Enforced Gata3 Expression Increases Susceptibility To Allergic Airway Inflammation In Mice

Abstract

RATIONALE: Allergic asthma is a multifactorial disease with involvement of dendritic cells, T-helper-2 (Th2) cells, mast cells, eosinophils and structural cells. The inflammation is mediated by Th2 cells, which express the transcription factor Gata3. Several studies have shown that reduced gata3 is associated with reduced release of Th2 cytokines. There are, however, no studies available indicating that elevated Gata3 expression in vivo would result in higher susceptibility for Th2 diseases. We hypothesized that increased Gata3 expression in T-cells is sufficient to increase susceptibility to allergic airway inflammation.METHODS: Mice with T-cell specific transgenic Gata3 overexpression driven by the CD2 promoter (CD2-Gata3tg) and wild-type (WT) controls underwent intratracheal ovalbumin (OVA) or a house dust mite (HDM) or sham sensitizations without adjuvant. Following allergen exposures, they were analyzed for eosinophilic inflammation and T-cell cytokine production.RESULTS: In both OVA and HDM model, Gata3 overexpressing mice showed clear eosinophilic inflammation and enhanced levels for IL-5 and IL-13 in bronchoalveolar lavage (BAL) and an abundant presence of IL-4+ T-cells and IL-5+ T-cells in BAL, lung tissue and mediastinal lymph node. The WT and control animals showed no signs of allergic inflammation in the OVA model. Moreover no differences were observed in levels of IFN-γ+ T-cells and IL-17+ T-cells. WT animals sensitized with HDM showed eosinophilic inflammation, which was less than in HDM sensitized CD2-Gata3tg animals.CONCLUSION: Here we prove, for the first time, that enforced expression of Gata3 in T-cells is sufficient to increase allergic airway inflammation in mice, demonstrating that Gata3 is a crucial factor in asthma. RATIONALE: Allergic asthma is a multifactorial disease with involvement of dendritic cells, T-helper-2 (Th2) cells, mast cells, eosinophils and structural cells. The inflammation is mediated by Th2 cells, which express the transcription factor Gata3. Several studies have shown that reduced gata3 is associated with reduced release of Th2 cytokines. There are, however, no studies available indicating that elevated Gata3 expression in vivo would result in higher susceptibility for Th2 diseases. We hypothesized that increased Gata3 expression in T-cells is sufficient to increase susceptibility to allergic airway inflammation. METHODS: Mice with T-cell specific transgenic Gata3 overexpression driven by the CD2 promoter (CD2-Gata3tg) and wild-type (WT) controls underwent intratracheal ovalbumin (OVA) or a house dust mite (HDM) or sham sensitizations without adjuvant. Following allergen exposures, they were analyzed for eosinophilic inflammation and T-cell cytokine production. RESULTS: In both OVA and HDM model, Gata3 overexpressing mice showed clear eosinophilic inflammation and enhanced levels for IL-5 and IL-13 in bronchoalveolar lavage (BAL) and an abundant presence of IL-4+ T-cells and IL-5+ T-cells in BAL, lung tissue and mediastinal lymph node. The WT and control animals showed no signs of allergic inflammation in the OVA model. Moreover no differences were observed in levels of IFN-γ+ T-cells and IL-17+ T-cells. WT animals sensitized with HDM showed eosinophilic inflammation, which was less than in HDM sensitized CD2-Gata3tg animals. CONCLUSION: Here we prove, for the first time, that enforced expression of Gata3 in T-cells is sufficient to increase allergic airway inflammation in mice, demonstrating that Gata3 is a crucial factor in asthma.