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.
- Klíčová slova
- astrocytes, cultures, inflammation, microRNA, subependymal giant cell astrocytoma, tuberous sclerosis complex,
- MeSH
- astrocytom metabolismus patologie MeSH
- astrocyty metabolismus MeSH
- buněčné kultury MeSH
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA metabolismus MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozek metabolismus MeSH
- neurony metabolismus MeSH
- předškolní dítě MeSH
- signální transdukce fyziologie MeSH
- tuberózní skleróza metabolismus MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- mikro RNA MeSH
- MIRN146 microRNA, human MeSH Prohlížeč
- MIRN155 microRNA, human MeSH Prohlížeč
- MIRN21 microRNA, human MeSH Prohlížeč
