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Astrocyte reactivity to unconjugated bilirubin requires TNF-alpha and IL-1beta receptor signaling pathways.

Authors: Fernandes, A  Barateiro, A  Falcao, AS  Silva, SL  Vaz, AR  Brito, MA  Silva, RF  Brites, D 
Citation: Fernandes A, etal., Glia. 2011 Jan;59(1):14-25. doi: 10.1002/glia.21072. Epub 2010 Oct 21.
Pubmed: (View Article at PubMed) PMID:20967881
DOI: Full-text: DOI:10.1002/glia.21072

Jaundice and sepsis are common neonatal conditions that can lead to neurodevelopment sequelae, namely if present at the same time. We have reported that tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta are produced by cultured neurons and mainly by glial cells exposed to unconjugated bilirubin (UCB). The effects of these cytokines are mediated by cell surface receptors through a nuclear factor (NF)-kappaB-dependent pathway that we have showed to be activated by UCB. The present study was designed to evaluate the role of TNF-alpha and IL-1beta signaling on astrocyte reactivity to UCB in rat cortical astrocytes. Exposure of astrocytes to UCB increased the expression of both TNF-alpha receptor (TNFR)1 and IL-1beta receptor (IL-1R)1, but not TNFR2, as well as their activation, observed by augmented binding of receptors' molecular adaptors, TRAF2 and TRAF6, respectively. Silencing of TNFR1, using siRNA technology, or blockade of IL-1beta cascade, using its endogenous antagonist, IL-1 receptor antagonist (IL-1ra), prevented UCB-induced cytokine release and NF-kappaB activation. Interestingly, lack of TNF-alpha signal transduction reduced UCB-induced cell death for short periods of incubation, although an increase was observed after extended exposure; in contrast, inhibition of IL-1beta cascade produced a sustained blockade of astrocyte injury by UCB. Together, our data show that inflammatory pathways are activated during in vitro exposure of rat cortical astrocytes to UCB and that this activation is prolonged in time. This supports the concept that inflammatory pathways play a role in brain damage by UCB, and that they may represent important pharmacological targets.

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CRRD Object Information
CRRD ID: 5130945
Created: 2011-04-15
Species: All species
Last Modified: 2011-04-15
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.