Interleukin 17(IL-17)is increasingly recognized as a key factor that contributes to the pathogenesis of multiple sclerosis(MS)and its experimental mouse autoimmune encephalomyelitis(EAE)model.However,the roles and reg...Interleukin 17(IL-17)is increasingly recognized as a key factor that contributes to the pathogenesis of multiple sclerosis(MS)and its experimental mouse autoimmune encephalomyelitis(EAE)model.However,the roles and regulatory mechanisms of IL-17-induced pro-inflammatory cytokine production in EAE mice remain largely unclear.In this study,the expression of IL-17,hypoxia inducible factor-1α(HIF-1α),IL-1β,IL-6 and microRNA-497(miR-497),as well as their intrinsic associations,was investigated using EAE model mice and cultured astrocytes exposed to IL-17 in vitro.We observed markedly increased production of IL-17,HIF-1α,IL-1βand IL-6 in the brain tissues of EAE mice,while the expression and secretion of HIF-1α,IL-1βand IL-6 were also significantly increased when cultured primary astrocytes from mice were stimulated with IL-17.Meanwhile,the expression of miR-497 was downregulated both in vivo and in vitro.Subsequent in vitro experiments revealed that IL-17 induced the production of IL-1βand IL-6 in astrocytes through the upregulation of HIF-1αas a transcriptional factor,indicating that IL-17-mediated downregulation of miR-497 enhanced HIF-1αexpression.Furthermore,astrocytespecific knockdown of IL-17RA and HIF-1αor astrocyte-specific overexpression of miR-497 by infection with different lentiviral vectors containing an astrocyte-specific promotor markedly decreased IL-1βand IL-6 production in brain tissues and alleviated the pathological changes and score of EAE mice.Collectively,these findings indicate that decreased miR-497 expression is responsible for IL-17-triggered high HIF-1αexpression and consequent IL-1βand IL-6 production by astrocytes in EAE mice.展开更多
基金by the grants from National Natural Science Foundations of China(31470853 and 81471626)grants from Natural Science Foundations of Jiangsu Province in China(BK20131386 and BK20151168)+1 种基金The study was also supported by grants from Jiangsu Province Key Lab of Neurodegeneration(No.SJ11KF07)the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions,Excellent Young or Middle aged Teachers Project of Nanjing Medical University and Xuzhou Technology Bureau Foundation(KC14SH074).
文摘Interleukin 17(IL-17)is increasingly recognized as a key factor that contributes to the pathogenesis of multiple sclerosis(MS)and its experimental mouse autoimmune encephalomyelitis(EAE)model.However,the roles and regulatory mechanisms of IL-17-induced pro-inflammatory cytokine production in EAE mice remain largely unclear.In this study,the expression of IL-17,hypoxia inducible factor-1α(HIF-1α),IL-1β,IL-6 and microRNA-497(miR-497),as well as their intrinsic associations,was investigated using EAE model mice and cultured astrocytes exposed to IL-17 in vitro.We observed markedly increased production of IL-17,HIF-1α,IL-1βand IL-6 in the brain tissues of EAE mice,while the expression and secretion of HIF-1α,IL-1βand IL-6 were also significantly increased when cultured primary astrocytes from mice were stimulated with IL-17.Meanwhile,the expression of miR-497 was downregulated both in vivo and in vitro.Subsequent in vitro experiments revealed that IL-17 induced the production of IL-1βand IL-6 in astrocytes through the upregulation of HIF-1αas a transcriptional factor,indicating that IL-17-mediated downregulation of miR-497 enhanced HIF-1αexpression.Furthermore,astrocytespecific knockdown of IL-17RA and HIF-1αor astrocyte-specific overexpression of miR-497 by infection with different lentiviral vectors containing an astrocyte-specific promotor markedly decreased IL-1βand IL-6 production in brain tissues and alleviated the pathological changes and score of EAE mice.Collectively,these findings indicate that decreased miR-497 expression is responsible for IL-17-triggered high HIF-1αexpression and consequent IL-1βand IL-6 production by astrocytes in EAE mice.
