Abstract
We have previously demonstrated the growth-promoting effect of intrathecal delivery of recombinant rat IL-6 immediately after corticospinal tract (CST) injury. Our present study aims to further clarify whether intrathecal delivery of IL-6 after CST injury could reactivate the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex which project long axons to the spinal cord. We examined, by ELISA, levels of cyclic adenosine monophosphate (cAMP), adenylyl cyclase (AC, which synthesizes cAMP), phosphodiesterases (PDE, which degrades cAMP), and, by RT-PCR, the expression of regeneration-associated genes in the rat sensorimotor cortex after intrathecal delivery of IL-6 for 7 days, started immediately after CST injury. Furthermore, we injected retrograde neuronal tracer Fluorogold (FG) to the spinal cord to label pyramidal cells in the sensorimotor cortex, layers V and VI, combined with βIII-tubulin immunostaining, then we analyzed by immunohistochemisty and western blot the expression of the co-receptor gp-130 of IL-6 family, and pSTAT3 and mTOR, downstream IL-6/JAK/STAT3 and PI3K/AKT/mTOR signaling pathways respectively. We showed that intrathecal delivery of IL-6 elevated cAMP level and upregulated the expression of regeneration-associated genes including GAP-43, SPRR1A, CAP-23 and JUN-B, and the expression of pSTAT3 and mTOR in pyramidal cells of the sensorimotor cortex. In contrast, AG490, an inhibitor of JAK, partially blocked these effects of IL-6. All these results indicate that intrathecal delivery of IL-6 immediately after spinal cord injury can reactivate the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex and these effects of IL-6 were partially JAK/STAT3-dependent.
Highlights
In the adult central nervous system (CNS), axons are usually not able to regenerate after lesions, while axons in the CNS during the first postnatal week and axons in the peripheralPLOS ONE | DOI:10.1371/journal.pone.0127772 May 19, 2015IL-6 Reactivates the Intrinsic Growth Capacity of Pyramidal Cells nervous system (PNS) do
We have previously shown that IL-6 promotes axonal regeneration of axotomized corticospinal tract (CST) and functional recovery by enhancing synapse formation and increasing the expression of mTOR
We further delineate that intrathecal delivery of IL-6 immediately after spinal cord injury induces pronounced up-regulation of cyclic adenosine monophosphate (cAMP) level and regeneration-associated genes GAP-43, SPRR1A, CAP-23 and JUN-B and activated JAK/STAT3 signaling pathway and PI3K/AKT/mTOR and extracellular signalregulated kinase (ERK) signaling pathways in pyramidal cells of the sensorimotor cortex
Summary
In the adult central nervous system (CNS), axons are usually not able to regenerate after lesions, while axons in the CNS during the first postnatal week and axons in the peripheral. A series of studies have shown that IL-6 can reactivate the intrinsic growth program of injured neurons and promote axonal regeneration, through modulating cAMP, JAK/STAT3 and/or PTEN/mTOR signaling pathways [7,8,9,10]. We showed that intrathecal delivery of IL-6 immediately after spinal cord injury elevated cAMP level in the sensorimotor cortex and increased the expression of growth-associated genes GAP-43, SPRR1A, CAP-23 and JUN-B and increased the expression of pSTAT3 and mTOR in the pyramidal cells of the sensorimotor cortex, layers V and VI. AG490, an inhibitor of JAK, partially blocked these effects of IL-6 All these results indicate that intrathecal delivery of IL-6 immediately after spinal cord injury can reactivate the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex and the effects of IL-6 was associated with the activation of JAK/STAT3 signaling pathway
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