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PMID: 18819987 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Role of microglial IKKbeta in kainic acid-induced hippocampal neuronal cell death.

Brain : a journal of neurology ·Vol. 131 ·No. Pt 11 ·2008-11-00 ·Pages 3019-33

Cho IH, Hong J, Suh EC, Kim JH, Lee H, Lee JE, Lee S, Kim CH, Kim DW, Jo EK, Lee KE, Karin M, Lee SJ

Abstract

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.

MeSH Terms
Animals Brain Ischemia/pathology Cell Death/drug effects Cells, Cultured Gene Deletion Gene Expression Regulation/drug effects Hippocampus/drug effects,metabolism,pathology I-kappa B Kinase/genetics,physiology Inflammation Mediators/metabolism Interleukin-1beta/metabolism,pharmacology Kainic Acid/pharmacology Male Mice Mice, Knockout Microglia/metabolism Reverse Transcriptase Polymerase Chain Reaction/methods Tumor Necrosis Factor-alpha/metabolism,pharmacology
Chemicals
Inflammation Mediators Interleukin-1beta Tumor Necrosis Factor-alpha I-kappa B Kinase Ikbkb protein, mouse Kainic Acid
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Cho Ik-Hyun
Program in Molecular and Cellular Neuroscience, DRI, and Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul, Korea.
Hong Jinpyo
Suh Eun Cheng
Kim Jae Hwan
Lee Hyunkyoung
Lee Jong Eun
Lee Soojin
Kim Chong-Hyun
Kim Dong Woon
Jo Eun-Kyeong
Lee Kyung Eun
Karin Michael
Lee Sung Joong
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Article Info
Journal
Brain : a journal of neurology
Abbr.
Brain
ISSN
1460-2156
DOI
10.1093/brain/awn230
Published
2008-11-00
Epub
2008-00-26
Pages
3019-33
Language
English
Region
England
NLM ID
0372537
PMCID
PMC2577806
Subset
IM
Grants
NIAID NIH HHS · AI043477 · United States
NIAID NIH HHS · R37 AI043477 · United States
NIEHS NIH HHS · R37 ES004151 · United States
NIEHS NIH HHS · ES006376 · United States
NIEHS NIH HHS · ES04151 · United States
NIAID NIH HHS · R01 AI043477 · United States
NIEHS NIH HHS · R01 ES006376 · United States
External Links
PubMed source DOI: 10.1093/brain/awn230 PMC Full Text View journal details
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