The failure of STAT6-deficient mice to develop airway eosinophilia and airway hyperresponsiveness is overcome by interleukin-5.
While signal transducer and activator of transcription protein 6 (STAT6) is important in interleukin-4 (IL-4)-induced commitment of CD4(+) T cells to the T helper cell, type 2 (Th2) phenotype and IgE isotype switching in B cells, its role in other IL-4-mediated events and their impact upon the allergic response is less evident. In the present study we demonstrate the critical role of STAT6 in the development of allergic airway eosinophilia and airway hyperresponsiveness (AHR) after allergen sensitization and challenge. STAT6-deficient (STAT6-/-) mice did not develop a Th2 cytokine response or an allergen-specific IgE response. Further, STAT6-/- mice had a reduced constitutive and allergen-induced expression of CD23 as well as lower mucus production in the airway epithelium. Critically, we show that IL-5 alone can reconstitute airway eosinophilia and AHR in sensitized and challenged STAT6-/- mice. This emphasizes the essential nature of the IL-4-dependent signaling of T cells to the Th2 phenotype and secretion of IL-5, resulting in the airway eosinophilia and AHR. These observations underscore the importance of targeting this pathway in new antiallergic asthma drug development.
Tomkinson
A
A
Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, 80206, USA.
Kanehiro
A
A
Rabinovitch
N
N
Joetham
A
A
Cieslewicz
G
G
Gelfand
E W
EW
D000485:Allergens; D000818:Animals; D020296:Animals, Congenic; D001249:Asthma / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004804:Eosinophils / Q000473:pathology* / Q000502:physiology; D005260:Female; D007114:Immunization; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D015848:Interleukin-5 / Q000032:analysis / Q000502:physiology*; D008297:Male; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D017455:Receptors, IgE / Q000032:analysis; D020545:Respiratory Mucosa / Q000473:pathology*; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000485:Allergens; D007074:Immunoglobulin G; D015848:Interleukin-5; D017455:Receptors, IgE; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin