Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin

J Neurochem. 2006 Mar;96(6):1667-79. doi: 10.1111/j.1471-4159.2006.03680.x. Epub 2006 Feb 10.


During neonatal hyperbilirubinaemia, astrocytes activated by unconjugated bilirubin (UCB) may contribute to brain toxicity through the production of cytokines. As a first step in addressing the signal transduction cascades involved in the UCB-induced astroglial immunological response, we tested whether tumour necrosis factor (TNF)-alpha receptor 1 (TNFR1), mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) would be activated in astrocytes exposed to UCB, and examined the profile of cytokine production. Astrocyte cultures stimulated with UCB showed a rapid rise in TNFR1 protein levels, followed by activation of the MAPKs p38, Jun N-terminal kinase1/2 and extracellular signal-regulated kinase1/2, and NF-kappaB. Interestingly, the induction of these signal effectors preceded the early up-regulation of TNF-alpha and interleukin (IL)-1beta mRNAs, and later secretion of TNF-alpha, IL-1beta and IL-6. Treatment of astrocytes with UCB also induced cell death, with levels comparable to those obtained after exposure of astrocytes to recombinant TNF-alpha and IL-1beta. Moreover, loss of cell viability and cytokine secretion were reduced when the NF-kappaB signal transduction pathway was inhibited, suggesting a key role for NF-kappaB in the astroglial response to UCB. These results demonstrate the complexity of the molecular mechanisms involved in cell injury by UCB during hyperbilirubinaemia and provide a basis for the development of novel therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Bilirubin / metabolism*
  • Bilirubin / toxicity
  • Brain / immunology
  • Brain / metabolism*
  • Brain / physiopathology
  • Cell Death / drug effects
  • Cell Death / immunology
  • Cells, Cultured
  • Cytokines / immunology
  • Cytokines / metabolism
  • Cytokines / toxicity
  • Encephalitis / etiology
  • Encephalitis / immunology
  • Encephalitis / metabolism*
  • Gliosis / etiology
  • Gliosis / immunology
  • Gliosis / metabolism*
  • Hyperbilirubinemia, Neonatal / immunology
  • Hyperbilirubinemia, Neonatal / metabolism
  • Hyperbilirubinemia, Neonatal / physiopathology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / immunology
  • Nerve Degeneration / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Tumor Necrosis Factor / drug effects
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor, Type I
  • Signal Transduction / immunology
  • Tumor Necrosis Factor Decoy Receptors
  • Up-Regulation / drug effects
  • Up-Regulation / immunology


  • Cytokines
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor Decoy Receptors
  • recombinant human tumor necrosis factor-binding protein-1
  • Bilirubin