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Background: Th2 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-Υδ T cells is poorly understood. In murine models, under some conditions, IL-17 promotes Th2-biased airway inflammatory responses. However, IL-17-Υδ T cells have been implicated in the inhibition and resolution of allergic airway inflammation and hyperresponsiveness (AHR). Methods: We 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 Υδ T cells in these responses was addressed in OVA/CFA sensitized mice using a Υδ T cell antibody. Results: Following 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 Υδ T cells. Additionally, OVA/CFA sensitized mice, given a Υδ TCR stimulatory antibody, showed increased frequencies of IL-17-Υδ T cells and diminished airway reactivity and eosinophilia. Conclusions: Thus, 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-Υδ T cells to reduce AHR and robust eosinophilic inflammation provides evidence that therapeutic approaches focused on stimulating and increasing airway IL-17-Υδ T cells may be an effective alternative in treating steroid resistant, severe asthma. [ABSTRACT FROM AUTHOR]

The Th2 cytokine IL-13 regulates several aspects of the asthmatic phenotype, including airway inflammation, airway hyperresponsiveness, and mucus production. The Thl7 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 wit 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]