Transcription Factors T-bet and GATA-3 Regulate Development of Airway Remodeling

Abstract

Rationale: Airway remodeling is an important feature of chronic asthma that causes irreversible airflow obstruction. Although asthma is considered to be a Th2 disease, the role of T-bet and GATA-3, the key transcription factors for differentiation toward Th1 and Th2 cells, in the pathogenesis of airway remodeling is poorly understood. Objectives: We therefore examined the effects of GATA-3 or T-bet induction of Th1/Th2 bias on the development of airway remodeling in mice. Methods: The development of airway remodeling after repeated allergen challenges was analyzed using transgenic mice overexpressing either GATA-3 or T-bet. Main Results: The degrees of subepithelial fibrosis and airway smooth muscle hyperplasia after repeated allergen exposure were significantly enhanced in mice overexpressing GATA-3, compared with wild-type mice. Allergen-induced goblet cell hyperplasia and mucus hypersecretion were significantly lower in mice overexpressing T-bet than in wild-type mice. Eosinophilic airway inflammation increased in mice overexpressing GATA-3, but decreased in mice overexpressing T-bet after repeated allergen exposure. Cytokine analysis revealed that the Th1/Th2 cytokine balance shifted to Th2 in lung homogenates and lung T cells of mice overexpressing GATA-3, whereas this balance shifted to Th1 in those of mice overexpressing T-bet after allergen exposure. Lung transforming growth factor-␤ and eotaxin levels were associated with the degree of subepithelial fibrosis and eosinophilic airway inflammation, respectively. Conclusions: Overall, the results indicate that development of airway remodeling is regulated by the lung Th1/Th2 bias induced by GATA-3 and T-bet.

Enforced Expression of Gata3 in T Cells and Group 2 Innate Lymphoid Cells Increases Susceptibility to Allergic Airway Inflammation in Mice

“…In chronic models that involve repeated allergen exposure, enforced Gata3 expression was associated with increased subepithelial fibrosis and airway smooth muscle hyperplasia (35). Although in most of these published models Gata3 expression was also driven by the human CD2 promoter, the effects of Gata3 overexpression on cytokine profiles appeared variable: limited effects on IL-4 but increased IL-5/IL-13 expression (33), increased IL-4 but similar IL-5 levels (35), and increased production of IL-4, IL-5, and IL-13 (36) have all been described.…”

“…Several other groups have generated Tg mice with overexpression of Gata3 and have consistently reported enhanced eosinophilic airway inflammation (33)(34)(35)(36). In chronic models that involve repeated allergen exposure, enforced Gata3 expression was associated with increased subepithelial fibrosis and airway smooth muscle hyperplasia (35).…”

“…These CD2-Gata3 Tg mice lacked Th1-mediated hypersensitivity responses and showed reduced differentiation or activity of the Th17 cell subset, and protection from autoimmune encephalomyelitis and rheumatoid arthritis (29,31,32). Overexpression of Gata3 in T cells has been associated with enhanced Th2 responses and eosinophilic airway inflammation in vivo (33)(34)(35)(36). However, effects of Gata3 overexpression on the ILC2 population in AAI remain unknown.…”

Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury

“…Total-RNA extraction using RNAiso™ Plus was prepared as previously described (23). The expression levels of genes were determined by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) using an ABI-Prism 7300 Sequence BioDetector (PE Biosystems, Foster City, CA).…”

Modulação da resposta alérgica por BCG recombinante em modelo murino de asma.

“…De forma análoga, T-bet é membro de uma família de fatores de transcrição do tipo "T-box". A expressão de T-bet é fortemente relacionada com a expressão de IFN-γ, e é regulado positivamente ao longo da via de diferenciação para Th1 (101) . Com base nesses dados da literatura, investigamos a expressão desses fatores de transcrição no pulmão dos animais submetidos ao protocolo profilático.…”