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65 Cards in this Set
- Front
- Back
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During physiology the levels of cytokines in the brain are
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barely detectable
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low levels of cytokines have important regulatory roles for
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CNS homeostasis and functions
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IL-1 R KO mice have deregulated
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sleep waves and an obese phenotype
ie. dereg in the brain, food intake, energy expenditure |
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After CNS disorders the levels of cytokines in the brain are
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detectable, nM range (pM at normal physiology)
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Role of cytokines is to regulate
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neuroinflammation
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Cytokines are produced by two pathways called
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Classical and Non classical pathways of protein secretion
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IL-6
Chemokine TNF-a are produced by which pathway? |
classical pathway
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IL-1a
IL-1b are produced by which pathway? |
non classical pathway
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Acute brain injury increases which cytokine?
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IL-1
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Before IL-1b can be secreted it has to be
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cleaved of the pro-piece > activated
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IL-1b is activated by
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caspase-1
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caspas-1 is activated by
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inflammasome, NLRP3
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unlike pro-IL-1b, IL-1a is
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Active
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IL-1a is cleaved by
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Ca2+ dependent calpain
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Ca2+ dependent calpain bound to the membrane will result in IL-1a..
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cleavage and secretion
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There are two isoforms of IL-1 R antagonists called
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icIL-1RA
sIL-1RA |
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icIL-1RA and sIL-1RA have clinical use in
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rhumatoid arthiritis
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IL-1 may be produced by PAMPs, DAMPs signalling and
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hypoxia, stress, UV, chemicals
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IL-1Rs have an intracellular domain and an extracellular domain except for..
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IL-1R2 which has no IC domain = non functional
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ALL IL-1Rs have similar sequence homology except for
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TLR4
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When IL-1 binds to site A..
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the structure falls and site B can interact
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IL-1 classical signalling pathway leads to the transcription of
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pro inflammatory genes
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IL-1 can bind to IL-1R1 and co-receptor
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IL-1RAcp
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IL-1 can also bind to
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TLR4
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IL-1 classical signalling pathways can activate two kinase pathways...
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TAK1 (NF-kb)
MAPKK (c-Jun) |
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How can we experiment IL-1 actions in mice brain?
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extract tissue (astrocyte, microglia culture etc) from mouse brain and treat with recombinant IL-1
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What can we measure from IL-1 experiments on mouse brain?
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The release of inflammatory mediators in the culture medium
The intracellular storage of mediators (lysates) The activation of signalling pathways |
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When we treat astrocytes with increasing concentrations of IL-1 we see an increase in
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IL-6 release
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IL-1RA has what effect on IL-1
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It blocks it
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Thornton et al, 2000 found that in response to increasing IL-1b concentration in neurones-astrocytes...
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neuronal cell death increased in neurones-astrocytes
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Which enzyme mediates IL-1 neurotoxicity?
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MMP-9
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treatment with MMP-9 inhibitor has what effect on neuronal death?
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Blocks cell death
prevents neurotoxic response! |
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What effect does IL-1 have on astrocytes?
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Induces astrogliosis
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What is astrogliosis?
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the proliferation of reactive astrocytes
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IL-1 induces astrogliosis through a signalling pathway and inhibition of
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ROCK-RhoA
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ROCK > RHOA > what effect?
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Cytoskeleton stabilisation
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IL-1 is not directly toxic on neurones.
So.. What mechanism of neurotoxicity does IL-1 have? |
It is toxic to Astrocytes > MMP-9 > neuronal cell death
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In neurons and glial cells IL-1 signalling pathway activates..
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MyD88
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In neurons, IL-1 signalling results in the activation of another R..
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NMDA R
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The NMDA R is activated by
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Src kinase
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The NMDA R activates which protein kinase?
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CaMKII
(Calcium/calmodulin dependent) |
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CaMKII phosphorylates
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CREB
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CREB is a
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transcription factor
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Tsakiri et al 2008 showed activation of.... in response to IL-1 neuronal signalling pathway
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Src kinases, NMDA R, CREB
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How can we analyse IL-1 induced gene expression in neurones?
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Microarray analysis > look for differentially expressed genes in untreated and IL-1 treated cultures
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Desson et al, 2003 showed that what happens to neuronal activity in response to IL-1
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Fire faster
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The glial response to IL-1b signalling is
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SLOW - gliosis
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the neuronal response to IL-1b signalling is
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FAST- depolarisation
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The neuronal response to IL-1b signalling occurs at what concentrations of IL-1b
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low (5-50 pM)
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Because neuronal responses to IL-1b occur at low concentrations this implies involvement in physiological responses e.g.
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fever, sleep, synaptic plasticity
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Which pathway does the glia response to IL-1b activate?
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MAPK, NF-kb > c-Jun, Elk-1
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which pathway does the neuronal response to IL-1b activate?
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Src kinase > NMDA R > CaMKII > CREB
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The outcome of Glial/neuronal response to IL-1b signalling pathway is
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production of pro-inflammatory mediators > neurotoxicity/neuroprotection
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What else is expressed in the brain in response to injury apart from IL-1?
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TNF-a
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Like IL-1, TNF-a is produced in response to
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PAMPs and DAMPs
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Pro-TNF-a is
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inactive
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Pro-TNF-a is secreted and
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cleaved outside the cell
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which enzyme converts and activates TNF-a
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TACE
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There are 2 TNF-a receptors called
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TNFR1 (p55)
TNFR2 (p75) |
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TNFR1 has what effect?
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neurotoxicity
Apoptosis and gene expression |
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TNFR2 has what effect?
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neuroprotective
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In neuronal culture from WT mice, TNF-a has what effect on neurones?
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neuronal cell death
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In neuronal culture from TNFR1 KO mice, TNF-a has what effect on neurons?
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a decrease in neuronal cell death because TNFR1 is neurotoxic
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In neuronal culture from TNFR2 KO mice, TNF-a has what effect on neurons?
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An increase in neuronal cell death because TNFR2 is neuroprotective
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TNF-a has positive feedback/autocrine mechanisms on which cells?
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astrocytes and microglia
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