Manganese potentiates lipopolysaccharide-induced expression of NOS2 in C6 glioma cells through mitochondrial-dependent activation of nuclear factor kappaB

被引:57
作者
Barhourni, R [1 ]
Faske, J [1 ]
Liu, XH [1 ]
Tjalkens, RB [1 ]
机构
[1] Texas A&M Univ, Coll Vet Med, Dept Anat, Program Neurosci, College Stn, TX 77843 USA
来源
MOLECULAR BRAIN RESEARCH | 2004年 / 122卷 / 02期
关键词
inducible nitric oxide synthase; nitric oxide; glia; manganese; mitochondria; nuclear factor kappa beta;
D O I
10.1016/j.molbrainres.2003.12.009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Neuronal injury in manganese neurotoxicity (manganism) is thought to involve activation of astroglial cells and subsequent overproduction of nitric oxide (NO) by inducible nitric oxide synthase (NOS2). Manganese (Mn) enhances the effects of proinflammatory cytokines on expression of NOS2 but the molecular basis for this effect has not been established. It was postulated in the present studies that Mn enhances expression of NOS2 through the cis-acting factor, nuclear factor kappaB (NF-kappaB). Exposure of C6 glioma cells to lipopopolysaccharide (LPS) resulted in increased expression of NOS2 and production of NO that was dramatically potentiated by Mn and was blocked through overexpression of mutant IkappaBalpha (S32/36A). LPS-induced DNA binding of p65/p50 was similarly enhanced by Mn and was decreased by mutant IkappaBalpha. Phosphorylation of IkappaBalpha was potentiated by Mn and LPS and was not blocked by U0126, a selective inhibitor of ERK1/2. Mn decreased mitochondrial membrane potential and increased matrix calcium, associated with a rise in intracellular reactive oxygen species (ROS) that was attenuated by the mitochondrial-specific antioxidant, MitoQ. Blocking mitochondrial ROS also attenuated the enhancing effect of Mn on LPS-induced phosphorylation of IkappaBalpha and expression of NOS2, suggesting a link between Mn-induced mitochondrial dysfunction and activation of NF-kappaB. Overexpression of a dominant-negative mutant of the NF-kappaB-interacting kinase (Nik) prevented enhancement of LPS-induced phosphorylation of IkappaBalpha by Mn. These data indicate that Mn augments LPS-induced expression of NOS2 in C6 cells by increasing mitochondrial ROS and activation of NF-kappaB. (C) 2004 Elsevier B.V. All rights reserved.
引用
收藏
页码:167 / 179
页数:13
相关论文
共 56 条
[1]   Mitochondrial and nonmitochondrial reduction of MTT: Interaction of MTT with TMRE, JC-1, and NAO mitochondrial fluorescent probes [J].
Bernas, T ;
Dobrucki, J .
CYTOMETRY, 2002, 47 (04) :236-242
[2]   p38 MAPK-mediated transcriptional activation of inducible nitric-oxide synthase in glial cells -: Roles of nuclear factors, nuclear factor κB, cAMP response element-binding protein, ccaat/enhancer-binding protein-β, and activating transcription factor-2 [J].
Bhat, NR ;
Feinstein, DL ;
Shen, Q ;
Bhat, AN .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (33) :29584-29592
[3]  
BOLANOS JP, 1995, J NEUROCHEM, V64, P1965
[4]   TRANSPORT OF IRON AND OTHER TRANSITION-METALS INTO CELLS AS REVEALED BY A FLUORESCENT-PROBE [J].
BREUER, W ;
EPSZTEJN, S ;
MILLGRAM, P ;
CABANTCHIK, IZ .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 1995, 268 (06) :C1354-C1361
[5]   MANGANESE INJECTION INTO THE RAT STRIATUM PRODUCES EXCITOTOXIC LESIONS BY IMPAIRING ENERGY-METABOLISM [J].
BROUILLET, EP ;
SHINOBU, L ;
MCGARVEY, U ;
HOCHBERG, F ;
BEAL, MF .
EXPERIMENTAL NEUROLOGY, 1993, 120 (01) :89-94
[6]   Alterations of excitatory amino acid receptors in the brain of manganese-treated mice [J].
Cano, G ;
SuarezRoca, H ;
Bonilla, E .
MOLECULAR AND CHEMICAL NEUROPATHOLOGY, 1997, 30 (1-2) :41-52
[7]   Implication of glutamate in the expression of inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain slices [J].
Cárdenas, A ;
Moro, MA ;
Hurtado, O ;
Leza, JC ;
Lorenzo, P ;
Castrillo, A ;
Bodelón, OG ;
Boscá, L ;
Lizasoain, I .
JOURNAL OF NEUROCHEMISTRY, 2000, 74 (05) :2041-2048
[8]   Inhibition of the nuclear factor κB (NF-κB) pathway by tetracyclic kaurene diterpenes in macrophages -: Specific effects on NF-κB-inducing kinase activity and on the coordinate activation of ERK and p38 MAPK [J].
Castrillo, A ;
de las Heras, B ;
Hortelano, S ;
Rodríguez, B ;
Villar, A ;
Boscá, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (19) :15854-15860
[9]   CHRONIC MANGANESE INTOXICATION [J].
COOK, DG ;
FAHN, S ;
BRAIT, KA .
ARCHIVES OF NEUROLOGY, 1974, 30 (01) :59-64
[10]   Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo [J].
Dehmer, T ;
Lindenau, J ;
Haid, S ;
Dichgans, J ;
Schulz, JB .
JOURNAL OF NEUROCHEMISTRY, 2000, 74 (05) :2213-2216