Transcriptional Regulation of Inflammation

Nuclear factor-KB (NF-kB) is a major transcription factor involved in the regulation of inflammation induced by focal cerebral ischemia (1). NF-kB is normally located in the cytoplasm and combines with its natural inhibitor, known as the IkB family. The IkB family consists of iKB-a, IkB-P, and iKB-y. Phosphorylation of IKB-a by an upstream IkB kinase (IKK) liberates NF-kB and allows it to translocate to the nucleus. ROS, cytokines, and excess intracellular Ca2+ might activate IKK during stroke. In the nucleus, NFk-B binds to kB sites, which are specific domains within the promoters of downstream genes to activate their transcription. It is known that a variety of genes involved in inflammation contain functional kB sites within their promoters and are induced by NF-kB; for example, genes that express proteins of TNF-a, ICAM-1, COX-2, and IL-6 are activated by focal ischemia. However, the function of NF-kB in stroke is still controversial. Consistent with a damaging role, mild hypothermia, a robust neuroprotectant, was found to attenuate NFk-B by inhibiting IKK-P and IKK-y following transient focal cerebral ischemia (138). Furthermore, mice deficient in NFk-B's p50 subunit were protected from experimental stroke (139). However, another study reported that rats given an NFk-B inhibitor, diethyldithiocarbamate, experienced enhanced neuron DNA fragmentation and larger infarct volume, compared with controls (140).

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