complexes, rendering the chemokine susceptible to proteolytic degradation. Clinical application of a CXCL8 decoy, such as PA401, may serve to decrease the inflammatory burden in the CF lung in vivo.
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Despite the fact that cyclooxygenase and its products, prostaglandins, have been traditionally associated with the development of inflammation, PGE2 was implicated early on as potentially beneficial in asthma. During the 1970s and 1980s, several studies reported the bronchodilator effect of PGE2 in asthma patients. In parallel, it was being shown to exert an inhibitory effect on mast cells in vitro. ⋯ Indeed, it has been shown that PGE2 prevents human and murine MC activity in vitro through activation of the EP2 receptor, and also that both exogenously administered and endogenous PGE2 inhibit airway MC activity in vivo in mouse models of asthma (likely through an EP2-mediated mechanism as well). In the last few years, we have furthered into the functional connection between PGE2-induced mast cells inhibition and attenuated damage, in asthma and allergy models. The validity of the findings supporting a beneficial effect of PGE2 in different asthma phases, the direct effect of PGE2 on mast cells populations, and the functional implications of the PGE2-MC interaction on airway function are some of the topics addressed in this review, under the assumption that increased understanding of the PGE2-EP2-mast cell axis will likely lead to the discovery of novel antiasthma targets.
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Molecular immunology · Dec 2013
Aloe vera downregulates LPS-induced inflammatory cytokine production and expression of NLRP3 inflammasome in human macrophages.
Aloe vera has been used in traditional herbal medicine as an immunomodulatory agent inducing anti-inflammatory effects. However, its role on the IL-1β inflammatory cytokine production has not been studied. IL-1β production is strictly regulated both at transcriptional and posttranslational levels through the activity of Nlrp3 inflammasome. ⋯ Altogether, we show for the first time that Aloe vera-mediated strong reduction of IL-1β appears to be the consequence of the reduced expression of both pro-IL-1β as well as Nlrp3 inflammasome components via suppressing specific signal transduction pathways. Furthermore, we show that the expression of the ATP sensor P2X7 receptor is also downregulated by Aloe vera that could also contribute to the attenuated IL-1β cytokine secretion. These results may provide a new therapeutic approach to regulate inflammasome-mediated responses.