title: Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures.
abstract: Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte-mediated inflammatory response. To study the role of inflammation-related microRNAs in TSC, we employed real-time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL-1β expression. In addition, cultured human astrocytes and SEGA-derived cell cultures were used to study the regulation of the expression of these miRNAs in response to the proinflammatory cytokine IL-1β and to evaluate the effects of overexpression or knockdown of miR21, miR146a, and miR155 on inflammatory signaling. IL-1β stimulation of cultured glial cells strongly induced intracellular miR21, miR146a, and miR155 expression, as well as miR146a extracellular release. IL-1β signaling was differentially modulated by overexpression of miR155 or miR146a, which resulted in pro- or anti-inflammatory effects, respectively. This study provides supportive evidence that inflammation-related microRNAs play a role in TSC. In particular, miR146a and miR155 appear to be key players in the regulation of astrocyte-mediated inflammatory response, with miR146a as most interesting anti-inflammatory therapeutic candidate.
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Scheppingen
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Iyer
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: A S
authors.initials: AS
authors.lastname: Prabowo
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Mühlebner
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Anink
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Scholl
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Feucht
authors.affiliation: Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: F E
authors.initials: FE
authors.lastname: Jansen
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: W G
authors.initials: WG
authors.lastname: Spliet
authors.affiliation: Department of Pediatric Neurology, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Krsek
authors.affiliation: Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Zamecnik
authors.affiliation: Pathology Unit, Anna Meyer Children's Hospital, Florence, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Buccoliero
authors.affiliation: Department of Neurosurgery, Anna Meyer Children's Hospital, Florence, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Giordano
authors.affiliation: Department of Neurosurgery, Anna Meyer Children's Hospital, Florence, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Genitori
authors.affiliation: Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Kotulska
authors.affiliation: Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: S
authors.initials: S
authors.lastname: Jozwiak
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Jaworski
authors.affiliation: Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Liszewska
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: E A
authors.initials: EA
authors.lastname: van Vliet
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, the Netherlands.|Stichting Epilepsie Instellingen Nederland (SEIN), the Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Aronica
mesh_terms: D000293:Adolescent; D000328:Adult; D001253:Astrocytes / Q000378:metabolism*; D001254:Astrocytoma / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014402:Tuberous Sclerosis / Q000378:metabolism*; D055815:Young Adult
chemical_list: C542542:MIRN146 microRNA, human; C524942:MIRN155 microRNA, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs
keywords: astrocytes; cultures; inflammation; microRNA; subependymal giant cell astrocytoma; tuberous sclerosis complex