Subsets of circulating miRNAs are uniquely expressed in patients with AR and asthmatic patients and have potential for use as noninvasive biomarkers to diagnose and characterize these diseases.

In Drosophila, P-element transposition causes mutagenesis and genome instability during hybrid dysgenesis. The P-element 31-bp terminal inverted repeats (TIRs) contain sequences essential for transposase cleavage and have been implicated in DNA repair via protein-DNA interactions with cellular proteins. The identity and function of these cellular proteins were unknown. Biochemical characterization of proteins that bind the TIRs identified a heterodimeric basic leucine zipper (bZIP) complex between an uncharacterized protein that we termed "Inverted Repeat Binding Protein (IRBP) 18" and its partner Xrp1. The reconstituted IRBP18/Xrp1 heterodimer binds sequence-specifically to its dsDNA-binding site within the P-element TIRs. Genetic analyses implicate both proteins as critical for repair of DNA breaks following transposase cleavage in vivo. These results identify a cellular protein complex that binds an active mobile element and plays a more general role in maintaining genome stability.T ransposable elements contribute significantly to the organization and evolution of all eukaryotic genomes. Recent estimates of transposon content within the Drosophila melanogaster genome are between 5% and 10%, and in humans over half the genome is composed of mobile elements (1, 2). Although many of these elements, including the Drosophila P-element transposon, are still active (3), the cellular mechanisms used to combat the genotoxic effects of DNA double-strand breaks (DSBs) generated by transpositional recombination are not fully understood. The Drosophila P-transposable element provides an excellent model for understanding the ancient mechanisms used by the cell to counteract newly invading parasitic mobile DNA elements (4).The P-element transposon is a mobile DNA element that spread through wild populations of D. melangaster ∼100 y ago after most common laboratory strains were isolated (5, 6). P elements were identified by studying a genetic syndrome called "P-M hybrid dysgenesis." It was observed that males from wild populations (P strains) crossed to females from isolated laboratory stocks (M strains) yielded progeny that had germline mutations, temperature-sensitive sterility, and atypical male recombination (6). Reciprocal crosses yielded phenotypically normal progeny. The P element was shown to be the causative agent of these so-called P-M hybrid dysgenesis phenotypes by molecular analyses showing that P elements were present in variable locations in P strains yet totally absent from most M strains (7,8).The Drosophila P-element transposon encodes a GTP-dependent site-specific DNA transposase/integrase family enzyme (9, 10). At each end of the P-element transposon are perfect 31-bp terminal inverted repeats (TIRs), 11-bp internal inverted repeats that serve as enhancers of transposition, and internal 10-bp transposase binding sites (11-13) (Fig. 1A). The P-element transposase catalyzes DNA cleavage within the 31-bp TIRs to create 17-nt 3′ single-strand extensions at both the donor site and the transposon ends (14, 15)...

BackgroundMicroRNAs (miRNAs) are emerging as central regulators of inflammation, but their role in asthma and airway epithelial cells is not well studied. Glucocorticoids are the cornerstone of therapy in asthma and other inflammatory disease, yet their mechanisms of action are not completely elucidated, and it is not clear whether miRNAs modulate their effects.ObjectiveWe aimed to identify miRNAs that regulate cytokine and chemokine expression in airway epithelial cells and whether these miRNAs are subject to the effects of glucocorticoids.Methods and resultsMicroRNAomic analyses of immortalized, normal human bronchial epithelial cells identified 7 miRNAs that were altered by inflammatory cytokine treatment and 22 that were regulated by glucocorticoids (n = 3 for each treatment condition). MiR-146a emerged as a central candidate, whose expression was induced by TNF-α and repressed by glucocorticoids. Its role as a candidate in asthmatic inflammation was supported by expression profiling in human asthmatics, which showed that plasma miR-146a expression was elevated in asthma and associated with measures related to worse asthma outcomes, including elevated blood eosinophil counts, higher asthma control questionnaire scores, and need for higher doses of inhaled glucocorticoids. However, transfection of miR-146a in A549 cells treated with TNF-α +/- glucocorticoids produced an anti-inflammatory effect and increased efficacy of glucocorticoids.ConclusionsWe propose a model whereby miR-146a is induced by inflammatory conditions as a feedback mechanism to limit inflammation. Exogenous administration of miR-146a augmented the effects of glucocorticoids and could be a novel therapeutic strategy to enhance efficacy of these medications.