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Inhibition of Experimental Allergic Airways Disease by Local Application of a Cell-Penetrating Dominant-Negative STAT-6 Peptide¹

Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada

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-, 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by operating grants (PPP-73349 and MOP-82766) from the Canadian Institutes of Health Research, with funding from the Montreal Children’s Hospital Research Institute and the JT Costello Memorial Research Fund. E.D.F. and C.T.M. are recipients of salary awards from the Fonds de la recherche en santé du Québec.

² Address correspondence and reprint requests to Dr. Elizabeth D. Fixman, Meakins-Christie Laboratories, McGill University, 3626 Saint Urbain, Montreal, Quebec, Canada H2X 2P2. E-mail address: elizabeth.fixman{at}mcgill.ca

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; hSTAT-6, human STAT-6; PAS, periodic acid Schiff; SH2, Src homology 2; STAT-6-CP, STAT-6 negative control peptide; STAT-6-IP, STAT-6 inhibitory peptide; Tyr, tyrosine; *Y, phosphotyrosine; NS, normal saline; PTD4, protein transduction domain 4.