Heterogeneity of transcription factor expression and regulation in human airway epithelial and smooth muscle cells

Abstract

Panebra A, Schwarb MR, Glinka CB, Liggett SB. Heterogeneity of transcription factor expression and regulation in human airway epithelial and smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 293: L453-L462, 2007. First published June 8, 2007; doi:10.1152/ajplung.00084.2007.-Transcription factors represent a major mechanism by which cells establish basal and conditional expression of proteins, the latter potentially being adaptive or maladaptive in disease. The complement of transcription factors in two major structural cells of the lung relevant to asthma, airway epithelial and smooth muscle cells, is not known. A plate-based platform using nuclear extracts from these cells was used to assess potential expression by binding to oligonucleotide consensus sequences representing Ͼ300 transcription factors. Four conditions were studied: basal, ␤-agonist exposure, culture under proasthmatic conditions (IL-13, IL-4, TGF-␤, and leukotriene D 4), and the dual setting of ␤-agonist with proasthmatic culture. Airway epithelial cells expressed 70 transcription factors, whereas airway smooth muscle expressed 110. High levels of multiple transcription factors not previously recognized as being expressed in these cells were identified. Moreover, expression/ binding patterns under these conditions revealed extreme discordance in the direction and magnitude of change between the cell types. Singular (one cell type displayed regulation) and antithetic (both cell types underwent expression changes but in opposite directions) regulation dominated these patterns, with concomitant regulation in both cell types being rare (Ͻ10%). ␤-Agonist evoked up-and downregulation of transcription factors, which was highly influenced by the proasthmatic condition, with little overlap of factors regulated by ␤-agonists under both conditions. Together, these results reveal complex, cell type-dependent networks of transcription factors in human airway epithelium and smooth muscle that are dynamically regulated in unique ways by ␤-agonists and inflammation. These factors may represent additional components in asthma pathophysiology or potential new drug targets. transcription; ␤-agonist; asthma; inflammation IN EUKARYOTIC CELLS, TRANSCRIPTION factors represent the major elements by which gene transcription by RNA polymerase II is controlled (18,26). Such factors regulate the basal expression of genes and serve to dynamically regulate gene expression during normal homeostatic conditions, exposures to xenobiotic agents such as therapeutic drugs or toxins, and pathological conditions, where they may be a basis for, or serve to counteract, aberrant cellular physiology (13,18,26). In asthma, two stromal cell types play significant roles in the syndrome: the airway epithelial cell and the airway smooth muscle cell (5, 9). Although some information is known about the regulation and action of selected transcription factors of immune cells of the lung and peripheral circulation (1,11,12,24), there is a paucity of data on the expression of transcription ...

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