Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression
Details
Serval ID
serval:BIB_9BC0C22DA66D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression
Journal
Journal of Experimental Medicine
ISSN
0022-1007
Publication state
Published
Issued date
2001
Peer-reviewed
Oui
Volume
193
Number
11
Pages
1247-1260
Language
english
Abstract
Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4-producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA-3, whereas nonsense control oligonucleotides were virtually inactive. In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate-labeled GATA-3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA-3 expression. Such intrapulmonary blockade of GATA-3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production. Furthermore, treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA-sensitized mice to levels comparable to saline-treated control mice, as assessed by both enhanced pause (PenH) responses and pulmonary resistance determined by body plethysmography. These data indicate a critical role for GATA-3 in the effector phase of a murine asthma model and suggest that local delivery of GATA-3 antisense oligonucleotides may be a novel approach for the treatment of air-way hyperresponsiveness such as in asthma. This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine.
Keywords
GATA-3 antisense DNA, asthma, T cells, Th2 cytokines, TRANSCRIPTION FACTOR GATA-3, CHRONIC INTESTINAL INFLAMMATION, DEVELOPING TH1 CELLS, CD4(+) T-CELLS, MOUSE MODEL, TH2-SPECIFIC EXPRESSION, GENE-EXPRESSION, TRANSGENIC MICE, ATOPIC ASTHMA, MURINE MODEL
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Create date
15/12/2011 22:02
Last modification date
20/08/2019 16:02