GATA binding protein 3 overexpression and suppression significantly contribute to the regulation of allergic skin inflammation

Abstract

Abstract. Gata binding protein 3 (Gata3) is a key molecule regulating the balance in the ratio of type 1 helper t (th1) cells to type 2 helper t (th2) cells, which is thought to be indicative of the pathogenesis of allergic diseases such as asthma and atopic dermatitis. the aim of this study was to investigate the role of GATA3 in allergic skin inflammation. transgenic (tg) mice overexpressing human Gata3 (hGata3) were produced by the microinjection of pCMV/hGATA3 constructs into fertilized mouse eggs. the hGata3 gene was successfully expressed at the protein level in the lymph node and thymus of cmV/hGata3 transfected cells and tg mice. CMV/hGATA3 Tg mice showed a significant increase in the allergic skin inflammation response such as ear thickness, draining auricular lymph node (aln) weight, epidermal thickness, inflammatory cell number and Th2 immunoglobulin (Ig) concentration compared to wild-type (Wt) mice after phthalic anhydride (Pa) treatment. furthermore, the secretion of th2 type cytokines was increased by Pa treatment in cmV/ hGata3 tg mice, while the secretion of th1 type cytokine was suppressed under the same conditions. However, the increased levels of th2 type cytokines in cmV/hGata3 tg mice were almost recovered by the down-regulation of Gata3 expression with D-pinitol treatment. Therefore, these findings suggest that Gata3 could be considered as a potential target regulating the mechanism responsible for the differences in allergic skin inflammation. Introductionallergic diseases, such as asthma, rhinitis and atopic dermatitis, are characterized by inflammation driven by type 2 helper T (th2) cells (1). in allergic individuals, the exposure to allergens results in activation of antigen-specific type 2 helper (Th2) cells and secretion of a variety of cytokines and inflammatory mediators that provoke the inflammatory response (2).th2 cytokines are predominantly regulated by the Gata binding protein 3 (Gata3). the zinc-finger transcription factor Gata3 is the master regulator of th2 cell differentiation and is strongly up-regulated during th2 differentiation (3). Generally, th1 and th2 cells are differentiated from common t precursor cells in the t cell developmental process (4,5). Two polarized subsets can be identified on the basis of the class of cytokines which secreted from each cell. th1 cells mainly secrete il-2 and ifn-γ, while th2 cells secrete il-4, il-5, il-6, il-10 and il-13 (6). Gata3 is believed to function by causing chromatin remodeling of the th2 cytokine locus by binding at multiple promoter sites and thus allowing th2 cells to express il-4, il-5 and il-13 (7,8). furthermore, several studies using Gata-3 deletion mutants have suggested that the Gata3 protein plays an important role in vertebrate development and th2 differentiation (9,10). in addition, transgenic (tg) mice that overexpress Gata3 spontaneously have asthma-like symptoms. in these mice, the number of Gata3-positive cells is increased in the asthmatic lung and in allergic rhinitis, while these cells are found to furthe...

Future Perspectives of Oral Delivery of Next Generation Therapies for Treatment of Skin Diseases

“…Several preclinical studies have validated the essential role that GATA3 (GATA binding protein 3), a transcription factor, plays in inflammatory disorders. Specifically, decreased expression of GATA3 enhances skin inflammation in many chronic inflammatory diseases including psoriasis and atopic dermatitis [ 88 , 89 ]. GATA3 is responsible for the production of key inflammatory cytokines including interleukin-13 (IL-13), which mediate inflammation.…”

Genetic Variants of Thymic Stromal Lymphopoietin in Nonsteroidal Anti-Inflammatory Drug-Induced Urticaria/Angioedema

“…Barhl1, CCNT2 and Hmx-2 have not previously been associated with NIUA or allergic diseases; however, GATA is a superfamily of transcription factors implicated in the regulation of cellular differentiation of important immune cells, such as basophils [43] and eosinophils [44]. Specifically, GATA-3 is implicated in the development of Th2 responses in allergic dermatitis [45,46] and in selective, single NSAID-induced urticaria/angioedema [47]. Furthermore, it has been suggested that GATA-3 blockage by corticosteroids could be used as a treatment for allergies due to the inhibition of the Th2 response [48].…”