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PMID: 18040799 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Up-regulation of BDNF in astrocytes by TNF-alpha: a case for the neuroprotective role of cytokine.

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology ·Vol. 1 ·No. 3 ·2006-09-00 ·Pages 212-22

Saha RN, Liu X, Pahan K

Abstract

Tumor necrosis factor-alpha (TNF-alpha) is widely known to be involved in physiological and pathophysiological processes of the brain where this proinflammatory cytokine is implicated with regulation of inflammatory and survival components. We report that TNF-alpha up-regulates exon-IV-bdnf mRNA and brain-derived neurotrophic factor (BDNF) protein in primary astrocytes. The BDNF protein was detectable both in cellular lysate and in the extracellular medium. Activation of NF-kappaB by TNF-alpha and inhibition of TNF-alpha-induced BDNF expression by Deltap65 (a dominant-negative mutant) and NEMO-binding domain peptide (an inhibitor of NF-kappaB) suggests that TNF-alpha induces BDNF expression through the activation of NF-kappaB. Similarly, TNF-alpha induced the activation of C/EBPbeta and the expression of BDNF was sensitive to overexpression of DeltaC/EBPbeta (a dominant-negative mutant) and ETO (an inhibitor of C/EBPbeta). Among three MAP kinases, TNF-alpha-induced BDNF up-regulation was sensitive only to inhibitors of ERK MAP kinase. However, the ERK MAP kinase pathway was coupled to activation of C/EBPbeta but not NF-kappaB. Taken together, this study identifies a novel property of TNF-alpha in inducing the expression of BDNF via NF-kappaB and C/EBPbeta in astrocytes that may be responsible for neurotrophic activity of the cytokine.

MeSH Terms
Animals Astrocytes/metabolism Blotting, Western Brain-Derived Neurotrophic Factor/metabolism Cells, Cultured Cytokines/metabolism Electrophoretic Mobility Shift Assay Enzyme-Linked Immunosorbent Assay Extracellular Signal-Regulated MAP Kinases/metabolism Gene Expression Immunohistochemistry NF-kappa B/metabolism Neuroimmunomodulation/physiology Rats Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha/metabolism Up-Regulation
Chemicals
Brain-Derived Neurotrophic Factor Cytokines NF-kappa B Tumor Necrosis Factor-alpha Extracellular Signal-Regulated MAP Kinases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Saha Ramendra N
Section of Neuroscience, Department of Oral Biology, University of Nebraska Medical Center, 40th and Holdrege, Lincoln, NE 68583-0740, USA.
Liu Xiaojuan
Pahan Kalipada
References (41)
41 references, click to expand
  1. TNF-alpha antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain.
    Exp Neurol. 2005 Nov;196(1):204-8 PMID: 16157335
  2. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease.
    Prog Neurobiol. 2001 Jan;63(1):71-124 PMID: 11040419
  3. Role of protein kinase R in double-stranded RNA-induced expression of nitric oxide synthase in human astroglia.
    FEBS Lett. 2004 Apr 9;563(1-3):223-8 PMID: 15063753
  4. Human immunodeficiency virus type 1 (HIV-1) tat induces nitric-oxide synthase in human astroglia.
    J Biol Chem. 2002 Oct 18;277(42):39312-9 PMID: 12167619
  5. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue.
    J Cell Biol. 1980 Jun;85(3):890-902 PMID: 6248568
  6. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice.
    Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19045-50 PMID: 16365293
  7. Anti-death properties of TNF against metabolic poisoning: mitochondrial stabilization by MnSOD.
    J Neuroimmunol. 1999 Jan 1;93(1-2):53-71 PMID: 10378869
  8. Tumor necrosis factor-alpha at the crossroads of neuronal life and death during HIV-associated dementia.
    J Neurochem. 2003 Sep;86(5):1057-71 PMID: 12911614
  9. CNS neurotrophins are biologically active and expressed by multiple cell types.
    J Mol Histol. 2004 Nov;35(8-9):771-83 PMID: 15609090
  10. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning.
    Learn Mem. 2002 Sep-Oct;9(5):224-37 PMID: 12359832
  11. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism.
    Cell. 1997 May 2;89(3):413-24 PMID: 9150141
  12. Induction of tumor necrosis factor-alpha (TNF-alpha) by interleukin-12 p40 monomer and homodimer in microglia and macrophages.
    J Neurochem. 2003 Jul;86(2):519-28 PMID: 12871593
  13. Neurotrophins and synaptic plasticity.
    Annu Rev Neurosci. 1999;22:295-318 PMID: 10202541
  14. Tumor necrosis factor-alpha in normal and diseased brain: Conflicting effects via intraneuronal receptor crosstalk?
    J Neurovirol. 2002 Dec;8(6):611-24 PMID: 12476354
  15. Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation.
    Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9328-32 PMID: 7568127
  16. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons.
    J Biol Chem. 1999 Mar 26;274(13):8531-8 PMID: 10085086
  17. Antineuroinflammatory effect of NF-kappaB essential modifier-binding domain peptides in the adoptive transfer model of experimental allergic encephalomyelitis.
    J Immunol. 2004 Jul 15;173(2):1344-54 PMID: 15240729
  18. The novel catecholaminergic and serotoninergic activity enhancer R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane up-regulates neurotrophic factor synthesis in mouse astrocytes.
    Neurosci Lett. 2002 Aug 16;328(3):205-8 PMID: 12147307
  19. Regulation of proliferation, survival and apoptosis by members of the TNF superfamily.
    Biochem Pharmacol. 2003 Oct 15;66(8):1403-8 PMID: 14555214
  20. Neurotrophins: a ticket to ride for BDNF.
    Curr Biol. 2005 Apr 12;15(7):R262-4 PMID: 15823529
  21. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.
    Science. 2001 Jul 20;293(5529):493-8 PMID: 11408619
  22. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis.
    Neuron. 1994 Jan;12(1):139-53 PMID: 7507336
  23. Riluzole stimulates nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis in cultured mouse astrocytes.
    Neurosci Lett. 2001 Sep 14;310(2-3):117-20 PMID: 11585581
  24. Prostaglandins are powerful inducers of NGF and BDNF production in mouse astrocyte cultures.
    FEBS Lett. 2004 Mar 26;562(1-3):211-5 PMID: 15044028
  25. Ligation of CD40 stimulates the induction of nitric-oxide synthase in microglial cells.
    J Biol Chem. 2001 Nov 30;276(48):44527-33 PMID: 11551948
  26. Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex.
    Science. 2000 Sep 1;289(5484):1550-4 PMID: 10968790
  27. Galectin-1 induces astrocyte differentiation, which leads to production of brain-derived neurotrophic factor.
    Glycobiology. 2004 Apr;14(4):357-63 PMID: 14693917
  28. Analysis on the promoter region of exon IV brain-derived neurotrophic factor in NG108-15 cells.
    J Neurochem. 2002 Oct;83(1):67-79 PMID: 12358730
  29. Regulation of inducible nitric oxide synthase in proinflammatory cytokine-stimulated human primary astrocytes.
    Free Radic Biol Med. 2005 Mar 1;38(5):655-64 PMID: 15683721
  30. Differential regulation of neurotrophin expression in basal forebrain astrocytes by neuronal signals.
    J Neurosci Res. 2004 Apr 1;76(1):76-85 PMID: 15048931
  31. ETO/MTG8 is an inhibitor of C/EBPbeta activity and a regulator of early adipogenesis.
    Mol Cell Biol. 2004 Nov;24(22):9863-72 PMID: 15509789
  32. Tumor necrosis factor facilitates regeneration of injured central nervous system axons.
    Brain Res. 1991 Apr 5;545(1-2):334-8 PMID: 1860055
  33. Endothelin increases expression of exon III- and exon IV-containing brain-derived neurotrophic factor transcripts in cultured astrocytes and rat brain.
    J Neurosci Res. 2005 Jun 15;80(6):809-16 PMID: 15898104
  34. A new concept in neurodegeneration: TNFalpha is a silencer of survival signals.
    Trends Neurosci. 2000 Apr;23(4):175-80 PMID: 10717677
  35. Inflammatory process in Parkinson's disease: role for cytokines.
    Curr Pharm Des. 2005;11(8):999-1016 PMID: 15777250
  36. NF-kappaB regulation in the immune system.
    Nat Rev Immunol. 2002 Oct;2(10):725-34 PMID: 12360211
  37. Expression of brain-derived neurotrophic factor (BDNF) and inducible nitric oxide synthase (iNOS) in rat astrocyte cultures treated with Levetiracetam.
    Brain Res. 2003 Jun 27;976(2):227-33 PMID: 12763257
  38. Differences in the regulation of BDNF and NGF synthesis in cultured neonatal rat astrocytes.
    Int J Dev Neurosci. 2004 May;22(3):119-30 PMID: 15140465
  39. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination.
    Nat Neurosci. 2001 Nov;4(11):1116-22 PMID: 11600888
  40. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors.
    Nat Med. 1996 Jul;2(7):788-94 PMID: 8673925
  41. Effect of the neuroprotective compound SR57746A on nerve growth factor synthesis in cultured astrocytes from neonatal rat cortex.
    Br J Pharmacol. 1999 May;127(1):139-44 PMID: 10369466
Article Info
Journal
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
Abbr.
J Neuroimmune Pharmacol
ISSN
1557-1904
DOI
10.1007/s11481-006-9020-8
Published
2006-09-00
Epub
2006-00-16
Pages
212-22
Language
English
Region
United States
NLM ID
101256586
PMCID
PMC2131740
Subset
IM
Grants
NINDS NIH HHS · R01 NS039940 · United States
NINDS NIH HHS · NS48923 · United States
NINDS NIH HHS · NS39940 · United States
NINDS NIH HHS · R21 NS048923-01A2 · United States
NINDS NIH HHS · R01 NS039940-05A1 · United States
NINDS NIH HHS · R21 NS048923 · United States
External Links
PubMed source DOI: 10.1007/s11481-006-9020-8 PMC Full Text View journal details
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