Macrophage inflammatory protein-3alpha plays a key role in the inflammatory cascade in rat focal cerebral ischemia.
Although hypothermia is one of the most robust neuroprotectants clinically available, its underlying mechanisms remain unclear. Through microarray gene expression analysis, we previously identified several key molecules potentially involved in the efficacy of hypothermia in a 2h middle cerebral artery occlusion (MCAO) rat model, including cytokine and chemokine genes. The present study demonstrated that the expressions of 2 genes, macrophage inflammatory protein-3alpha (MIP-3alpha) and its receptor, CC-chemokine receptor 6 (CCR6), were upregulated in the model and were suppressed by hypothermia. To investigate the role of cerebral MIP-3alpha, it was administered into the rat striatum; dose- and time-dependent induction of CCR6 gene expression was observed. Interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha injection also induced sequential expressions of MIP-3alpha and CCR6. MIP-3alpha was found to be produced by proinflammatory cytokines in rat astrocytes, while it was suppressed by hypothermia. In turn, MIP-3alpha stimulated IL-1beta and inducible nitric oxide synthase expressions in rat microglia and rat brains. Furthermore, intracerebroventricular administration of an anti-rat MIP-3alpha-neutralizing antibody significantly reduced the infarct in MCAO rat brains. These findings suggest that MIP-3alpha plays a pivotal role in inflammatory cascades in ischemic brains, and may be a novel therapeutic target for cerebral ischemia.
Terao
Yasuko
Y
Pharmacology Research Laboratories III, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
Ohta
Hiroyuki
H
Oda
Akira
A
Nakagaito
Yumiko
Y
Kiyota
Yoshihiro
Y
Shintani
Yasushi
Y
D000818:Animals; D000906:Antibodies; D001253:Astrocytes / Q000276:immunology; D001921:Brain / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D007035:Hypothermia / Q000276:immunology; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054389:Receptors, CCR1 / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D054399:Receptors, CCR6 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000906:Antibodies; C486997:Ccl20 protein, rat; C515302:Ccr1 protein, rat; C515336:Ccr2 protein, rat; D054418:Chemokine CCL20; D016207:Cytokines; D053583:Interleukin-1beta; D012333:RNA, Messenger; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D054399:Receptors, CCR6; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II