NF-kappaB signalling in cerebral ischaemia.
In acute stroke, neuronal apoptosis and inflammation are considered to be important mechanisms on the road to tissue loss and neurological deficit. Both apoptosis and inflammation depend on gene transcription. We have identified a signalling pathway that regulates transcription of genes involved in apoptosis and inflammation. In a mouse model of focal cerebral ischaemia, there is an induction of the cytokine TWEAK (tumour necrosis factor-like weak inducer of apoptosis) and its membrane receptor Fn14. TWEAK promotes neuronal cell death and activates the transcription factor NF-kappaB (nuclear factor kappaB) through the upstream kinase IKK [IkappaB (inhibitory kappaB) kinase]. In vivo, IKK is activated in neurons. Neuron-specific deletion of the subunit IKK2 or inhibition of IKK activity reduced the infarct size and neuronal cell loss. A pharmacological inhibitor of IKK also showed neuroprotective properties. IKK-dependent ischaemic brain damage is likely to be mediated by NF-kappaB, because neuron-specific inhibition of NF-kappaB through transgenic expression of the NF-kappaB superrepressor was found to reduce the infarct size. In summary, there is evidence that IKK/NF-kappaB signalling contributes to ischaemic brain damage and may provide suitable drug targets for the treatment of stroke.
Schwaninger
M
M
Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. markus.schwaninger@med.uni-heidelberg.de
Inta
I
I
Herrmann
O
O
D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D000074049:Cytokine TWEAK; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008959:Models, Neurological; D016328:NF-kappa B / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000502:physiology
D000074049:Cytokine TWEAK; D016207:Cytokines; D016328:NF-kappa B; D021122:Protein Subunits; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors; D051550:I-kappa B Kinase