Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death
| Autor: | Sung Joong Lee, Jong Eun Lee, Jinpyo Hong, Ik Hyun Cho, Chong Hyun Kim, Kyung Eun Lee, Eun Cheng Suh, Michael Karin, Hyunkyoung Lee, Dong Woon Kim, Eun-Kyeong Jo, Soojin Lee, Jae Hwan Kim |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Interleukin-1beta Excitotoxicity Biology medicine.disease_cause Hippocampus Brain Ischemia Proinflammatory cytokine Mice Conditional gene knockout medicine Animals Cells Cultured Mice Knockout Kainic Acid Cell Death Microglia Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Neurodegeneration Original Articles medicine.disease I-kappa B Kinase Cell biology medicine.anatomical_structure Gene Expression Regulation nervous system Immunology Neuroglia Neurology (clinical) Inflammation Mediators Cell activation Neuron death Gene Deletion |
| Zdroj: | Brain. 131:3019-3033 |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awn230 |
| Popis: | Microglial cells are activated during excitotoxin-induced neurodegeneration. However, the in vivo role of microglia activation in neurodegeneration has not yet been fully elucidated. To this end, we used Ikkbeta conditional knockout mice (LysM-Cre/Ikkbeta(F/F)) in which the Ikkbeta gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced IkappaB kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (Ikkbeta(F/F)), and lipopolysaccharide-induced proinflammatory gene expression was also compromised. Kainic acid (KA)-induced hippocampal neuronal cell death was reduced by 30% in LysM-Cre/Ikkbeta(F/F) mice compared with wild-type mice. Reduced neuronal cell death was accompanied by decreased KA-induced glial cell activation and subsequent expression of proinflammatory genes such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/Ikkbeta(F/F) mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-alpha and IL-1beta expression. Based on these data, we concluded that IKK/nuclear factor-kappaB dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators. |
| Databáze: | OpenAIRE |
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