Activation of JAK/STAT signaling in neruons following spinal cord injury in mice

Department of Neurosurgery, Nagoya University, Graduate School of Medicine, Nagoya, Japan.
Journal of Neurochemistry (Impact Factor: 4.28). 03/2006; 96(4):1060-70. DOI: 10.1111/j.1471-4159.2005.03559.x
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The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway is one of the most important in transducing signals from the cell surface to the nucleus in response to cytokines. In the present study, we investigated chronological alteration and cellular location of JAK1, STAT3, phosphorylated (p)-Tyr1022/1023-JAK1, p-Tyr705-STAT3, and interleukin-6 (IL-6) following spinal cord injury (SCI) in mice. Western blot analysis showed JAK1 to be significantly phosphorylated at Tyr1022/1023 from 6 h after SCI, peaking at 12 h and gradually decreasing thereafter, accompanied by phosphorylation of STAT3 at Tyr705 with a similar time course. ELISA analysis showed the concentration of IL-6 in injured spinal cord to also significantly increase from 3 h after SCI, peaking at 12 h, then gradually decreasing. Immunohistochemistry revealed p-Tyr1022/1023-JAK1, p-Tyr705-STAT3, and IL-6 to be mainly expressed in neurons of the anterior horns at 12 h after SCI. Pretreatment with a JAK inhibitor, AG-490, suppressed phosphorylation of JAK1 and STAT3 at 12 h after SCI, reducing recovery of motor functions. These findings suggest that SCI at the acute stage produces IL-6 mainly in neurons of the injured spinal cord, which activates the JAK/STAT pathway, and that this pathway may be involved with neuronal response to SCI.

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Available from: Nobuteru Usuda, Nov 04, 2014
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    • "In rodent models of SCI, levels of pro-inflammatory interleukin such as IL-6 peak acutely in the injured areas and lead to activation of the JAK1-STAT3 signaling pathway, which contributes to development of neuropathic pain [5], [6]. Moreover, in previous work, conditional ablation of STAT3 increased motor deficits after spinal cord injury [7]. "
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    ABSTRACT: Spinal cord injury or amyotrophic lateral sclerosis damages spinal motor neurons and forms a glial scar, which prevents neural regeneration. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in astrogliogenesis and scar formation, and thus a fine modulation of STAT3 signaling may help to control the excessive gliogenic environment and enhance neural repair. The objective of this study was to determine the effect of STAT3 inhibition on human neural stem cells (hNSCs). In vitro hNSCs primed with fibroblast growth factor 2 (FGF2) exhibited a lower level of phosphorylated STAT3 than cells primed by epidermal growth factor (EGF), which correlated with a higher number of motor neurons differentiated from FGF2-primed hNSCs. Treatment with STAT3 inhibitors, Stattic and Niclosamide, enhanced motor neuron differentiation only in FGF2-primed hNSCs, as shown by increased homeobox gene Hb9 mRNA levels as well as HB9+ and microtubule-associated protein 2 (MAP2)+ co-labeled cells. The increased motor neuron differentiation was accompanied by a decrease in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes. Interestingly, Stattic and Niclosamide did not affect the level of STAT3 phosphorylation; rather, they perturbed the nuclear translocation of phosphorylated STAT3. In summary, we demonstrate that FGF2 is required for motor neuron differentiation from hNSCs and that inhibition of STAT3 further increases motor neuron differentiation at the expense of astrogliogenesis. Our study thus suggests a potential benefit of targeting the STAT3 pathway for neurotrauma or neurodegenerative diseases.
    PLoS ONE 06/2014; 9(6):e100405. DOI:10.1371/journal.pone.0100405 · 3.23 Impact Factor
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    • "It is secreted mostly by macrophages, but also by microglial cells (Kreutzberg, 1996; Milligan et al., 2003). Peripheral nerve damage leads to an increase in IL-6 levels at dorsal spinal level, particularly in layers I-II (DeLeo et al., 1996; Murphy et al., 1995), both in microglial cells (Dominguez et al., 2008) and in neurons (Yamauchi et al., 2006). IL-6 is not only known as peripheral immune modulator. "
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    ABSTRACT: Glia plays a crucial role in the maintenance of neuronal homeostasis in the central nervous system. The microglial production of immune factors is believed to play an important role in nociceptive transmission. Pain may now be considered a neuro-immune disorder, since it is known that the activation of immune and immune-like glial cells in the dorsal root ganglia and spinal cord results in the release of both pro- and anti-inflammatory cytokines, as well as algesic and analgesic mediators. In this review we presented an important role of cytokines (IL-1alfa, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-15, IL-18, TNFalpha, IFNgamma, TGF-beta 1, fractalkine and CCL2); complement components (C1q, C3, C5); metaloproteinases (MMP-2,-9) and many other factors, which become activated on spinal cord and DRG level under neuropathic pain. We discussed the role of the immune system in modulating chronic pain. At present, unsatisfactory treatment of neuropathic pain will seek alternative targets for new drugs and it is possible that anti-inflammatory factors like IL-10, IL-4, IL-1alpha, TGF-beta 1 would fulfill this role. Another novel approach for controlling neuropathic pain can be pharmacological attenuation of glial and immune cell activation. It has been found that propentofylline, pentoxifylline, minocycline and fluorocitrate suppress the development of neuropathic pain. The other way of pain control can be the decrease of pro-nociceptive agents like transcription factor synthesis (NF-kappaB, AP-1); kinase synthesis (MEK, p38MAPK, JNK) and protease activation (cathepsin S, MMP9, MMP2). Additionally, since it is known that the opioid-induced glial activation opposes opioid analgesia, some glial inhibitors, which are safe and clinically well tolerated, are proposed as potential useful ko-analgesic agents for opioid treatment of neuropathic pain. This review pointed to some important mechanisms underlying the development of neuropathic pain, which led to identify some possible new approaches to the treatment of neuropathic pain, based on the more comprehensive knowledge of the interaction between the nervous system and glial and immune cells.
    European journal of pharmacology 03/2013; 716(1-3). DOI:10.1016/j.ejphar.2013.01.072 · 2.53 Impact Factor
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    • "STAT3 is a member of the Janus kinase-signal transducers and activators of transcription (Jak-STATs) signaling family that transduces signals for many cytokines and growth factors, including interleukin-6 (IL-6), IL-10, epidermal growth factor (EGF), transforming growth factor-a (TGF-a), leukemia inhibitory factor (LIF), and CNTF [41]–[45]. STAT3 is expressed by astrocytes, neurons, and other cell types in CNS [46], [47]. Recently, it has been reported that STAT3 play a Critical role in the regulation of astrogliosis and scar formation in Spinal Cord Injury [48]. "
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    ABSTRACT: Lamina cribosa, an astrocyte-rich region, is the origin of axonal degeneration in glaucomatous neuropathy. Astrocytes are particularly activated during optic nerve (ON) degeneration and are likely to contribute to the pathogenesis of glaucomatous optic neuropathy. Signalling mechanisms that regulate different aspects of astrocyte reactiviation in response to intraocular hypertensive injury are not well defined. Signal transducer and activator of transcription protein-3 (STAT3) is a transcription factor that participates in many biological processes and has been implicated as activator of reactive astrogliosis. In this study, we investigated the role of STAT3 in regulating the activation of astrocytes to transient intraocular hypertension in vivo by using a rat ocular hypertension model. ON astrocytes hypertrophy was observed early after intraocular hypertensive stress. Morphological changes in glial fibrillary acidic protein (GFAP) positive cells coupled with axon loss in the optic nerve was detected at day 7 after the injury. Nestin was significantly upregulated in ON astrocytes as early as day 2 post injury and kept elevated through post injury day 7. Phosphorylated STAT3 (pSTAT3) was markedly upregulated in ON astrocytes at post injury day 1, prior to the reactivation of ON astrocytes. These findings indicate that STAT3 signalling is involved in the initiation of astrocyte reactivation in optic nerve injury.
    PLoS ONE 01/2013; 8(1):e55683. DOI:10.1371/journal.pone.0055683 · 3.23 Impact Factor
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