Abnormal production of macrophage inflammatory protein-1alpha by microglial cell lines derived from neonatal brains of Sandhoff disease model mice.
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-1alpha (MIP-1alpha) 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-1alpha in SD-Mg. Inhibitors of protein kinase C (PKC) and Akt reduced the production of MIP-1alpha by SD-Mg. Elevated activation of Akt and partial translocation of PKC isozymes (alpha, betaI, betaII, 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-1alpha 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-1alpha 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.
Kawashita
Eri
E
Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Tokushima, Japan.
Tsuji
Daisuke
D
Kawashima
Nagako
N
Nakayama
Ken-ichi
K
Matsuno
Hiroyuki
H
Itoh
Kohji
K
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012497:Sandhoff Disease / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D054821:beta-Hexosaminidase beta Chain / Q000235:genetics
C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D051058:Oncogene Protein v-akt; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3; D054821:beta-Hexosaminidase beta Chain