Resistance of interleukin-6 to the extracellular inhibitory environment promotes axonal regeneration and functional recovery following spinal cord injury.

Abstract

Interleukin-6(IL)-6 was originally discovered as a factor that contributes to the secondarypathological and inflammatory response in the central nervous system(CNS) following injury. However, accumulating evidence suggests that IL-6 is also involved in functional and structural recovery following CNS injury by promoting axonal sprou-ting. This suggests a potential dual role of IL-6 in CNS injury. However, the definitive function of IL-6 in neural injury and the corresponding underlying mechanisms are still topics of controversy. The present study was carried out to examine the potential function of IL-6 in resistance to neurite growth‑inhibitory effects via regulation of the expression of growth associated protein-43(GAP-43), myelin-associated neurite outgrowth inhibitor(Nogo-A) and its receptor(NgR). Rat dorsal root ganglion(DRG) neurons cultured in an inhibitory microenvironment mimicking injured CNS were used to investigate the effects of IL-6 on the outgrowth of neuronal processes. Additionally, IL-6 was subarachnoidally injected into rats to establish a spinal cord injury(SCI) model, and the neurobehavioral manifestations and neural morphology were subsequently evaluated to determine the effect of IL-6 on neural regeneration. Finally, the potential molecular mechanisms of IL-6-mediated rege-neration and functional recovery following CNS injury are discussed. The results of the present study demonstrated that the invitro administration of IL-6 enhanced the neurite outgrowth of DRG neurons in a dose-dependent manner via resisting the inhibitory function of myelin proteins. All doses of the IL-6 subarachnoid injection improved the Basso, Beattie and Bresnahan scores following SCI, with a large number of axonal sproutings observed at the spinal lesion site, and several sprouting fibers being elongated and bypassing the lesion and entered the caudal spinal cord. Additionally, a significantly increased density area of diaminobenzidine-labeled neural fiber was observed in rats that received a subarachnoid injection of IL-6, and the rats exhibited increased expression of GAP-43 and decreased expression of Nogo-A. Inconclusion, the results of the present study indicated that IL-6 interferes with the inhibitory functions of myelin proteins by upregulating the expression of GAP-43 and simultaneously downregulating the expression of Nogo-A andNgR to promote axonal sprouting and functional recovery following SCI.