Interleukin-6 contributes to CNS axon regeneration upon inflammatory stimulation

Mature retinal ganglion cells (RGCs) do not normally regenerate injured axons and undergo apoptosis after axotomy. Inflammatory stimulation (IS) in the eye mediates neuroprotection and induces axon regeneration into the injured optic nerve. Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) have been identified as key mediators of these effects. Here, we investigated the role of interleukin-6 (IL-6), another member of the glycoprotein 130-activating cytokine family, as additonal contributing factor. Expression of IL-6 was markedly induced in the retina upon optic nerve injury and IS, and mature RGCs expressed the IL-6 receptor. Treatment of cultured RGCs with IL-6 or specific IL-6 receptor agonist, significantly increased neurite outgrowth janus kinase/signal transducers and activators of transcription-3 (JAK/STAT3) and phosphatidylinositide 3-kinase/protein kinase B (PI3K/Akt) dependently. Moreover, IL-6 reduced myelin, but not neurocan-mediated growth inhibition mammalian target of rapamycin (mTOR) dependently in cultured RGCs. In vivo, intravitreal application of IL-6 transformed RGCs into a regenerative state, enabling axon regeneration beyond the lesion site of the optic nerve. On the other hand, genetic ablation of IL-6 in mice significantly reduced IS-mediated myelin disinhibition and axon regeneration in the optic nerve. Therefore, IL-6 contributes to the beneficial effects of IS and its disinhibitory effect adds an important feature to the effects of so far identified IS-mediating factors. Consequently, application of IL-6 or activation of its receptor might provide suitable strategies for enhancing optic nerve regeneration.