title: A microRNA network dysregulated in asthma controls IL-6 production in bronchial epithelial cells.
abstract: MicroRNAs are short non-coding single stranded RNAs that regulate gene expression. While much is known about the effects of individual microRNAs, there is now growing evidence that they can work in co-operative networks. MicroRNAs are known to be dysregulated in many diseases and affect pathways involved in the pathology. We investigated dysregulation of microRNA networks using asthma as the disease model. Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness and airway remodelling. The airway epithelium is a major contributor to asthma pathology and has been shown to produce an excess of inflammatory and pro-remodelling cytokines such as TGF-β, IL-6 and IL-8 as well as deficient amounts of anti-viral interferons. After performing microRNA arrays, we found that microRNAs -18a, -27a, -128 and -155 are down-regulated in asthmatic bronchial epithelial cells, compared to cells from healthy donors. Interestingly, these microRNAs are predicted in silico to target several components of the TGF-β, IL-6, IL-8 and interferons pathways. Manipulation of the levels of individual microRNAs in bronchial epithelial cells did not have an effect on any of these pathways. Importantly, knock-down of the network of microRNAs miR-18a, -27a, -128 and -155 led to a significant increase of IL-8 and IL-6 expression. Interestingly, despite strong in silico predictions, down-regulation of the pool of microRNAs did not have an effect on the TGF-β and Interferon pathways. In conclusion, using both bioinformatics and experimental tools we found a highly relevant potential role for microRNA dysregulation in the control of IL-6 and IL-8 expression in asthma. Our results suggest that microRNAs may have different roles depending on the presence of other microRNAs. Thus, interpretation of in silico analysis of microRNA function should be confirmed experimentally in the relevant cellular context taking into account interactions with other microRNAs when studying disease.
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Rocio T
authors.initials: RT
authors.lastname: Martinez-Nunez
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Victor P
authors.initials: VP
authors.lastname: Bondanese
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Fethi
authors.initials: F
authors.lastname: Louafi
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Francisco-Garcia
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Hitasha
authors.initials: H
authors.lastname: Rupani
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bedke
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Holgate
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom; National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit, Southampton Centre for Biomedical Research MP218, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Howarth
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Tilman
authors.initials: T
authors.lastname: Sanchez-Elsner
mesh_terms: D001249:Asthma / Q000235:genetics*; D001483:Base Sequence; D001980:Bronchi / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D035683:MicroRNAs; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta