• Glia · Jan 2011

    Astrocyte reactivity to unconjugated bilirubin requires TNF-α and IL-1β receptor signaling pathways.

    • Adelaide Fernandes, Andreia Barateiro, Ana Sofia Falcão, Sandra Leit-Ao Silva, Ana Rita Vaz, Maria Alexandra Brito, Rui Fernando Marques Silva, and Dora Brites.
    • Research Institute for Medicines and Pharmaceutical Sciences (IMedUL), Faculdade de Farmácia, University of Lisbon, Lisbon, Portugal.
    • Glia. 2011 Jan 1;59(1):14-25.

    AbstractJaundice 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)-α and interleukin (IL)-1β 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)-κB-dependent pathway that we have showed to be activated by UCB. The present study was designed to evaluate the role of TNF-α and IL-1β signaling on astrocyte reactivity to UCB in rat cortical astrocytes. Exposure of astrocytes to UCB increased the expression of both TNF-α receptor (TNFR)1 and IL-1β 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-1β cascade, using its endogenous antagonist, IL-1 receptor antagonist (IL-1ra), prevented UCB-induced cytokine release and NF-κB activation. Interestingly, lack of TNF-α 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-1β 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.Copyright © 2010 Wiley-Liss, Inc.

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