Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT-6 peptide.
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.
McCusker
Christine T
CT
Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Wang
Yufa
Y
Shan
Jichuan
J
Kinyanjui
Margaret W
MW
Villeneuve
Annie
A
Michael
Husheem
H
Fixman
Elizabeth D
ED
D000208:Acute Disease; D000281:Administration, Intranasal; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D009093:Mucus / Q000276:immunology; D010047:Ovalbumin / Q000633:toxicity; D010455:Peptides / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology; D012221:Rhinitis, Allergic, Perennial / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D050800:STAT6 Transcription Factor / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
D018793:Interleukin-13; D010455:Peptides; D011993:Recombinant Fusion Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D010047:Ovalbumin