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

Yamauchi, Katsuaki; Osuka, Koji; Takayasu, Misako; Usuda, Nobuteru; Nakazawa, Ayami; Nakahara, Norimoto; Yoshida, Mitsuhiro; Aoshima, Chihiro; Hara, Masahito; Yoshida, Jun

doi:10.1111/j.1471-4159.2005.03559.x

Cited by 100 publications

(93 citation statements)

References 48 publications

(106 reference statements)

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“…Several studies have also indicated that Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are activated by interleukin 6 (IL6) in cardiomyocytes, macrophages, carcinoma cells and neurons and by hypoxia in pulmonary arterial smooth muscle cells, rat cardiomyocytes, retinal microvascular endothelial cells (Negoro et al, 2001;Mascareno et al, 2005;Wang et al, 2005;Dawn et al, 2004;Lee et al, 2006;Yamauchi et al, 2006;Terrell et al, 2006). STATs comprise a family of seven transcription factors that are activated by the JAK family of protein tyrosine kinases in response to stimulation by cytokines, hormones and growth factors.…”

Section: Introductionmentioning

confidence: 99%

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Wang

Pei

Jackson

et al. 2008

The International Journal of Biochemistry & Cell Biology

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Xanthine dehydrogenase/oxidase (XDH/XO) is associated with various pathological conditions related to the endothelial injury. However, the molecular mechanism underlying the activation of XDH/XO by hypoxia remains largely unknown. In this report, we determined whether the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling pathway is involved in hypoxia-induced activation of XDH/XO in primary cultures of lung microvascular endothelial cells (LMVEC). We found that hypoxia significantly increased interleukin 6 (IL6) production in a time-dependent manner in LMVEC. Hypoxia also markedly augmented phosphorylation/activation of JAKs (JAK1, JAK2 and JAK3) and the JAK downstream effectors STATs (STAT3 and STAT5). Hypoxia-induced activation of STAT3 was blocked by IL6 antibodies, the JAK inhibitor AG490 and the suppressor of cytokine signaling 3 (SOCS3), implying that hypoxiapromoted IL6 secretion activates the JAK/STAT pathway in LMVEC. Phosphorylation and DNAbinding activity of STAT3 was also inhibited by the p38 MAPK inhibitor SB203580 and the phosphatidylinositol 3-kinase inhibitor LY294002, suggesting that multiple signaling pathways involved in STAT activation by hypoxia. Importantly, hypoxia promoted XDH/XO activation in LMVEC, which was markedly reversed by inhibiting the JAK/STAT pathway using IL6 antibodies, AG490 and SOCS3. These data demonstrated that JAKs, STATs and XDH/XO were sequentially activated by hypoxia. These data also provide the first evidence indicating that the JAK-STAT pathway is involved in hypoxia-mediated XDH/XO activation in LMVEC.

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Section: Introductionmentioning

confidence: 99%

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Wang

Pei

Jackson

et al. 2008

The International Journal of Biochemistry & Cell Biology

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“…Yamauchi et al (104) demonstrated the peak expression of IL-6 to be consistent with the maximum activation of JAK1 and STAT3 in neurons, with translocation of phosphorylated STAT3 to the nucleus. It has previously been validated that the co-administration of IL-6 and soluble IL-6 receptor can improve neurological manifestations and protect motor neurons of the spinal cord from degeneration (105). Additional research also indicated that, compared with wild-type mice after injury, IL-6 gene knockout mice exhibited more severe damage and death of the spinal cord neurons (106).…”

Section: Astrocyte-secretory Polypeptides Promote Neuroprotection Viamentioning

confidence: 80%

The role of the JAK-STAT pathway in neural stem cells, neural progenitor cells and reactive astrocytes after spinal cord injury

et al. 2014

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Abstract.Patients with spinal cord injuries can develop severe neurological damage and dysfunction, which is not only induced by primary but also by secondary injuries. As an evolutionarily conserved pathway of eukaryotes, the JAK-STAT pathway is associated with cell growth, survival, development and differentiation; activation of the JAK-STAT pathway has been previously reported in central nervous system injury. The JAK-STAT pathway is directly associated with neurogenesis and glia scar formation in the injury region. Following injury of the axon, the overexpression and activation of STAT3 is exhibited specifically in protecting neurons. To investigate the role of the JAK-STAT pathway in neuroprotection, we summarized the effect of JAK-STAT pathway in the following three sections: Firstly, the modulation of JAK-STAT pathway in proliferation and differentiation of neural stem cells and neural progenitor cells is discussed; secondly, the time-dependent effect of JAK-STAT pathway in reactive astrocytes to reveal their capability of neuroprotection is revealed and lastly, we focus on how the astrocyte-secretory polypeptides (astrocyte-derived cytokines and trophic factors) accomplish neuroprotection via the JAK-STAT pathway.

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“…AG490 inhibits cytokine-induced activation of JAK-2 in eosinophils stimulated with granulocyte-macrophage colony stimulating factor and selectively blocks leukemic cell growth by inducing programmed cell death (25). Related studies have suggested that AG490 also inhibits the IL-2 signaling pathway in the T cell line, d10, which fails to activate JAK-1, JAK-2, or Tyk2 (26,27). Furthermore, AG490 is an inhibitor of the JAK-2, JAK-3/STAT, JAK-3/acute protein-1 and the JAK-3/mitogen-activated protein kinase signaling pathways and potently inhibits cytokine-independent cell growth in vitro.…”

Section: Discussionmentioning

confidence: 99%

The antagonist of the JAK-1/STAT-1 signaling pathway improves the severity of cerulein-stimulated pancreatic injury via inhibition of NF-κB activity

Chen

Huang²,

Zhang³

et al. 2011

Int J Mol Med

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Abstract. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is widely involved in cell migration, apoptosis and inflammation. However, its exact mechanisms in severe acute pancreatitis (SAP) remain unclear. The aim of this study was to explore the activity of the JAK/STAT signaling pathway in pancreatic injury, investigate the functional mechanisms of SAP in vitro, and thus elucidate the underlying therapeutic effects for SAP in vivo. The activation of the JAK-1/STAT-1 signaling pathway and the expessions of TNF-α, IL-1β and IL-6 proteins were investigated in AR42J cells induced with cerulein and treated with either PBS, RPM, or AG490. One group of cells was left untreated as a control group. Subsequently the activity of NF-κB was evaluated. Rats were given RPM or AG490 just before the induction of SAP, the severity of which was assessed at 24 h. The findings revealed that the up-regulated expressions of JAK-1/STAT-1, STAT-3 protein were closely correlated with the transcription of TNF-α, IL-1β, and IL-6 in cerulein-stimulated cells. Administration of RPM or AG490 decreased the activity of NF-κB and inhibited the release of TNF-α, IL-1β, and IL-6. The reflective markers of severity of SAP were also decreased by RPM or AG490 treatment compared to SAP rats. This study indicates that the JAK-1/STAT-1 signaling pathway activity is an early event in pancreatic inflammatory injury. Therefore, early treatment with its inhibitors might be beneficial for attenuation of pancreatic injury in SAP. IntroductionSevere acute pancreatitis (SAP) is an inflammatory disease characterized by interstitial edema, vacuolization, acinar necrosis, and inflammatory infiltration of the pancreas. Its high mortality makes SAP a real challenge for clinical treatment (1). Although it has become increasingly clear that the excessive inflammatory response is a determining factor in the process of SAP (2), the exact mechanisms that regulate the severity of SAP remain unclear.The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is widely involved in cell migration and apoptosis (3). Some studies have shown that the JAK/STAT signaling pathway plays an important role in the inflammatory response. The blockade of the JAK/STAT signaling pathway prevents the lethal effects of the excessive inflammatory response during sepsis (4,5). However, the role of the JAK/STAT signaling pathway in the excessive systemic inflammatory response observed in SAP has not been fully elucidated. In addition, the precise mechanisms determining the effect of the JAK/STAT signaling pathway inhibitors on SAP in relation to the degree of pancreatic injury are largely unclear.AR42J cells are the currently available cell line that shows receptor expression and signal transduction mechanisms parallel to those of normal pancreatic acinar cells. Therefore, AR42J cells have been widely used as an in vitro model to study the secretion, signal transduction, cytoskeleton function, apoptosis and th...

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

Cited by 100 publications

References 48 publications

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells

The role of the JAK-STAT pathway in neural stem cells, neural progenitor cells and reactive astrocytes after spinal cord injury

The antagonist of the JAK-1/STAT-1 signaling pathway improves the severity of cerulein-stimulated pancreatic injury via inhibition of NF-κB activity

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