)| PMID |
16436205 ( ) |
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| Title | Primary glia expressing the G93A-SOD1 mutation present a neuroinflammatory phenotype and provide a cellular system for studies of glial inflammation. |
| Abstract | Detailed study of glial inflammation has been hindered by lack of cell culture systems that spontaneously demonstrate the "neuroinflammatory phenotype". Mice expressing a glycine --> alanine substitution in cytosolic Cu, Zn-superoxide dismutase (G93A-SOD1) associated with familial amyotrophic lateral sclerosis (ALS) demonstrate age-dependent neuroinflammation associated with broad-spectrum cytokine, eicosanoid and oxidant production. In order to more precisely study the cellular mechanisms underlying glial activation in the G93A-SOD1 mouse, primary astrocytes were cultured from 7 day mouse neonates. At this age, G93A-SOD1 mice demonstrated no in vivo hallmarks of neuroinflammation. Nonetheless astrocytes cultured from G93A-SOD1 (but not wild-type human SOD1-expressing) transgenic mouse pups demonstrated a significant elevation in either the basal or the tumor necrosis alpha (TNFalpha)-stimulated levels of proinflammatory eicosanoids prostaglandin E2 (PGE2) and leukotriene B4 (LTB4); inducible nitric oxide synthase (iNOS) and *NO (indexed by nitrite release into the culture medium); and protein carbonyl products. Specific cytokine- and TNFalpha death-receptor-associated components were similarly upregulated in cultured G93A-SOD1 cells as assessed by multiprobe ribonuclease protection assays (RPAs) for their mRNA transcripts. Thus, endogenous glial expression of G93A-SOD1 produces a metastable condition in which glia are more prone to enter an activated neuroinflammatory state associated with broad-spectrum increased production of paracrine-acting substances. These findings support a role for active glial involvement in ALS and may provide a useful cell culture tool for the study of glial inflammation. Foundation (OMRF), 825 NE 13th Street, Oklahoma City, OK 73104, USA . kenneth-hensley@omrf.ouhsc.edu |
NOTE: Color highlight is limited to the abstract and SciMiner text-mining mode. If you see much more identified targets below from "Targets by SciMiner Summary" and "Targets by SciMiner Full list", they may have been identified from the full text.
Targets by SciMiner Summary
| HUGO ID | Symbol | Target Name | #Occur | ActualStr |
|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | 28 | SOD1 | SOD1-expressing | superoxide dismutase | |
| 6711 | LTB | lymphotoxin beta (TNF superfamily, member 3) | 8 | LTB | |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | 6 | iNOS | nitric oxide synthase | |
| 4141 | GAPDH | glyceraldehyde-3-phosphate dehydrogenase | 4 | GAPDH | |
| 4235 | GFAP | glial fibrillary acidic protein | 3 | glial fibrillary acidic protein | GFAP | |
| 435 | ALOX5 | arachidonate 5-lipoxygenase | 3 | 5 lox | arachidonic acid 5 lipoxygenase | 5-LOX | |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | 3 | IL-6 | IL6 | il 6 | |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | 2 | tumor necrosis factor | TNF-Related | |
| 11925 | TNFSF10 | tumor necrosis factor (ligand) superfamily, member 10 | 1 | TRAIL | |
| 5438 | IFNG | interferon, gamma | 1 | interferon gamma | |
| 399 | ALB | albumin | 1 | serum albumin | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-expressing | 1.4 | Nonetheless astrocytes cultured from G93A-SOD1 (but but not wild-type human SOD1-expressing transgenic mouse pups demonstrated a significant elevation in either the |
| 6711 | LTB | lymphotoxin beta (TNF superfamily, member 3) | LTB | 1.8 | E 2 (PGE PGE 2 and leukotriene B 4 (LTB LTB 4 inducible nitric oxide synthase (iNOS) iNOS and _amp_#x02022 NO |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | iNOS | 3.2 | B 4 (LTB LTB 4 inducible nitric oxide synthase (iNOS) iNOS and _amp_#x02022 NO (indexed indexed by nitrite release into the |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | al created a strain of transgenic mice that express mutant SOD1 specifically in neurons |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | Selective expression of mutant SOD1 only in astroglia causes a type of astrogliosis but fails |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | motor neuron disease 3 in the absence of simultaneous mutant SOD1 expression in neurons |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | recently showed that the rate of disease progression in mutant SOD1 chimeric mice depends on the extraneuronal expression of mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | SOD1 chimeric mice depends on the extraneuronal expression of mutant SOD1 4 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | The survival of chimeric mice was dependent upon mutant SOD1 expression in neurons but also highly dependent on the number |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-expressing | 1.4 | but also highly dependent on the number of ambient mutant SOD1-expressing non-neuronal cells |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | Expression of high copy numbers of wild-type human SOD1 had no effect or slightly diminished the inflammatory indices |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | These findings suggest that SOD1 mutations fundamentally alter the phenotype of astrocytes placing the cells |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | Jackson Laboratories (Bar Bar Harbor ME strain designation B6SJL-Tg(SOD1 B6SJL-Tg SOD1 G93A)1Gur/J; G93A 1Gur J 15 -17 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | were used that express equivalent protein levels of wild-type human SOD1 (B6SJL-TgN-(SOD1 B6SJL-TgN- SOD1 G93A -2Gur Jackson Laboratories |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | express equivalent protein levels of wild-type human SOD1 (B6SJL-TgN-(SOD1 B6SJL-TgN- SOD1 G93A -2Gur Jackson Laboratories |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | methods 18 from G93A-SOD1 mice matched nontransgenic littermates or wildtype-human SOD1 expressing mice |
| 4235 | GFAP | glial fibrillary acidic protein | GFAP | 2.5 | to identify microglia and rhodamine-conjugated rabbit anti-glial fibrillary protein (GFAP) GFAP antibody (Chemicon) Chemicon to identify astroctyes |
| 4141 | GAPDH | glyceraldehyde-3-phosphate dehydrogenase | GAPDH | 0.0 | mRNA band was normalized to the sum of the L32 GAPDH bands |
| 6711 | LTB | lymphotoxin beta (TNF superfamily, member 3) | LTB | 1.8 | Materials and methods Eicosanoid assays PGE 2 and LTB 4 were measured in cell culture medium using commercially available |
| 4235 | GFAP | glial fibrillary acidic protein | GFAP | 2.5 | based on immunocytochemical staining with anti-glial fibrillary acidic protein (GFAP) GFAP (not not illustrated |
| 4141 | GAPDH | glyceraldehyde-3-phosphate dehydrogenase | GAPDH | 0.0 | G93A-SOD1 cells demonstrated lower levels of housekeeping messages L32 and GAPDH than did non-transgenic matched cell cultures (Fig Fig 1 |
| 4141 | GAPDH | glyceraldehyde-3-phosphate dehydrogenase | GAPDH | 0.0 | of non-housekeeping genes such that the ratio of L32 and GAPDH to total mRNA is fundamentally skewed in G93A-SOD1 gial cultures |
| 4141 | GAPDH | glyceraldehyde-3-phosphate dehydrogenase | GAPDH | 0.0 | (% % change in TNF_amp_#x003b1 bands without normalization to L32 GAPDH = 1132 _amp_#x000b1 618% in G93A-SOD1 cells vs 242 _amp_#x000b1 |
| 11925 | TNFSF10 | tumor necrosis factor (ligand) superfamily, member 10 | TRAIL | 2.2 | TRAIL (TNF-Related TNF-Related Apoptosis-Inducing Ligand was likewise very markedly upregulated in |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | TNF-Related | 1.2 | TRAIL (TNF-Related TNF-Related Apoptosis-Inducing Ligand was likewise very markedly upregulated in G93A-SOD1 cells |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | IL-6 | 1.8 | IL-6 which has some neuroprotective functions 20 tended to decrease in |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | or from mice expressing high copy numbers of wildtype human SOD1 (wt-hSOD1) wt-hSOD1 were stimulated with IFN_amp_#x003b3 TNF_amp_#x003b1 or both for |
| 6711 | LTB | lymphotoxin beta (TNF superfamily, member 3) | LTB | 1.8 | for 24 hours and medium was assayed by ELISA for LTB 4 and PGE 2 |
| 6711 | LTB | lymphotoxin beta (TNF superfamily, member 3) | LTB | 1.8 | A somewhat different pattern was observed for LTB 4 |
| 6711 | LTB | lymphotoxin beta (TNF superfamily, member 3) | LTB | 1.8 | However LTB 4 was synergistically inducible by IFN_amp_#x003b3 TNF_amp_#x003b1 in both genotypes |
| 6711 | LTB | lymphotoxin beta (TNF superfamily, member 3) | LTB | 1.8 | The relative increase in LTB 4 during cytokine stimulation was similar between the genotypes but |
| 6711 | LTB | lymphotoxin beta (TNF superfamily, member 3) | LTB | 1.8 | 4 during cytokine stimulation was similar between the genotypes but LTB 4 remained at least 2-fold elevated in G93A-SOD1 cultures relative |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | glial arachidonic acid metabolism as a function of the mutant SOD1 transgene |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | iNOS | 3.2 | Results iNOS expression and nitric oxide synthesis is increased in G93A-SOD1 glia |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | iNOS | 3.2 | Elevated levels of iNOS protein could be detected in G93A-SOD1 astrocytes relative to nontransgenic |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | Curiously no major protein carbonylation band assignable to SOD1 was found in any G93A-SOD1 astrocyte lysates whereas a major |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | G93A-SOD1 astrocyte lysates whereas a major carbonylated protein identifiable as SOD1 was previously demonstrated in spinal cord extracts from symptomatic G93A-SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | relevant pathways that are perturbed by the insertion of mutant SOD1 transgenes and has slowed the development of new therapeutic modalities |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | studies of signal transduction pathways that are sensitive to mutant SOD1 |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | recent reports of cytokine hyper-expression in the CNS of mutant SOD1 mice preceding motor neuron death 6 -8 |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | iNOS | 3.2 | of TNF_amp_#x003b1 COX-II and to a lesser extent 5LOX and iNOS |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | Thus glial over-expression of mutant SOD1 (but but not wild-type SOD1 elicits a fundamental influence upon |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | Thus glial over-expression of mutant SOD1 (but but not wild-type SOD1 elicits a fundamental influence upon multiple gene regulatory pathways |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | is to elucidate the toxic gain-of-function(s) gain-of-function s inherent to SOD1 mutants |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | One likely mode of action is through accumulation of mutant SOD1 within the mitochondrial intermembrane space 21 22 which may facilitate |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1 | 1.7 | be released from glial mitochondria secondary to accumulation of mutant SOD1 |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | IL6 | 1.8 | Most cytokines including TNF_amp_#x003b1 and IL6 that we find upregulated in primary glial cultures or in |
| 6711 | LTB | lymphotoxin beta (TNF superfamily, member 3) | LTB | 1.8 | Figure 2 Comparison of basal and cytokine-stimulated PGE 2 and LTB 4 production by nontransgenic primary mouse astrocytes G93A-SOD1 mouse astrocytes |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | SOD1-expressing | 1.4 | primary mouse astrocytes G93A-SOD1 mouse astrocytes or wild type human SOD1-expressing mouse astrocytes |
| 435 | ALOX5 | arachidonate 5-lipoxygenase | 5-LOX | 2.3 | Insets show western blot analysis of basal COX-II and 5-LOX (more more ... |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | iNOS | 3.2 | Figure 3 iNOS protein expression and NO 2 -formation in cultured nontransgenic or |
| 11179 | SOD1 | superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult)) | superoxide dismutase | 1.0 | mice expressing a glycine _amp_#x02192; alanine substitution in cytosolic cu zn superoxide dismutase g93a sod1 associated with familial amyotrophic lateral sclerosis als demonstrate age dependent neuroinflammation associated with broad spectrum cytokine eicosanoid and oxidant production. |
| 7873 | NOS2A | nitric oxide synthase 2A (inducible, hepatocytes) | nitric oxide synthase | 1.0 | a significant elevation in either the basal or the tumor necrosis alpha tnf_amp_#x003b1; stimulated levels of proinflammatory eicosanoids prostaglandin e 2 pge 2 and leukotriene b 4 ltb 4 ; inducible nitric oxide synthase inos and _amp_#x02022;no indexed by nitrite release into the culture medium ; and protein carbonyl products. |
| 11892 | TNF | tumor necrosis factor (TNF superfamily, member 2) | tumor necrosis factor | 1.0 | tumor necrosis factor _amp_#x003b1; tnf_amp_#x003b1; and its principle receptor tnf ri are particularly elevated at pre and post symptomatic stages of disease [ 6 9 ] suggesting a rationale for the application of this cyt |
| 435 | ALOX5 | arachidonate 5-lipoxygenase | arachidonic acid 5 lipoxygenase | 1.0 | likewise arachidonic acid 5 lipoxygenase 5lox is elevated in g93a sod1 spinal cords and the 5lox antagonist nordihydroguaiaretic acid ndga slows disease progression in the als mouse [ 14 ]. |
| 5438 | IFNG | interferon, gamma | interferon gamma | 1.0 | cells were treated with recombinant murine tnf_amp_#x003b1; and/or interferon gamma ifn_amp_#x003b3; bd pharmingen san diego ca usa as indicated in specific experiments. |
| 399 | ALB | albumin | serum albumin | 1.0 | cytokines were predissolved in 4% fatty acid free bovine serum albumin bsa in 0.9% saline at 100 fold working concentration. |
| 4235 | GFAP | glial fibrillary acidic protein | glial fibrillary acidic protein | 1.0 | primary astrocyte cultures from g93a sod1 or nontransgenic mice were almost exclusively astrocytic based on immunocytochemical staining with anti glial fibrillary acidic protein gfap not illustrated . |
| 6018 | IL6 | interleukin 6 (interferon, beta 2) | il 6 | 1.0 | il 6 which has some neuroprotective functions [ 20 ] tended to decrease in g93a sod1 cultures. |
| 435 | ALOX5 | arachidonate 5-lipoxygenase | 5 lox | 1.0 | insets show western blot analysis of basal cox ii and 5 lox more ... |