This model was employed since secretagogue induced pancreatitis, elicited

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 This model was employed since secretagogue induced pancreatitis, elicited  Empty This model was employed since secretagogue induced pancreatitis, elicited

Post  wangqian on Fri May 23, 2014 8:32 am

Therefore, we investigated the effects of removing IFNAR1 on committed caspase 3 driven apop tosis in this environment. Western blot analysis for cleaved caspase 3 identified significantly elevated cleavage at 4 and 24 h reperfusion post OGD in NC shRNA but not in IFNAR1 KD cultures. This finding high オーダー ARQ 197 lights that removal of type 1 IFN signalling is protective through mechanisms of reduced committed apoptosis in response to OGD. Discussion Reducing the cellular damage within the core infarct area following hypoxic ischaemic brain injury is consid ered to be largely uncontrollable, however limiting the development of the penumbra and progression of this injury may be more achievable. Therapeutic intervention requires a greater understanding of the cellular processes occurring in the injured environment, which remain uncharacterised.

Neuro inflammatory cascades are known to be involved in the progression of hypoxic ischaemic in jury, however the cytokine profile and cell specific re sponses have not been fully elucidated. Our data suggest a previously unrecognised role for type 1 IFN production and signalling purchase AZD0530 in response to OGD insult. IFN produc tion and downstream pro inflammatory Stat 1 phosphor ylation were upregulated during early stage reperfusion in vitro following OGD treatment. This phenomenon occurred in a neuro inflammatory environment where the hallmark pro inflammatory cytokines, IL 1B, IL 6 and TNF, are readily secreted. Removing type 1 IFN signal ling in the IFNAR1 KD cells decreased pro inflammatory cytokine release and type 1 IFN levels in response to OGD.

These same cultures were protected from the hypoxic ischaemic insult and displayed reduced caspase 3 cleavage. This response Alvocidib 臨床試験 was reversed when IFNAR1 over expressing cells, promoting type 1 IFN signalling, were ex posed to the same conditions. Type 1 IFNs have well characterised pro inflammatory and anti viral roles in peripheral physiology but remain largely uncharacterised in the CNS. Neurons and glia are known to produce and respond to type 1 IFNs, how ever their role in neuropathologies is still largely unknown. Among a myriad of signalling cascades, type 1 IFNs can activate the Jak Stat pathway and induce pro inflammatory gene transcription, however much about ligand specificity and subsequent Stat isoform phosphorylation in CNS cell types is still not known.

This current study identified an ability of type 1 IFNs to induce differential phosphorylation of Stat isoforms based on the initial IFN subtype. IFN displays preference to ac tivating Stat 1 as opposed to Stat 3, while IFNB stimula tion of the M17 cultures induced phosphorylation of both isoforms. This finding gives insight into type 1 IFN ligand specificity in a CNS derived cell line and supports previ ous findings that downstream type 1 IFN cascades are se lectively activated based on ligand subtype. At this time, 13 subtypes of IFN alone have been discovered, with a universal type 1 IFN used in this study. Therefore, further characterisation of individual IFN subtypes is required.


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