The role of IL-6 in regeneration both in vitro and in vivo

【摘要】：正The failure of mature CNS neurons to regenerate injured axons has been mainly attributed to the inhibitory signal associated with myelin and a lower intrinsic growth state of neuron.As IL-6 is the highest increase one among the 11 molecules in DRG neurons after conditioning lesion or dbcAMP injection,it is postulated that IL-6 could alter neuron gene expression profile and switch into a strong growth state and then promote neurite outgrowth.In this study we investigated whether IL-6 could increase the intrinsic growth capacity of adult rat dissociated DRG neurons as result in promoting neurite outgrowth by administration of exogenous IL-6 in the medium in vitro,and promote cortical spinal tract regeneration and functional recovery by intratheral delivery IL-6 for 7 days after spinal cord injury in vivo.Methods Primary DRG neurons culture,RT-PCR,immunohistochemical staining,Western blot,dorsal column transection,intratheral cannal,BDA anterograde tracing,confocal image,BBB functional test,etc.Results We found that addition of exogenous IL-6 to the culture medium resulted in an IL-6 dose-dependent enhancement of neurite outgrowth and a higher expression of growth-associated genes,such as GAP-43,SPRRL and Arginase I.IL-6 also could promote neurite outgrowth in mimick CNS injury microenvironment.In vivo,intratheral delivery of IL-6 for 7 days after dorsal column transection resulted in a promoting regeneration and functional recovery.Also IL-6 increased the expression of mTOR(mammalian target of rapamycin)in neuron while decreased the expression of mTOR in astrocyte which inhibited glia scar formation.We also observed that the SOCS3 expression both in neuron and astrocytes while the STAT3 expression only observed in IL-6 treatment group.Conclusion IL-6 reactivates the growth-associated gene and increases the expression of mTOR in neuron result in reactivating the regeneration program and intrinsic growth state of neuron.And intratheral delivery of IL-6 downregulates the expression of mTOR in astrocytes and then limits astrocytes reactive and glial scar formation.To our knowledge,this is the first time we investigate that IL-6 promotes regeneration partly by downregulating the expression of mTOR in astrocytes.These results indicate that using IL-6 could promote axonal regeneration,which may be developed into a treatment for many types of CNS injuries.