Inhibition of Experimental Allergic Airways Disease by Local Application of a Cell-penetrating Dominant-negative Stat-6 Peptide.
From: Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Journal of immunology (Baltimore, Md. : 1950)
- Publish Date: Aug 2007
- ISSN: 0022-1767
- Volume: 179
- Issue: 4
- Pages: 2556-64
- Medium: Print
- Language: English
- Citation (JAMA): McCusker Christine T, Wang Yufa, Shan Jichuan, et al. Inhibition of Experimental Allergic Airways Disease by Local Application of a Cell-penetrating Dominant-negative Stat-6 Peptide.. J. Immunol. Aug 2007;179:2556-64
Abstract
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-gamma, 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.
Mesh Headings (Keywords): Acute Disease, Administration, Intranasal, Animals, Asthma, Bronchoalveolar Lavage Fluid, Disease Models, Animal, Eosinophils, Interleukin-13, Interleukin-4, Mice, Mucus, Ovalbumin, Peptides, Pneumonia, Protein Binding, Recombinant Fusion Proteins, Respiratory Mucosa, Rhinitis, Allergic, Perennial, STAT6 Transcription Factor, Th2 Cells
Check for Full Text / PubMed Unique Identifier (PMID): 17675518
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