Activation of Cytokine Signaling through Leukemia Inhibitory Factor Receptor (LIFR)/gp130 Attenuates Ischemic Brain Injury in Rats

Suzuki, Shigeaki; Yamashita, Toru; Tanaka, Kortaro; Hattori, Hidenori; Sawamoto, Kazunobu; Okano, Hideyuki; Suzuki, Norihiro

doi:10.1038/sj.jcbfm.9600061

Cited by 45 publications

(32 citation statements)

References 33 publications

(56 reference statements)

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“…The phosphorylation of STAT3 correlated with a downregulation of damage to the CNS, including a decrease in the number of TUNEL-positive cells in the damage area (123,124). Another study was also consistent with this finding; inhibition of STAT3 phosphorylation following damage to the CNS was associated with an increased seriousness of the secondary injury, and potential enlargement of the lesion, and exacerbation of neurological deficits (125). Neuroprotection requires the active suppression of apoptosis, which is accomplished either through suppressing caspases or by inhibiting their activation.…”

Section: Astrocyte-secretory Polypeptides Promote Neuroprotection Viasupporting

confidence: 74%

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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Section: Astrocyte-secretory Polypeptides Promote Neuroprotection Viasupporting

confidence: 74%

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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“…In their study, a dominant negative form of Stat3 induced the premature differentiation of olfactory receptor neurons, indicating that Stat3 function is essential (Moon et al, 2002). Suzuki et al (2005) injected LIF into the boundary area of an ischemic infarct which rapidly induced Stat3 phosphorylation and a decreased the severity of insult. Similarly we report increased levels of pStat3 when LIF mRNA is maximal and we show that LIF induces pStat3 phosphorylation in cultured neurospheres.…”

Section: Discussionmentioning

confidence: 99%

Leukemia inhibitory factor participates in the expansion of neural stem/progenitors after perinatal hypoxia/ischemia

Covey

Levison

2007

Neuroscience

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Subsequent to perinatal hypoxia/ischemia there is an increase in the number of neural stem/progenitor cells (NSP) within the subventricular zone. Gene expression analyses have implicated Notch signaling in the expansion of these tripotential cells but there are limited data as to which signals are stimulating Notch activation. There is evidence that the LIFR/gp130 receptor heterodimer induces Notch1 to maintain NSP populations during normal development. LIF and CNTF bind to these receptor components and they coordinate injury responses in the CNS. Therefore, the aim of these studies was to investigate whether CNTF and/or LIF participate in NSP expansion in the SVZ after H/I as well as to characterize the downstream events that regulate NSP numbers. We report that LIF mRNA is induced 48 hours post insult by 13 fold but that it returns almost to baseline by 72 hours. Commensurate with increased LIF expression there is a corresponding increase in phosphorylated STAT-3 within the SVZ. Modeling the changes that occur in vivo, we show that LIF induces STAT-3 phosphorylation in neurospheres to enhance Delta-like-1 and Notch1 expression as well as to increase Notch1 activation. LIF also expands neurosphere number and size in vitro. Whereas CNTF can mimic the effects of LIF in vitro, CNTF expression in the SVZ was unchanged during recovery from H/I. Cumulatively, these data implicate LIF and not CNTF in the expansion of NSPs in the SVZ after perinatal brain injury. As both LIF expression and the endogenous regenerative response after brain injury are time-delimited, these findings provide insights into strategies to expand the endogenous pool of NSPs to repopulate the damaged brain.

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“…Recently, blocking the IL-6 receptor has been shown to decrease levels of pSTAT3 (34) but not pERK and pAKT. Moreover, injection of leukemia inhibitory factor, a member of the IL-6 family, leads to an increase in pSTAT3, but not pERK or pAKT, after MCAO (38). pSTAT3 has been shown to increase the expression of bcl-2 (27, 39).…”

Section: Discussionmentioning

confidence: 99%

Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6

Ohtaki

Nakamachi

Dohi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

180

192

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Pituitary adenylate cyclase-activating polypeptide (PACAP) has been reported to decrease ischemic neuronal damage and increase IL-6 secretion in rats. However, the mechanisms underlying neuroprotection are still to be fully elucidated. The present study was designed to investigate the role played by PACAP and IL-6 in mediating neuroprotection after ischemia in a null mouse. Infarct volume, neurological deficits, and cytochrome c in cytoplasm were higher in PACAP ؉/؊ and PACAP ؊/؊ mice than in PACAP ؉/؉ animals after focal ischemia, although the severity of response was ameliorated by the injection of PACAP38. A decrease in mitochondrial bcl-2 was also accentuated in PACAP ؉/؊ and PACAP ؊/؊ mice, but the decrease could be prevented by PACAP38 injection. PACAP receptor 1 (PAC1R) immunoreactivity was colocalized with IL-6 immunoreactivity in neurons, although the intensity of IL-6 immunoreactivity in PACAP ؉/؊ mice was less than that in PACAP ؉/؉ animals. IL-6 levels increased in response to PACAP38 injection, an effect that was canceled by cotreatment with the PAC1R antagonist. However, unlike in wild-type controls, PACAP38 treatment did not reduce the infarction in IL-6 null mice. To clarify the signaling pathway associated with the activity of PACAP and IL-6, phosphorylated STAT (signal transducer and activator of transcription) 3, ERK (extracellular signal-regulated kinase), and AKT levels were examined in PACAP ؉/؊ and IL-6 null mice after ischemia. Lower levels of pSTAT3 and pERK were observed in the PACAP ؉/؊ mice, whereas a reduction in pSTAT3 was recorded in the IL-6 null mice. These results suggest that PACAP prevents neuronal cell death after ischemia via a signaling mechanism involving IL-6.bcl-2 ͉ extracellular signal-regulated kinase ͉ ischemia ͉ pituitary adenylate cyclase-activating polypeptide-specific receptor ͉ signal transducer and activator of transcription 3

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Activation of Cytokine Signaling through Leukemia Inhibitory Factor Receptor (LIFR)/gp130 Attenuates Ischemic Brain Injury in Rats

Cited by 45 publications

References 33 publications

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

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

Leukemia inhibitory factor participates in the expansion of neural stem/progenitors after perinatal hypoxia/ischemia

Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6

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