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Up-regulation of BDNF in Astrocytes by TNF-α: A Case for the Neuroprotective Role of Cytokine

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Abstract

Tumor necrosis factor-alpha (TNF-α) 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-α 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-κB by TNF-α and inhibition of TNF-α-induced BDNF expression by Δp65 (a dominant-negative mutant) and NEMO-binding domain peptide (an inhibitor of NF-κB) suggests that TNF-α induces BDNF expression through the activation of NF-κB. Similarly, TNF-α induced the activation of C/EBPβ and the expression of BDNF was sensitive to overexpression of ΔC/EBPβ (a dominant-negative mutant) and ETO (an inhibitor of C/EBPβ). Among three MAP kinases, TNF-α-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/EBPβ but not NF-κB. Taken together, this study identifies a novel property of TNF-α in inducing the expression of BDNF via NF-κB and C/EBPβ in astrocytes that may be responsible for neurotrophic activity of the cytokine.

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References

  • Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R (2005) The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc Natl Acad Sci USA 102:19045–19050

    Article  PubMed  CAS  Google Scholar 

  • Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122

    Article  PubMed  CAS  Google Scholar 

  • Auch CJ, Saha RN, Sheikh FG, Liu X, Jacobs BL, Pahan K (2004) Role of protein kinase R in double-stranded RNA-induced expression of nitric oxide synthase in human astroglia. FEBS Lett 563:223–228

    Article  PubMed  CAS  Google Scholar 

  • Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J, Mattson MP (1995) 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 USA 92:9328–9332

    Article  PubMed  CAS  Google Scholar 

  • Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP (1996) Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 2:788–794

    Article  PubMed  CAS  Google Scholar 

  • Bruce-Keller AJ, Geddes JW, Knapp PE, McFall RW, Keller JN, Holtsberg FW, Parthasarathy S, Steiner SM, Mattson MP (1999) Anti-death properties of TNF against metabolic poisoning: mitochondrial stabilization by MnSOD. J Neuroimmunol 93:53–71

    Article  PubMed  CAS  Google Scholar 

  • Cardile V, Pavone A, Gulino R, Renis M, Scifo C, Perciavalle V (2003) Expression of brain-derived neurotrophic factor (BDNF) and inducible nitric oxide synthase (iNOS) in rat astrocyte cultures treated with Levetiracetam. Brain Res 976:227–233

    Article  PubMed  CAS  Google Scholar 

  • Cheng B, Christakos S, Mattson MP (1994) Tumor necrosis factors protect neurons against metabolic–excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12:139–153

    Article  PubMed  CAS  Google Scholar 

  • Dasgupta S, Jana M, Zhou Y, Fung YK, Ghosh S, Pahan K (2004) Antineuroinflammatory effect of NF-kappaB essential modifier-binding domain peptides in the adoptive transfer model of experimental allergic encephalomyelitis. J Immunol 173:1344–1354

    PubMed  CAS  Google Scholar 

  • Gaur U, Aggarwal BB (2003) Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochem Pharmacol 66:1403–1408

    Article  PubMed  CAS  Google Scholar 

  • Heldmann U, Thored P, Claasen JH, Arvidsson A, Kokaia Z, Lindvall O (2005) TNF-alpha antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain. Exp Neurol 196:204–208

    Article  PubMed  CAS  Google Scholar 

  • Jana M, Liu X, Koka S, Ghosh S, Petro TM, Pahan K (2001) Ligation of CD40 stimulates the induction of nitric-oxide synthase in microglial cells. J Biol Chem 276:44527–44533

    Article  PubMed  CAS  Google Scholar 

  • Jana M, Dasgupta S, Saha RN, Liu X, Pahan K (2003) Induction of tumor necrosis factor-alpha (TNF-alpha) by interleukin-12 p40 monomer and homodimer in microglia and macrophages. J Neurochem 86:519–528

    Article  PubMed  CAS  Google Scholar 

  • Jana M, Anderson JA, Saha RN, Liu X, Pahan K (2005) Regulation of inducible nitric oxide synthase in proinflammatory cytokine-stimulated human primary astrocytes. Free Radic Biol Med 38:655–664

    Article  PubMed  CAS  Google Scholar 

  • Koyama Y, Tsujikawa K, Matsuda T, Baba A (2005) Endothelin increases expression of exon III- and exon IV-containing brain-derived neurotrophic factor transcripts in cultured astrocytes and rat brain. J Neurosci Res 80:809–816

    Article  PubMed  CAS  Google Scholar 

  • Labie C, Lafon C, Marmouget C, Saubusse P, Fournier J, Keane PE, Le Fur G, Soubrie P (1999) Effect of the neuroprotective compound SR57746A on nerve growth factor synthesis in cultured astrocytes from neonatal rat cortex. Br J Pharmacol 127:139–144

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2:725–734

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Jana M, Dasgupta S, Koka S, He J, Wood C, Pahan K (2002) Human immunodeficiency virus type 1 (HIV-1) tat induces nitric-oxide synthase in human astroglia. J Biol Chem 277:39312–39319

    Article  PubMed  CAS  Google Scholar 

  • May MJ, D'Acquisto F, Madge LA, Glockner J, Pober JS, Ghosh S (2000) Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science 289:1550–1554

    Article  PubMed  CAS  Google Scholar 

  • McAllister AK, Katz LC, Lo DC (1999) Neurotrophins and synaptic plasticity. Annu Rev Neurosci 22:295–318

    Article  PubMed  CAS  Google Scholar 

  • McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85:890–902

    Article  PubMed  CAS  Google Scholar 

  • Miklic S, Juric DM, Carman-Krzan M (2004) Differences in the regulation of BDNF and NGF synthesis in cultured neonatal rat astrocytes. Int J Dev Neurosci 22:119–130

    Article  PubMed  CAS  Google Scholar 

  • Mizuta I, Ohta M, Ohta K, Nishimura M, Mizuta E, Kuno S (2001) Riluzole stimulates nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis in cultured mouse astrocytes. Neurosci Lett 310:117–120

    Article  PubMed  CAS  Google Scholar 

  • Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease. Prog Neurobiol 63:71–124

    Article  PubMed  CAS  Google Scholar 

  • Nagatsu T, Sawada M (2005) Inflammatory process in Parkinson's disease: role for cytokines. Curr Pharm Des 11:999–1016

    Article  PubMed  CAS  Google Scholar 

  • Ohta K, Ohta M, Mizuta I, Fujinami A, Shimazu S, Sato N, Yoneda F, Hayashi K, Kuno S (2002) The novel catecholaminergic and serotoninergic activity enhancer R-(−)-1-(benzofuran-2-yl)-2-propylaminopentane up-regulates neurotrophic factor synthesis in mouse astrocytes. Neurosci Lett 328:205–208

    Article  PubMed  CAS  Google Scholar 

  • Perry SW, Dewhurst S, Bellizzi MJ, Gelbard HA (2002) Tumor necrosis factor-alpha in normal and diseased brain: Conflicting effects via intraneuronal receptor crosstalk? J Neurovirol 8:611–624

    Article  PubMed  CAS  Google Scholar 

  • Riley CP, Cope TC, Buck CR (2004) CNS neurotrophins are biologically active and expressed by multiple cell types. J Mol Histol 35:771–783

    Article  PubMed  CAS  Google Scholar 

  • Rochford JJ, Semple RK, Laudes M, Boyle KB, Christodoulides C, Mulligan C, Lelliott CJ, Schinner S, Hadaschik D, Mahadevan M, Sethi JK, Vidal-Puig A, O'Rahilly S (2004) ETO/MTG8 is an inhibitor of C/EBPbeta activity and a regulator of early adipogenesis. Mol Cell Biol 24:9863–9872

    Article  PubMed  CAS  Google Scholar 

  • Saha RN, Pahan K (2003) Tumor necrosis factor-alpha at the crossroads of neuronal life and death during HIV-associated dementia. J Neurochem 86:1057–1071

    Article  PubMed  CAS  Google Scholar 

  • Sasaki T, Hirabayashi J, Manya H, Kasai K, Endo T (2004) Galectin-1 induces astrocyte differentiation, which leads to production of brain-derived neurotrophic factor. Glycobiology 14:357–363

    Article  PubMed  CAS  Google Scholar 

  • Schwartz M, Solomon A, Lavie V, Ben-Bassat S, Belkin M, Cohen A (1991) Tumor necrosis factor facilitates regeneration of injured central nervous system axons. Brain Res 545:334–338

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi Y, Miyamoto E, Fukunaga K (2002) Analysis on the promoter region of exon IV brain-derived neurotrophic factor in NG108-15 cells. J Neurochem 83:67–79

    Article  PubMed  CAS  Google Scholar 

  • Tamatani M, Che YH, Matsuzaki H, Ogawa S, Okado H, Miyake S, Mizuno T, Tohyama M (1999) Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons. J Biol Chem 274:8531–8538

    Article  PubMed  CAS  Google Scholar 

  • Thomas K, Davies A (2005) Neurotrophins: a ticket to ride for BDNF. Curr Biol 15:R262–R264

    Article  PubMed  CAS  Google Scholar 

  • Toyomoto M, Ohta M, Okumura K, Yano H, Matsumoto K, Inoue S, Hayashi K, Ikeda K (2004) Prostaglandins are powerful inducers of NGF and BDNF production in mouse astrocyte cultures. FEBS Lett 562:211–215

    Article  PubMed  CAS  Google Scholar 

  • Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224–237

    Article  PubMed  Google Scholar 

  • Venters HD, Dantzer R, Kelley KW (2000) A new concept in neurodegeneration: TNFalpha is a silencer of survival signals. Trends Neurosci 23:175–180

    Article  PubMed  CAS  Google Scholar 

  • Wu H, Friedman WJ, Dreyfus CF (2004) Differential regulation of neurotrophin expression in basal forebrain astrocytes by neuronal signals. J Neurosci Res 76:76–85

    Article  PubMed  CAS  Google Scholar 

  • Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S (1997) The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell 89:413–424

    Article  PubMed  CAS  Google Scholar 

  • Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 293:493–498

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported by grants from NIH (NS39940 and NS48923), National Multiple Sclerosis Society (RG3422A1/1), and Michael J. Fox Foundation for Parkinson's research. The authors would like to acknowledge Marian Schmidt of UNMC for her excellent work in animal handling, Dr. Steve O'Rahilly and Dr. Justin Rochford of the University of Cambridge for ETO constructs, and Avik Roy of Pahan Laboratory for his help in the initial stages of this study.

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Correspondence to Kalipada Pahan.

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Saha, R.N., Liu, X. & Pahan, K. Up-regulation of BDNF in Astrocytes by TNF-α: A Case for the Neuroprotective Role of Cytokine. Jrnl Neuroimmune Pharm 1, 212–222 (2006). https://doi.org/10.1007/s11481-006-9020-8

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  • DOI: https://doi.org/10.1007/s11481-006-9020-8

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