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Glucocorticoids are potent regulators of the innate immune response, and alteration in this inhibitory feedback has detrimental consequences for the neural tissue. This study profiled and investigated functionally candidate genes mediating this switch between cell survival and death during an acute inflammatory reaction subsequent to the absence of glucocorticoid signaling. Oligonucleotide microarray analysis revealed that following lipopolysaccharide (LPS) intracerebral administration at striatum level, more modulated genes presented transcription impairment than exacerbation upon glucocorticoid receptor blockage. Among impaired genes we identified ceruloplasmin (Cp), which plays a key role in iron metabolism and is implicated in a neurodegenative disease. Microglial and endothelial induction of Cp is a natural neuroprotective mechanism during inflammation, because Cp-deficient mice exhibited increased iron accumulation and demyelination when exposed to LPS and neurovascular reactivity to pneumococcal meningitis. This study has identified genes that can play a critical role in programming the innate immune response, helping to clarify the mechanisms leading to protection or damage during inflammatory conditions in the CNS. © 2007 Glezer et al.


Documento: Artículo
Título:Genes involved in the balance between neuronal survival and death during inflammation
Autor:Glezer, I.; Chernomoretz, A.; David, S.; Plante, M.-M.; Rivest, S.
Filiación:Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval (CHUL), Research Center and Department of Anatomy and Physiology, Laurier, QC, Canada
Physics Department, FCEyN, University of Buenos Aires, Buenos Aires, Argentina
Center for Research in Neuroscience, Research Institute of the McGill University Health Center, Montreal General Hospital Research Institute, Montreal, QC, Canada
Palabras clave:ceruloplasmin; glucocorticoid; glucocorticoid receptor; lipopolysaccharide; oligonucleotide; ceruloplasmin; glucocorticoid; iron; lipopolysaccharide; animal cell; animal experiment; animal model; article; bacterial meningitis; cell survival; central nervous system disease; controlled study; corpus striatum; degenerative disease; demyelination; endothelium; gene expression regulation; gene function; gene identification; genetic transcription; immunopathogenesis; innate immunity; iron metabolism; microarray analysis; microglia; molecular mechanics; mouse; nerve cell necrosis; neurodegeneration with brain iron accumulation; neuroprotection; nonhuman; receptor blocking; signal transduction; animal; cell survival; chemically induced disorder; demyelinating disease; DNA microarray; genetics; inflammation; metabolism; methodology; mouse mutant; nerve cell; pathology; Mus; Animals; Cell Survival; Ceruloplasmin; Demyelinating Diseases; Glucocorticoids; Inflammation; Iron; Lipopolysaccharides; Mice; Mice, Knockout; Microarray Analysis; Neurons; Oligonucleotide Array Sequence Analysis
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
CAS:ceruloplasmin, 9031-37-2; iron, 14093-02-8, 53858-86-9, 7439-89-6; Ceruloplasmin,; Glucocorticoids; Iron, 7439-89-6; Lipopolysaccharides


  • Akira, S., Uematsu, S., Takeuchi, O., Pathogen recognition and innate immunity (2006) Cell, 124, pp. 783-801
  • Poltorak, A., He, X., Smirnova, I., Liu, M.Y., Van Huffel, C., Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene (1998) Science, 282, pp. 2085-2088
  • Xu, Y., Tao, X., Shen, B., Horng, T., Medzhitov, R., Structural basis for signal transduction by the Toll/interleukin-1 receptor domains (2000) Nature, 408, pp. 111-115
  • Ghosh, S., Karin, M., Missing pieces in the NF-kappaB puzzle (2002) Cell, 109 (SUPPL.), pp. S81-S96
  • De Bosscher, K., Vanden Berghe, W., Haegeman, G., The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: Molecular mechanisms for gene repression (2003) Endocr Rev, 24, pp. 488-522
  • Glezer, I., Rivest, S., Glucocorticoids: Protectors of the brain during innate immune responses (2004) Neuroscientist, 10, pp. 538-552
  • Nadeau, S., Rivest, S., Endotoxemia Prevents the Cerebral Inflammatory Wave Induced by Intraparenchymal Lipopolysaccharide Injection: Role of Glucocorticoids and CD14 (2002) J Immunol, 169, pp. 3370-3381
  • Glezer, I., Zekki, H., Scavone, C., Rivest, S., Modulation of the innate immune response by NMDA receptors has neuropathological consequences (2003) J Neurosci, 23, pp. 11094-11103
  • Nadeau, S., Rivest, S., Glucocorticoids play a fundamental role in protecting the brain during innate immune response (2003) J Neurosci, 23, pp. 5536-5544
  • Soulet, D., Rivest, S., Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system (2003) J Cell Biol, 162, pp. 257-268
  • Glezer, I., Lapointe, A., Rivest, S., Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries (2006) Faseb J, 20, pp. 750-752
  • Ogawa, S., Lozach, J., Benner, C., Pascual, G., Tangirala, R.K., Molecular determinants of crosstalk between nuclear receptors and toll-like receptors (2005) Cell, 122, pp. 707-721
  • Kwon, B., Kim, B.S., Cho, H.R., Park, J.E., Kwon, B.S., Involvement of tumor necrosis factor receptor superfamily(TNFRSF) members in the pathogenesis of inflammatory diseases (2003) Exp Mol Med, 35, pp. 8-16
  • Zinser, E., Lechmann, M., Golka, A., Lutz, M.B., Steinkasserer, A., Prevention and treatment of experimental autoimmune encephalomyelitis by soluble CD83 (2004) J Exp Med, 200, pp. 345-351
  • Gabay, C., Kushner, I., Acute-phase proteins and other systemic responses to inflammation (1999) N Engl J Med, 340, pp. 448-454
  • Vizzardelli, C., Pavelka, N., Luchini, A., Zanoni, I., Bendickson, L., Effects of dexamethazone on LPS-induced activationand migration of mouse dendritic cells revealed by a genome-wide transcriptional analysis (2006) Eur J Immunol, 36, pp. 1504-1515
  • Galon, J., Franchimont, D., Hiroi, N., Frey, G., Boettner, A., Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells (2002) Faseb J, 16, pp. 61-71
  • Meylan, E., Tschopp, J., Karin, M., Intracellular pattern recognition receptors in the host response (2006) Nature, 442, pp. 39-44
  • Takaoka, A., Yanai, H., Interferon signalling network in innate defence (2006) Cell Microbiol, 8, pp. 907-922
  • Singh, S.B., Davis, A.S., Taylor, G.A., Deretic, V., Human IRGM induces autophagy to eliminate intracellular mycobacteria (2006) Science, 313, pp. 1438-1441
  • Simmons, C.P., Thwaites, G.E., Quyen, N.T., Chau, T.T., Mai, P.P., The clinical benefit of adjunctive dexamethasone in tuberculous meningitis is not associated with measurable attenuation of peripheral or local immune responses (2005) J Immunol, 175, pp. 579-590
  • Annane, D., Sebille, V., Charpentier, C., Bollaert, P.E., Francois, B., Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock (2002) Jama, 288, pp. 862-871
  • Fischer, M., Bhatnagar, J., Guarner, J., Reagan, S., Hacker, J.K., Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion (2005) N Engl J Med, 353, pp. 2352-2360
  • Sorrells, S.F., Sapolsky, R.M., An inflammatory review of glucocorticoid actions in the CNS (2007) Brain Behav Immun, 21, pp. 259-272
  • Ma, J., Yee, A., Brewer Jr, H.B., Das, S., Potter, H., Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments (1994) Nature, 372, pp. 92-94
  • Papassotiropoulos, A., Lambert, J.C., Wavrant-De Vrieze, F., Wollmer, M.A., von der Kammer, H., Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease (2005) Neurodegener Dis, 2, pp. 233-241
  • Koo, E.H., Kopan, R., Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration (2004) Nat Med, 10 (SUPPL.), pp. S26-S33
  • Aisen, P.S., The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease (2002) Lancet Neurol, 1, pp. 279-284
  • Maier, J., Kincaid, C., Pagenstecher, A., Campbell, I.L., Regulation of signal transducer and activator of transcription and suppressor of cytokine-signaling gene expression in the brain of mice with astrocyte-targeted production of interleukin-12 or experimental autoimmune encephalomyelitis (2002) Am J Pathol, 160, pp. 271-288
  • Dinkel, K., MacPherson, A., Sapolsky, R.M., Novel glucocorticoid effects on acute inflammation in the CNS (2003) J Neurochem, 84, pp. 705-716
  • Norflus, F., Tifft, C.J., McDonald, M.P., Goldstein, G., Crawley, J.N., Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice (1998) J Clin Invest, 101, pp. 1881-1888
  • Flo, T.H., Smith, K.D., Sato, S., Rodriguez, D.J., Holmes, M.A., Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron (2004) Nature, 432, pp. 917-921
  • Doraiswamy, P.M., Finefrock, A.E., Metals in our minds: Therapeutic implications for neurodegenerative disorders (2004) Lancet Neurol, 3, pp. 431-434
  • Levine, S.M., Chakrabarty, A., The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis (2004) Ann N Y Acad Sci, 1012, pp. 252-266
  • Miyajima, H., Nishimura, Y., Mizoguchi, K., Sakamoto, M., Shimizu, T., Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration (1987) Neurology, 37, pp. 761-767
  • Harris, Z.L., Takahashi, Y., Miyajima, H., Serizawa, M., MacGillivray, R.T., Aceruloplasminemia: Molecular characterization of this disorder of iron metabolism (1995) Proc Natl Acad Sci U S A, 92, pp. 2539-2543
  • Harris, Z.L., Durley, A.P., Man, T.K., Gitlin, J.D., Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux (1999) Proc Natl Acad Sci U S A, 96, pp. 10812-10817
  • Patel, B.N., Dunn, R.J., Jeong, S.Y., Zhu, Q., Julien, J.P., Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury (2002) J Neurosci, 22, pp. 6578-6586
  • Jeong, S.Y., David, S., Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system (2003) J Biol Chem, 278, pp. 27144-27148
  • Mukhopadhyay, C.K., Attieh, Z.K., Fox, P.L., Role of ceruloplasmin in cellular iron uptake (1998) Science, 279, pp. 714-717
  • Koedel, U., Scheld, W.M., Pfister, H.W., Pathogenesis and pathophysiology of pneumococcal meningitis (2002) Lancet Infect Dis, 2, pp. 721-736
  • Kerfoot, S.M., Long, E.M., Hickey, M.J., Andonegui, G., Lapointe, B.M., TLR4 contributes to disease-inducing mechanisms resulting in central nervous system autoimmune disease (2004) J Immunol, 173, pp. 7070-7077
  • Paxino, G., Franklin, K.B.J., (2001) The mouse brain in stereotaxic coordinates, , San Diego: Academic Press
  • Vasseur, S., Malicet, C., Calvo, E.L., Labrie, C., Berthezene, P., Gene expression profiling by DNA microarray analysis in mouse embryonic fibroblasts transformed by rasV12 mutated protein and the E1A oncogene (2003) Mol Cancer, 2, p. 19
  • Irizarry, R.A., Hobbs, B., Collin, F., Beazer-Barclay, Y.D., Antonellis, K.J., Exploration, normalization, and summaries of high density oligonucleotide array probe level data (2003) Biostatistics, 4, pp. 249-264
  • Smyth, G.K., (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol, 3. , Article3
  • Luu-The, V., Paquet, N., Calvo, E., Cumps, J., Improved real-time RT-PCR method for high-throughput measurements using second derivative calculation and double correction (2005) Biotechniques, 38, pp. 287-293
  • Laflamme, N., Lacroix, S., Rivest, S., An essential role of interleukin-1beta in mediating NF-kappaB activity and COX-2 transcription in cells of the blood-brain barrier in response to a systemic and localized inflammation but not during endotoxemia (1999) J Neurosci, 19, pp. 10923-10930
  • Smith, M.A., Harris, P.L., Sayre, L.M., Perry, G., Iron accumulation in Alzheimer disease is a source of redox-generated free radicals (1997) Proc Natl Acad Sci U S A, 94, pp. 9866-9868


---------- APA ----------
Glezer, I., Chernomoretz, A., David, S., Plante, M.-M. & Rivest, S. (2007) . Genes involved in the balance between neuronal survival and death during inflammation. PLoS ONE, 2(3).
---------- CHICAGO ----------
Glezer, I., Chernomoretz, A., David, S., Plante, M.-M., Rivest, S. "Genes involved in the balance between neuronal survival and death during inflammation" . PLoS ONE 2, no. 3 (2007).
---------- MLA ----------
Glezer, I., Chernomoretz, A., David, S., Plante, M.-M., Rivest, S. "Genes involved in the balance between neuronal survival and death during inflammation" . PLoS ONE, vol. 2, no. 3, 2007.
---------- VANCOUVER ----------
Glezer, I., Chernomoretz, A., David, S., Plante, M.-M., Rivest, S. Genes involved in the balance between neuronal survival and death during inflammation. PLoS ONE. 2007;2(3).