期刊
CELLULAR AND MOLECULAR NEUROBIOLOGY
卷 33, 期 2, 页码 241-251出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10571-012-9891-6
关键词
IL-6; Cerebellar granule neurons; NMDA; Ca2+ overload; cPLA2; Gp130
资金
- Natural Science Foundation of Jiangsu Province of China [BK2010278, BK2011386]
- Nantong Applied Research Program of China [K2010047, BK2012014, BK2012015, CP12012003]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
We have previously shown that interleukin-6 (IL-6) has neuroprotective effect against N-methyl-d-aspartate (NMDA)-induced excitotoxicity. The current study aimed to reveal signal transduction pathways involved in the IL-6 neuroprotection. Cerebellar granule neurons (CGNs) from postnatal 8-day infant rats were exposed to IL-6 (120 ng/ml) for 8 days and stimulated with NMDA (100 mu M) for 15 or 30 min. Dynamic intracellular Ca2+ fluorescence intensity, cytosolic Ca2+-dependent phospholipase A2 (cPLA2) expression, and apoptosis and necrosis in cultured CGNs were measured by laser scanning confocal microscope, real-time PCR and Western blot, and annexin V-FITC/propidium iodide staining, respectively. NMDA stimulation of neurons evoked an intracellular Ca2+ overload, an upregulated expression of cPLA2, and an increase in cell death. Chronic IL-6 exposure prevented the NMDA-evoked neuronal Ca2+ overload, cPLA2 expression upregulation, and apoptosis and necrosis. Anti-gp130 monoclonal antibody (mAb), a blocker of gp130 that is a 130-kDa signal-transducing beta-subunit of IL-6 receptor complex, blocked these effects of IL-6 preventing NMDA neurotoxicity. AG490, PD98059, or LY294002, inhibitors specific for the intracellular signals, JAK, MAPK, and PI3K, respectively, partially blocked these IL-6 neuroprotective effects. Phosphorylation levels of STAT3, ERK1/2, and AKT, the downstream proteins for these enzymes of JAK, MAPK, and PI3K, respectively, were elevated by IL-6 pretreatment. The enhanced activation of STAT3, ERK1/2, and AKT by IL-6 was abolished by AG490, PD98059, and LY294002, respectively. Anti-gp130 mAb attenuated the activation of all the three detected signaling molecules. The present findings suggest that IL-6 neuroprotection is jointly mediated by the cellular signal transduction pathways, gp130-JAK-STAT3, gp130-MAPK-ERK, and gp130-PI3K-AKT.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据