Abnormal production of macrophage inflammatory protein-1 alpha by microglial cell lines derived from neonatal brains of Sandhoff disease model mice

作者：Kawashita Eri; Tsuji Daisuke; Kawashima Nagako; Nakayama Ken ichi; Matsuno Hiroyuki; Itoh Kohji^*

来源：Journal of Neurochemistry, 2009, 109(5): 1215-1224.

DOI：10.1111/j.1471-4159.2009.06041.x

• GM2 ganglioside
• macrophage inflammatory protein-1 alpha
• microglia
• Sandhoff disease
• signal transduction

Sandhoff disease (SD) is a lysosomal beta-hexosaminidase deficiency involving excessive accumulation of undegraded substrates, including terminal N-acetylglucosamine-oligosaccharides and GM2 ganglioside, and progressive neurodegeneration. Our previous study demonstrated remarkable induction of macrophage inflammatory factor-1 alpha (MIP-1 alpha) in microglia in the brains of SD model mice as a putative pathogenic factor for SD via microglia-mediated neuroinflammation. In this study, we established microglial cell lines (WT- and SD-Mg) from wild-type and SD mice, and first demonstrated the enhanced production of MIP-1 alpha in SD-Mg. Inhibitors of protein kinase C (PKC) and Akt reduced the production of MIP-1 alpha by SD-Mg. Elevated activation of Akt and partial translocation of PKC isozymes (alpha, beta I, beta II, and delta) from the cytoplasm to the membrane in SD-Mg were also revealed by means of immunoblotting. Furthermore, it was demonstrated that intracellular extracellular signal-regulated kinase, c-Jun N-terminal kinase, and phospholipase C (PLC), but not phosphoinositide 3-kinase, should contribute to the induction of MIP-1 alpha in SD-Mg, and that PLC could independently regulate the activation of both PKC and Akt. We proposed here that the deregulated activation of PLC should cause the enhanced MIP-1 alpha production via plural signaling pathways mediated by PKC and Akt, followed by extracellular signal-regulated kinase and c-Jun N-terminal kinase, in SD-Mg.

• 出版日期2009-6
• 单位河北医科大学