Activation of JAK/STAT signalling in neurons following spinal cord injury in mice.

Department of Neurosurgery, Nagoya University, Graduate School of Medicine, Nagoya, Japan.
Journal of Neurochemistry (Impact Factor: 3.97). 03/2006; 96(4):1060-70. DOI: 10.1111/j.1471-4159.2005.03559.x
Source: PubMed

ABSTRACT 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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    PLoS ONE 06/2014; 9(6):e100405. · 3.53 Impact Factor
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    ABSTRACT: The signal transducer and activator of transcription 1 (STAT1) is associated with neuronal cell death after cerebral ischemia. However, the role of STAT1 in the spinal cord injury (SCI) remains unclear. Here, we examined whether STAT1 blockade reduces neural tissue damage and locomotor impairment after SCI in mice. The small interfering RNA against STAT1 (STAT1 siRNA) or control non-targeting siRNA was injected intraperitoneally into SCI mice. Histological damage and locomotor function were evaluated. Inflammatory markers and apoptosis were determined. STAT1 siRNA treatment significantly decreased the histological damage following SCI. STAT1 siRNA-treated mice showed significantly improved locomotor function compared with the controls. Furthermore, TNF-α, IL-1β, and IL-6 levels at the injured site from the STAT1 siRNA-treated group were significantly reduced and IL-10 increased, in comparison with controls. The NF-κB activation and apoptosis in SCI were also inhibited. These results reveal that selective STAT1 inhibition reduced neural tissue damage and locomotor impairment by regulating inflammatory response and possibly apoptosis. STAT1 represents a novel therapeutic target after SCI.
    Neuroscience Letters 12/2013; · 2.03 Impact Factor
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    ABSTRACT: Activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation is thought to mediate anti-inflammatory responses to CNS injury. Several studies have reported an increase in phosphorylated STAT3 (pSTAT3) in peripheral T cells and monocytes from patients with multiple sclerosis (MS) during relapses, suggesting that pSTAT3 might represent an inflammatory marker. Here, we examined immunoreactivity for pSTAT3 in brain tissue samples from MS patients and controls. Phosphorylated STAT3 immunoreactivity was sparse within lesions, with no difference between active and inactive lesions. It was, however, significantly greater in white matter (WM) adjacent to active and inactive lesions; moreover, it was significantly greater in WM adjacent to active versus inactive lesions. Phosphorylated STAT3-positive cells were identified as astrocytes and macrophages/microglia. Phosphorylated STAT3 expression was also detected by Western blotting in WM of patients with MS. In comparison, pSTAT3 immunoreactivity was either rare or found focally in brain tissue samples from patients with other neurologic diseases. Our findings show that pSTAT3 does not correlate with inflammatory activity in MS lesions, but that it may play an important role in regulating reactive changes proximal to MS lesions.
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