Allergic airways disease is initiated and perpetuated by an aberrant Th2 inflammatory response regulated in part by the cytokines IL-4 and IL-13, each of which induces activation of the STAT-6 transcription factor. Data from murine models indicate that the clinical manifestations of acute asthma are STAT-6 dependent, and thus, STAT-6 is a target for drug development in allergic airways disease. We designed a novel chimeric peptide (STAT-6 inhibitory peptide (STAT-6-IP)) comprised of a sequence predicted to bind to and inhibit STAT-6, fused to a protein transduction domain, to facilitate cellular uptake of the STAT-6-binding peptide. Our data demonstrate that the STAT-6-IP inhibited OVA-induced production of Th2 cytokines IL-4 and IL-13 in vitro. In contrast, the STAT-6-IP did not affect production of IFN-γ, demonstrating specificity for Th2 cytokine inhibition. Following intranasal administration, the STAT-6-IP was localized to epithelial cells in the airways. Finally, in in vivo murine models of allergic rhinitis and asthma, intranasal delivery of the STAT-6-IP inhibited OVA-induced lung inflammation and mucus production as well as accumulation of eosinophils and IL-13 in bronchoalveolar lavage fluid and OVA-dependent airway hyperresponsiveness. Together these data show that local application of cell-penetrating peptide inhibitors of STAT-6 has significant potential for the treatment of allergic rhinitis and asthma.
The Th2 cytokine IL-13 regulates several aspects of the asthmatic phenotype, including airway inflammation, airway hyperresponsiveness, and mucus production. The Th17 cytokine IL-17A is also implicated in asthma and has been shown to both positively and negatively regulate Th2-dependent responses in murine models of allergic airways disease. Our objective in this study was to better understand the role of IL-17 in airway inflammation by examining how IL-17 modifies IL-13–induced airway inflammatory responses. We treated BALB/c mice intranasally with IL-13 or IL-17 alone or in combination for 8 consecutive days, after which airway hyperresponsiveness, inflammatory cell influx into the lung, and lung chemokine/cytokine expression were assessed. As expected, IL-13 increased airway inflammation and airway hyperresponsiveness. IL-13 also increased numbers of IL-17–producing CD4+ and γδ T cells. Treating mice with a combination of IL-13 and IL-17 reduced infiltration of IL-17+ γδ T cells, but increased the number of infiltrating eosinophils. In contrast, coadministration of IL-13 with a higher dose of IL-17 decreased all IL-13–induced inflammatory responses, including infiltration of both IL-17+CD4+ and γδ T cells. To examine the inhibitory activity of IL-17–expressing γδ T cells in this model, these cells were adoptively transferred into naive recipients. Consistent with an inhibitory role for γδ T cells, IL-13–induced infiltration of eosinophils, lymphocytes, and IL-17+CD4+ T cells was diminished in recipients of the γδ T cells. Collectively, our data indicate that allergic airway inflammatory responses induced by IL-13 are modulated by both the quantity and the cellular source of IL-17.
BackgroundTh2 immune responses are linked primarily to mild and moderate asthma, while Th17 cells, Interleukin-17A (IL-17) and neutrophilia have been implicated in more severe forms of disease. How Th2-dependent allergic reactions are influenced by Th17 and IL-17-γδ T cells is poorly understood. In murine models, under some conditions, IL-17 promotes Th2-biased airway inflammatory responses. However, IL-17-γδ T cells have been implicated in the inhibition and resolution of allergic airway inflammation and hyperresponsiveness (AHR).MethodsWe compared airway responses in Balb/c mice sensitized to OVA with (and without) a Th2-skewing aluminum-based adjuvant and the IL-17 skewing, complete Freund’s adjuvant (CFA). AHR was measured invasively by flexiVent, while serum OVA-IgE was quantified by an enzyme immunoassay. Airway inflammatory and cytokine profiles, and cellular sources of IL-17 were assessed from bronchoalveolar lavage and/or lungs. The role of γδ T cells in these responses was addressed in OVA/CFA sensitized mice using a γδ T cell antibody.ResultsFollowing OVA challenge, all mice exhibited mixed eosinophilic/neutrophilic airway inflammatory profiles and elevated serum OVA-IgE. Whereas OVA/alum sensitized mice had moderate inflammation and AHR, OVA/CFA sensitized mice had significantly greater inflammation but lacked AHR. This correlated with a shift in IL-17 production from CD4+ to γδ T cells. Additionally, OVA/CFA sensitized mice, given a γδ TCR stimulatory antibody, showed increased frequencies of IL-17-γδ T cells and diminished airway reactivity and eosinophilia.ConclusionsThus, the conditions of antigen sensitization influence the profile of cells that produce IL-17, the balance of which may then modulate the airway inflammatory responses, including AHR. The possibility for IL-17-γδ T cells to reduce AHR and robust eosinophilic inflammation provides evidence that therapeutic approaches focused on stimulating and increasing airway IL-17-γδ T cells may be an effective alternative in treating steroid resistant, severe asthma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-014-0090-5) contains supplementary material, which is available to authorized users.
Cell-penetrating peptides (CPPs) or protein transduction domains (PTDs) are peptides that have the ability to efficiently traverse cellular membranes, either alone or in association with molecular cargo. Several naturally occurring PTDs, including those from HIV TAT and Drosophila antennapedia, have this unique activity. Synthetic CPPs, such as polyarginine, also have the ability to enter cells and transport a variety of cargo. While the precise mechanism(s) of cellular entry for individual CPPs may vary, it is likely that uptake is mediated, at least in part, through endocytosis. Moreover, biological activity of cell-penetrating peptides and proteins has been clearly demonstrated in a number of in vitro and in vivo studies. Recently, cell-penetrating proteins targeting the Ras GTPase and the phospholipid kinase PI3K (phosphoinositide 3-kinase) have been shown to inhibit eosinophil trafficking and survival in vitro. These proteins, as well as CPPs targeting the STAT-6 transcription factor or the T-cell costimulatory molecule CTLA-4 (cytotoxic T lymphocyte-associated antigen-4), have also been tested in animal models of asthma. Data from several groups, including ours, indicate that these molecules inhibit airway eosinophilic inflammation, airway hyperresponsiveness (AHR), and mucus production in experimental allergic airways disease. Thus, CPPs targeting these and other signaling molecules may also effectively inhibit allergic airways disease in humans.
Purpose: The general objective of this study was to investigate the influence of multichannel retailing networks on the performance of selected fashion outlets in Nairobi.Methodology: The researcher used a descriptive research design, and the population and area of study was drawn from sampled outlets within Nairobi. The studies adopted stratified random sampling technique from the target population, as well as carried out a pilot study to pretest and validate the questionnaire. Multiple regression models were used to find out the importance of each of the four variables with reverence to the influence of multichannel retailing networks on the performance of selected fashion outlets in Nairobi.Results: Data analysis revealed that shopping experience was important in explaining performance. This is supported by a p value of 0.01 which means that shopping experience is a statistically significant predictor of performance. Findings also revealed that distribution channel is important in determining performance as demonstrated by a p value of 0.00 and a beta coefficient of 0.468.this implied that distribution channel was a statistically significant predictor of performance. Findings also indicated that organization structure was important in determining performance as demonstrated by a p value of 0.000 and a beta coefficient of 0.352. Findings reveal that capital was important in explaining performance. This was supported by a p value of 0.03 and a beta coefficient of 0.107 which means that capital was a statistically significant predictor of performance.Unique contribution to theory, practice and policy: The study recommends that the management of retail fashion outlets in Nairobi to conduct a market survey in order to establish the optimal shopping experience levels in order to reach out to more customers’ and hence achieve high performance.
Several features associated with allergic airways disease are regulated by the Th2 cytokine IL-13. IL-17 is also known to regulate aspects of allergic disease since production of IL-17 is associated with severe asthma and correlates with an increase in airway neutrophilia. The mechanism by which these IL-17 producing cells develop during airways disease is still unclear. To better understand what factors regulate the development of IL-17 producing cells we used an acute model of IL-13-induced airway inflammation in which IL-13 was intranasally administered to anaesthetized mice. As expected, administration of IL-13 induced airway eosinophilia, airway hyperresponsiveness, and mucus production. In addition, IL-13 induced airway neutrophilia as well as increases in expression of neutrophil chemokines. IL-13 also induced increased mRNA expression of IL-17 and IL-6 in the lung. Intracellular cytokine staining of bronchoalveolar lavage cells showed that IL-13 increased the number of IL-17+ve cells when compared to control. These cells did not produce IL-22 or IFN-gamma and were identified as either CD4 or γδ T cells. Animals were then treated with IL-13 in the presence of BrdU to follow development of IL-17 expresing cells in vivo. The majority of these cells incorporated BrdU suggesting that these IL-17+ve cells proliferated in the lung. Further studies to characterize these IL17+ve T cells are under way.
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