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Interleukin--6 protects cerebellar granule neurons from NMDA--induced neurotoxicity

Wang Xiaochun, Qiu Yihua, Peng Yuping

Department of Physiology, Faculty of Medicine, and Key Laboratory of Neuroregeneration of Jiangsu Province, Nantong University.Nantong 226001,Jiangsu

Abstract

Interleukin-6 (IL-6) is an important cytokine that participates in inflammation reaction and cell growth and differentiation in the immune and nervous systems. However, the neuroprotection of IL-6 against N-methyl-D-aspartate (NMDA)-induced neurotoxicity and the related underlying mechanisms are still not identified. In the present study, the cultured cerebellar granule neurons (CGNs) from postnatal (8-day) infant rats were chronically exposed to IL-6 for 8 d, and then NMDA (100 μmol/L) was applied to the cultured CGNs for 30 min. Methyl-thiazole-tetrazolium (MTT) assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and confocal laser scanning microscope (CLSM) were used to detect neuronal vitality, apoptosis and dynamic changes of intracellular Ca~(2+) levels in the neurons, respectively. Anti-gp130 monoclonal antibody (75 ng/mL) was employed to the cultured CGNs with IL-6 to inhibit IL-6 activity so as to evaluate the role of gp130 (a 130 kDa glucoprotein transducing IL-6 signal) in mediating IL-6 neuroprotection. Western blot was used to measure the expressions of phospho-signal transducer and activator of transcription 3 (STAT3) and phospho-extracellular signal regulated kinase 1/2 (ERK1/2) in the cultured CGNs. The NMDA stimulation of the cultured CGNs without IL-6 pretreatment resulted in a significant reduction of the neuronal vitality, notable enhancement of the neuronal apoptosis and intracellular Ca~(2+) overload in the neurons. The NMDA stimulation of the CGNs chronically pretreated with IL-6 caused a remarkable increase in the neuronal vitality, marked suppression of neuronal apoptosis and intracellular Ca~(2+) overload in the neurons, compared with that in the control neurons without IL-6 pretreatment. Furthermore, anti-gp130 antibody blocked the inhibitory effect of IL-6 on NMDA-induced intracellular Ca~(2+) overload in the neurons. The levels of phospho-STAT3 and phospho-ERK1/2 were significantly higher in IL-6-pretreated CGNs than those in IL-6-untreated neurons. The results suggest that chronic IL-6 pretreatment of CGNs protects the neurons against NMDA-induced neurotoxicity. The neuroprotective effect of IL-6 is closely related to its suppression of NMDA-induced intracellular Ca~(2+) overload and is possibly mediated by gp130/JAK-STAT3 and gp130/RASERK1/2 transduction pathways.

Key words: Cerebellar granule neurons;interleukin-6;N-methyl-D-aspartate;Neurotoxicity;neuroprotection;Apoptosis;Ca~(2+) overload;gp130;signal transducer and activator of transcription 3;extracellular signal regulated kinase 1/2

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Citing This Article：

Wang Xiaochun, Qiu Yihua, Peng Yuping. Interleukin--6 protects cerebellar granule neurons from NMDA--induced neurotoxicity. Acta Physiol Sin 2007; 59 (2): 150-156 (in Chinese with English abstract).