PMID- 30781615 OWN - NLM STAT- MEDLINE DCOM- 20190531 LR - 20200225 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 4 DP - 2019 Feb 18 TI - IgE Downregulates PTEN through MicroRNA-21-5p and Stimulates Airway Smooth Muscle Cell Remodeling. LID - 10.3390/ijms20040875 [doi] LID - 875 AB - 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-alpha (PGC1-alpha)-->peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-->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. FAU - Fang, Lei AU - Fang L AD - Pneumology & Pulmonary Cell Research, Departments of Internal Medicine & Biomedicine, University & University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. lei.fang@unibas.ch. FAU - Wang, Xinggang AU - Wang X AD - Gynecological Endocrinology, Department of Biomedicine, University & University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. xinggang.wang@unibas.ch. FAU - Sun, Qingzhu AU - Sun Q AD - Pneumology & Pulmonary Cell Research, Departments of Internal Medicine & Biomedicine, University & University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. sunqingzhu@nwafu.edu.cn. AD - College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China. sunqingzhu@nwafu.edu.cn. FAU - Papakonstantinou, Eleni AU - Papakonstantinou E AD - Pneumology & Pulmonary Cell Research, Departments of Internal Medicine & Biomedicine, University & University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. epap@med.auth.gr. AD - Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. epap@med.auth.gr. FAU - S'ng, Chongteck AU - S'ng C AD - PersCellMed S'ng, CH-4450 Sissach, Switzerland. ctsng@hotmail.com. FAU - Tamm, Michael AU - Tamm M AD - Pneumology & Pulmonary Cell Research, Departments of Internal Medicine & Biomedicine, University & University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. michael.tamm@usb.ch. FAU - Stolz, Daiana AU - Stolz D AD - Pneumology & Pulmonary Cell Research, Departments of Internal Medicine & Biomedicine, University & University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Daiana.Stolz@usb.ch. FAU - Roth, Michael AU - Roth M AUID- ORCID: 0000-0002-8139-2821 AD - Pneumology & Pulmonary Cell Research, Departments of Internal Medicine & Biomedicine, University & University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Michael.roth@usb.ch. LA - eng PT - Journal Article DEP - 20190218 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (MIRN21 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Receptors, IgE) RN - 0 (STAT3 Transcription Factor) RN - 37341-29-0 (Immunoglobulin E) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - *Airway Remodeling MH - Asthma/immunology/pathology MH - Cell Movement MH - *Down-Regulation MH - Extracellular Matrix/metabolism MH - Female MH - Humans MH - Immunoglobulin E/*metabolism MH - Male MH - MicroRNAs/genetics/*metabolism MH - Middle Aged MH - Mitochondria/metabolism MH - Myocytes, Smooth Muscle/*metabolism MH - PTEN Phosphohydrolase/*metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Receptors, IgE/metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - STAT3 Transcription Factor/metabolism MH - Signal Transduction MH - Up-Regulation PMC - PMC6412688 OTO - NOTNLM OT - STAT3 OT - airway smooth muscle cells OT - microRNA-21-5p OT - mitochondria COIS- The authors declare no conflict of interest. EDAT- 2019/02/20 06:00 MHDA- 2019/06/01 06:00 PMCR- 2019/02/01 CRDT- 2019/02/21 06:00 PHST- 2018/12/31 00:00 [received] PHST- 2019/02/04 00:00 [revised] PHST- 2019/02/14 00:00 [accepted] PHST- 2019/02/21 06:00 [entrez] PHST- 2019/02/20 06:00 [pubmed] PHST- 2019/06/01 06:00 [medline] PHST- 2019/02/01 00:00 [pmc-release] AID - ijms20040875 [pii] AID - ijms-20-00875 [pii] AID - 10.3390/ijms20040875 [doi] PST - epublish SO - Int J Mol Sci. 2019 Feb 18;20(4):875. doi: 10.3390/ijms20040875.