MR image-guided investigation of regional signal transducers and activators of transcription-1 activation in a rat model of focal cerebral ischemia

West, Daniel; Valentim, Lauren Martins; Lythgoe, Mark F.; Stephanou, Anastasis; Proctor, E; Weerd, Louise van der; Ordidge, Roger J.; Latchman, David S.; Gadian, David G.

doi:10.1016/j.neuroscience.2004.05.022

Cited by 21 publications

(18 citation statements)

References 33 publications

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“…47 It has been shown that cerebral ischemia is associated with phosphorylation of STAT1 at Tyr701 but not Ser727. 48 In addition, a JAK2 inhibitor could inhibit hydrogen peroxide-induced STAT1 Tyr701 phosphorylation. 49 Therefore, the detailed mechanisms and functions underlying Tat abrogation of IFN␥-induced STAT1 phosphorylation remain to be investigated.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFNγ signaling

Cheng¹,

Lin³

et al. 2009

Blood

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IntroductionAIDS is characterized by a profound reduction of CD4 ϩ T lymphocytes, immune defects, and cytokine dysregulation, leading to opportunistic infections and tumorgenesis. 1 HIV-1 has been identified to be the primary etiologic agent. Among HIV-1 gene products, transactivator protein (Tat) is required for efficient viral gene expression by interacting with the HIV long terminal repeat to enhance transcription and RNA processing. 2 Apart from its effects on viral replication, Tat is secreted extracellularly by the infected cells and exerts its paracrine effects on neighboring cells. 3 It has been shown that extracellular Tat may play a diverse role in dysregulating the host immune response via the modulation of cellular gene expression. 4 For example, previous reports including ours showed Tat induces the overexpression of interleukin-10 (IL-10), which is a well known immunosuppressive cytokine capable of down-regulating TH1 cell function and IL-2 synthesis. 5 We recently demonstrated Tat induces IL-10 expression via cellular kinase PKR activity and the activation of transcription factor Ets-1. 6,7 PKR, one of the key genes in the mediation of interferoninduced activities, is a prototype kinase modulated by Tat in HIV-1 perturbation of the cytokine systems. 8 Infection with HIV-1 marks the onset of changes in the microenvironment of the host cell. Throughout all stages of HIV-1 infection, chronic immune activation and dysfunctional cytokine production have been observed. 9 Soluble mediators, including cytokines and viral products such as Tat, produced by the infected cells may enhance the progression of HIV-1 infection either by direct effects or through deregulation of cytokine expression such as interferon-␥ (IFN␥) and tumor necrosis factor-␣ (TNF␣). 7,10 Therefore, elucidating the transcriptional regulation of host genes including cytokines and their regulated pathways upon HIV-1 viral protein stimulation can be used as a tool to delineate the mechanisms of host-virus interactions, and to understand the molecular basis of AIDS pathogenesis.Interferon-␥ is a pleiotropic cytokine produced primarily by T lymphocytes and natural killer (NK) cells in response to viral infection. It is an important mediator with multiple biological activities including macrophage activation, and antimicrobial, antiproliferative, and immunomodulatory effects. 11 It has been shown that IFN␥ receptor-deficient mice are significantly impaired in their abilities to resist infection by microbes including virus, bacteria, and protozoa. 12 Central to IFN␥-induced cellular responses is the activation of Janus kinase-1 (Jak1) and Jak2 and consequent phosphorylation of STAT1. The phosphorylated STAT1 (pSTAT1) undergoes dimerization and translocation into the nucleus, where it binds to IFN␥-activated sequence (GAS) elements present in the promoter of IFN␥-regulated genes, and consequently leads to initiation of transcription. 13 Previous studies of IFN-induced signaling cascade suggested overexpression of suppressor of cytokine signalin...

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Section: Discussionmentioning

confidence: 99%

HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFNγ signaling

Cheng¹,

Lin³

et al. 2009

Blood

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“…Activated STAT3 was found in neurons after focal ischaemia [33,34], but its function is controversial as different studies associated it with survival [33], while others related it with cell death [34]. STAT1 was also found phosphorylated in the lesion core and in the periphery [35], and STAT1 knockout mice were more resistant to ischaemic brain damage [36]. Taken together, these results show activation of STAT proteins after ischaemia and suggest a contribution of the JAK/STAT pathway to the cell fate.…”

Section: Jak/stat: a Main Signalling Pathway Mediating Cellular Respomentioning

confidence: 95%

Signalling pathways mediating inflammatory responses in brain ischaemia

Planas

Gorina

Chamorro

2006

Biochemical Society Transactions

119

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Stroke causes neuronal necrosis and generates inflammation. Pro-inflammatory molecules intervene in this process by triggering glial cell activation and leucocyte infiltration to the injured tissue. Cytokines are major mediators of the inflammatory response. Pro-inflammatory and anti-inflammatory cytokines are released in the ischaemic brain. Anti-inflammatory cytokines, such as interleukin-10, promote cell survival, whereas pro-inflammatory cytokines, such as TNFalpha (tumour necrosis factor alpha), can induce cell death. However, deleterious effects of certain cytokines can turn to beneficial actions, depending on particular features such as the concentration, time point and the very intricate network of intracellular signals that become activated and interact. A key player in the intracellular response to cytokines is the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway that induces alterations in the pattern of gene transcription. These changes are associated either with cell death or survival depending, among other things, on the specific proteins involved. STAT1 activation is related to cell death, whereas STAT3 activation is often associated with survival. Yet, it is clear that STAT activation must be tightly controlled, and for this reason the function of JAK/STAT modulators, such as SOCS (suppressors of cytokine signalling) and PIAS (protein inhibitor of activated STAT), and phosphatases is most relevant. Besides local effects in the ischaemic brain, cytokines are released to the circulation and affect the immune system. Unbalanced pro-inflammatory and anti-inflammatory plasma cytokine concentrations favouring an 'anti-inflammatory' state can decrease the immune response. Robust evidence now supports that stroke can induce an immunodepression syndrome, increasing the risk of infection. The contribution of individual cytokines and their intracellular signalling pathways to this response needs to be further investigated.

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Section: Discussionmentioning

confidence: 99%

“…Additionally, STAT1 is activated in neurons after cerebral ischemia and contributes to ischemic brain injury [12,13]. Its mechanism is the inhibition of the neuroprotective PI3-kinase/Akt pathway during ischemia [12] and the enhanced expression of the apoptotic death receptor Fas [13]. Free radical scavengers and strong antioxidant flavonoids protect cardiac myocytes and the brain against ischemia/ reperfusion through the inhibition of STAT1 phosphorylation [16,17].…”

Section: Discussionmentioning

confidence: 99%

“…MP prevents the AMPA-induced death of oligodendrocytes through the binding of activated STAT5 with the glucocorticoid receptor, which subsequently binds to the promoter region of bcl-x and activates the expression of bcl-X L [11]. STAT1 is activated in neurons after cerebral ischemia and contributes to ischemic brain injury [12,13]. SCI induces ischemic-reperfusion injury.…”

Section: Introductionmentioning

confidence: 99%

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Activation of STAT1 in Neurons Following Spinal Cord Injury in Mice

et al. 2011

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The signal transducer and activator of transcription 1 (STAT1) has been reported to be associated with neuronal cell death after cerebral ischemia. On the contrary, STAT3 has been revealed to regulate cell survival. We examined the chronological alteration and cellular localization of phosphorylated (p)-JAK1, p-STAT1 and p-STAT3 following mild spinal cord injury (SCI) in mice. Western blot analysis indicated that JAK1 is significantly phosphorylated, accompanied by the phosphorylation of STAT1 at Tyr(701) within a similar timeframe. Immunofluorescence staining indicated that signal transduction of STAT3 is introduced into the nucleus of the neurons within the anterior horns; however, in mirror sections, that of STAT1 is limited to the cytoplasm. These findings suggest that STAT3 signal is predominantly transduced into the nucleus and plays a stronger role in neuronal survival than STAT1. Modulation of the functional balance between STAT1 and STAT3 might determine the survival or death of neurons after SCI.

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MR image-guided investigation of regional signal transducers and activators of transcription-1 activation in a rat model of focal cerebral ischemia

Cited by 21 publications

References 33 publications

HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFNγ signaling

HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFNγ signaling

Signalling pathways mediating inflammatory responses in brain ischaemia

Activation of STAT1 in Neurons Following Spinal Cord Injury in Mice

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