Activation of nuclear factor-κB signaling pathway by interleukin-1 after hypoxia/ischemia in neonatal rat hippocampus and cortex
Brain and Mind Institute
Perinatal hypoxia/ischemia (HI) is a common cause of neurological deficits in children. Interleukin-1 (IL-1) activity has been implicated in HI-induced brain damage. However, the mechanisms underlying its action in HI have not been characterized. We used a 7-day-old rat model to elucidate the role of nuclear factor-κB (NF-κB) activation in HI stimulation of IL-1 signaling. HI was induced by permanent ligation of the left carotid artery followed by 90 min of hypoxia (7.8% O2). Using ELISA assays, we observed increased cell death and caspase 3 activity in hippocampus and cortex 3, 6, 12, 24 and 48 h post-HI. IL-1β protein expression increased, beginning at 3 h after HI and lasting until 24 h post-HI in hippocampus and 12 h post-HI in cortex. Intracerebroventricular injection of 2µg IL-1 receptor antagonist (IL-1Ra) 2 h after HI significantly reduced cell death and caspase 3 activity. Electrophoretic mobility shift assay analyses of hippocampus and cortex after HI for NF-κB activity showed increased p65/p50 DNA-binding activity at 24 h post-HI. Western blot analyses showed significant nuclear translocation of p65. Protein expression levels of two known inflammatory agents, inducible nitric oxide synthase and cycloxygenase 2, known to be transcriptionally regulated by NF-κB, also increased at 24 h after HI. All these HI-induced changes were reversed by IL-1Ra blockade of IL-1 signaling, consistent with IL-1 triggering of inflammatory apoptotic outcomes via NF-κB transcriptional activation. The observed increase in cytoplasmic phosphorylated inhibitor κBα (IκBα) and nuclear translocation of Bcl-3 24 h after HI was also significantly attenuated by IL-1Ra blockade, suggesting that HI-induced IL-1 activation of NF-κB is via both the degradation of IκBα and the nuclear translocation of Bcl-3.
Journal of neurochemistry
Taylor,, O. N.,
Rea, H. C.,
Rassin, D. K.,
Perez-Polo, J. R.
(2005). Activation of nuclear factor-κB signaling pathway by interleukin-1 after hypoxia/ischemia in neonatal rat hippocampus and cortex. Journal of neurochemistry, 93(1), 26-37.
Available at: https://ecommons.aku.edu/bmi/35