Abstract
Foxa2 [The forkhead box transcription factor-2; also known as HNF3B(hepatocyte nuclear factors-3), or TCF3B(transcription factor-3b) ] [Costa, 1989 #64], is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells lining conducting airways and in alveolar type Ⅱ cells in the development and mature lung. Foxa2 plays critical roles in lung development, which is required for normal lung maturation, surfactant protein and lipid synthesis, epithelial differentiation, and cross talking between epithelium and innate immune. Foxa2 can determine gene expression and cell fate in the lung, and is required for the suppression of Th2 immunity, mucus production, and goblet cell metaplasia in the developing lung in a process determined in part by its regulation of the Cysteinyl leukotriene (CysLT) pathway. Recent studies have implicated that Foxa2 is a suppressor of lung cancer. This review will summarize the role of Foxa2 in lung development, pulmonary diseases, and also the possible signaling pathways regulated by Foxa2.
Highlights
LTs signaling pathwayLTs, the metabolic products of arachidonic acid, are important lipid mediators of airway inflammation and bronchospasm in asthma, allergic inflammation and innate immunity
Foxa2 is a member of the forkhead nuclear transcription factors family that contains a modified helix-turn-helix, known as the winged helix DNA binding domain [1] and a unique AKT2/PKB phosphorylation site at the N terminus of the forkhead domain [2, 3]
Foxa2 amino terminus, region IV, a second HNF-3β activation domain [21], is composed of 52 amino acids which enriches serine and tyrosine residues [22] and contains two putative casein kinase I (CKI) phosphorylation sites[23], which was shown to be important for transcriptional activation (Fig.1)
Summary
LTs, the metabolic products of arachidonic acid, are important lipid mediators of airway inflammation and bronchospasm in asthma, allergic inflammation and innate immunity. Arachidonate 15-lipoxygenase (LO)-1 [72], 5-lipoxygenase (5-LO) [73] and 5-lipoxygenase activating protein (FLAP) [74] are the encoding key lipoxygenases in LTs pathway, which expressed in many of the cells implicated in allergic inflammation and asthma pathology. Recent evidence indicates that LT pathway is required for the Th2-mediated pulmonary inflammation caused by deletion of. Indicate a potential mechanism that Foxa is required for the suppression of Th2 immunity and mucus metaplasia in the developing lung in a process determined in part by its regulation of the CysLT pathway. A selective antagonist of the CysLT1 receptor, montelukast, inhibited the Th2-mediated inflammation and goblet cell differentiation caused by the deletion of Foxa in the developing mouse lung supporting that LT pathway plays an important role in Th2-mediated pulmonary inflammation during lung development. We conclude that Foxa can regulate the LT pathway to suppress Th2-mediated inflammation in the lung
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