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IgE Downregulates PTEN through MicroRNA-21-5p and Stimulates Airway Smooth Muscle Cell Remodeling.

TitleIgE Downregulates PTEN through MicroRNA-21-5p and Stimulates Airway Smooth Muscle Cell Remodeling.
Publication TypeJournal Article
Year of Publication2019
AuthorsFang, L., Wang X., Sun Q., Papakonstantinou E., S'ng C., Tamm M., Stolz D., & Roth M.
JournalInt J Mol Sci
Volume20
Issue4
Date Published2019 Feb 18
ISSN1422-0067
KeywordsAdult, Aged, Aged, 80 and over, Airway Remodeling, Asthma, Cell Movement, Down-Regulation, Extracellular Matrix, Female, Humans, Immunoglobulin E, Male, MicroRNAs, Middle Aged, Mitochondria, Myocytes, Smooth Muscle, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Receptors, IgE, Ribosomal Protein S6 Kinases, 70-kDa, Signal Transduction, STAT3 Transcription Factor, Up-Regulation
Abstract

The patho-mechanism leading to airway wall remodeling in allergic asthma is not well understood and remodeling is resistant to therapies. This study assessed the effect of immunoglobulin E (IgE) in the absence of allergens on human primary airway smooth muscle cell (ASMC) remodeling in vitro. ASMCs were obtained from five allergic asthma patients and five controls. Proliferation was determined by direct cell counts, mitochondrial activity by expression of cytochrome c, protein expression by immunoblotting and immuno-fluorescence, cell migration by microscopy imaging, and collagen deposition by cell based ELISA and RNA expression by real time PCR. Non-immune IgE activated two signaling pathways: (i) signal transducer and activator of transcription 3 (STAT3)→miR-21-5p→downregulating phosphatase and tensin homolog (PTEN) expression, and (ii) phosphatidylinositol 3-kinases (PI3K)→protein kinase B (Akt)→mammalian target of rapamycin (mTOR)→ribosomal protein S6 kinase beta-1 (p70s6k)→peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1-α)→peroxisome proliferator-activated receptor-γ (PPAR-γ)→cyclooxygenase-2 (COX-2)→mitochondrial activity, proliferation, migration, and extracellular matrix deposition. Reduced PTEN expression correlated with enhanced PI3K signaling, which upregulated ASMC remodeling. The inhibition of microRNA-21-5p increased PTEN and reduced mTOR signaling and remodeling. Mimics of microRNA-21-5p had opposing effects. IgE induced ASMC remodeling was significantly reduced by inhibition of mTOR or STAT3. In conclusion, non-immune IgE alone is sufficient for stimulated ASMC remodeling by upregulating microRNA-21-5p. Our findings suggest that the suppression of micoRNA-21-5p may present a therapeutic target to reduce airway wall remodeling.

DOI10.3390/ijms20040875
Alternate JournalInt J Mol Sci
PubMed ID30781615
PubMed Central IDPMC6412688

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