Hypoxic induction of caspase-11/caspase-1/interleukin-1beta in brain microglia.
Caspase-11 is an inducible protease that plays an important role in both inflammation and apoptosis. Inflammatory stimuli induce and activate caspase-11, which is required for the activation of caspase-1 or interleukin-1beta (IL-1beta) converting enzyme (ICE). Caspase-1 in turn mediates the maturation of proinflammatory cytokines such as IL-1beta, which is one of the crucial mediators of neurodegeneration in the central nervous system. Here, we report that hypoxic exposure of cultured brain microglia (BV-2 mouse microglia cells and rat primary microglial cultures) induces expression and activation of caspase-11, which is accompanied by activation of caspase-1 and secretion of mature IL-1beta and IL-18. Hypoxic induction of caspase-11 was observed in both mRNA and protein levels, and was mediated through p38 mitogen-activated protein kinase pathway. Transient global ischemia in rats also induced caspase-11 expression and IL-1beta production in hippocampus supporting our in vitro findings. Caspase-11-expressing cells in hippocampus were morphologically identified as microglia. Taken together, our results indicate that hypoxia induces a sequential event-caspase-11 induction, caspase-1 activation, and IL-1beta release-in brain microglia, and point out the importance of initial caspase-11 induction in hypoxia-induced inflammatory activation of microglia.
Kim
Nam-Gon
NG
Department of Anatomy and Neurobiology, Institute of Health Sciences, and Research Institute of Natural Science, Gyeongsang National University College of Medicine, 92 Chilam-dong, Jinju, Kyungnam 660-751, South Korea.
Lee
Heasuk
H
Son
Eunyung
E
Kwon
Oh-Young
OY
Park
Jae-Yong
JY
Park
Jae-Hoon
JH
Cho
Gyeong Jae
GJ
Choi
Wan Sung
WS
Suk
Kyoungho
K
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000201:enzymology* / Q000503:physiopathology; D020170:Caspase 1 / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D002478:Cells, Cultured; D004660:Encephalitis / Q000201:enzymology* / Q000503:physiopathology; D005911:Gliosis / Q000201:enzymology*; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000503:physiopathology; D002534:Hypoxia, Brain / Q000201:enzymology* / Q000503:physiopathology; D007375:Interleukin-1 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D020382:Interleukin-18; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C101136:Casp4 protein, mouse; C491071:Casp4 protein, rat; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1