Premium
MAPKs are key players in mediating cytokine release and cell death induced by unconjugated bilirubin in cultured rat cortical astrocytes
Author(s) -
Fernandes Adelaide,
Falcão Ana S.,
Silva Rui F. M.,
Brito Maria A.,
Brites Dora
Publication year - 2007
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2007.05340.x
Subject(s) - mapk/erk pathway , astrocyte , p38 mitogen activated protein kinases , microbiology and biotechnology , kinase , signal transduction , cytokine , neurotoxicity , chemistry , biology , medicine , immunology , neuroscience , central nervous system , toxicity
When activated by unconjugated bilirubin (UCB), astrocytes are important sources of inflammatory mediators such as TNF‐α, IL‐1β and IL‐6, which may contribute for the neurotoxicity observed during severe neonatal hyperbilirubinemia. In the present study, we have addressed the role of the mitogen‐activated protein kinases (MAPKs) p38, Jun N‐terminal kinase (JNK)1/2 and extracellular signal‐regulated kinase (ERK)1/2 pathways and their relation with the nuclear factor κB (NF‐κB) cascade in the signalling events involved in cytokine release and cell death caused by UCB in primary cultures of rat astrocytes. Stimulation of astrocytes with UCB in the presence of all the MAPK inhibitors prevented UCB‐induced release of TNF‐α and IL‐6, while IL‐1β secretion was only reduced by JNK1/2 and ERK1/2 inhibitors. In addition, activation of the NF‐κB transcription factor, needed for cytokine release by UCB‐stimulated astrocytes, was shown to be dependent on JNK1/2 and ERK1/2 phosphorylation. Moreover, all MAPK inhibitors prevented astroglial apoptosis triggered by UCB. Interestingly, UCB‐induced lactate dehydrogenase release was prevented by blockade of JNK1/2, ERK1/2 and NF‐κB cascades but enhanced by p38 inhibition. Taken together, our data demonstrate for the first time that MAPK transduction pathways are key players in the UCB‐induced inflammatory response and cell death in astrocytes, probably also involving NF‐κB modulation. These findings contribute to unraveling the complex mechanisms of astrocyte reactivity to UCB and may ultimately prove useful in the development of new therapeutic strategies to prevent nerve cell damage during acute bilirubin encephalopathy.