Pro-inflammatory cytokine; tumor-necrosis factor-alpha (TNF-α) inhibits astrocytic support of neuronal survival and neurites outgrowth


Reactive astrogliosis has been implicated in the failure of axonal regeneration in adult mammalian Central Nervous System (CNS). It is our hypothesis that inflammatory cytokines act upon astrocytes to alter their biochemical and physical properties, which may in turn be responsible for the failure of neuronal regeneration. We have therefore examined the effect of tumor-necrosis factor-alpha (TNF-α) on the ability of astrocytes to support the survival of the cortical neurons and the growth of the neurites. Mouse astrocytes and cortical neuronal cultures were prepared. It was observed that when neurons were cultured in absence of astrocytes only a few of them grew and survived only for 5-6 days. These neurons had small cell bodies and few, short neurites. However, when the same numbers of neurons were cultured on the top of astrocytes, more neurons grew and survived up to 16-18 days. They had bigger cell bodies and many long branched neurites that formed anestamosing networks. The neurons then coalesced and the neurites formed thick bundles. When the same numbers of neurons were grown on the top of astrocytes pre-treated with TNF-α, few neurons survived up to 13 days. The neurites of the survived neurons were shorter than neurites of neurons grown on normal astrocytes and did not form bundles. In addition, TNF-α stimulated the expression of glial fibrillary acidic protein (GFAP) by astrocytes. These results support that the pro-inflammatory cytokine, TNF-α modulates the gliosis and that the astrocytic cell supports neuronal survival and neurite outgrowth.

Share and Cite:

Abd-El-Basse, E. (2013) Pro-inflammatory cytokine; tumor-necrosis factor-alpha (TNF-α) inhibits astrocytic support of neuronal survival and neurites outgrowth. Advances in Bioscience and Biotechnology, 4, 73-80. doi: 10.4236/abb.2013.48A2010.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] [1] Gorden, G.R., Mulligan, S.J. and MacVicar, B.A. (2007) Astrocyte control of the cerebrovasculature. Glia, 55, 1214-1221. doi:10.1002/glia.20543
[2] Prebil, M., Vardjan, N., Jensen, R., Zorec, R. and Kreft, M. (2011) Dynamic monitoring of cytosolic glucose in single astrocytes. Glia, 59, 903-913. doi:10.1002/glia.21161
[3] Furukawa, S., Furukawa, Y. and Satoyoshi, E. (1986) Synthesis and secretion of nerve growth factor by mouse astroglial cells in culture. Biochemical and Biophysical Research Communications, 136, 57-63. doi:10.1016/0006-291X(86)90876-4
[4] Yoshida, K. and Gage, F.H. (1992) Cooperative regulation of nerve growth factor synthesis and secretion in fibroblasts and astrocytes by fibroblast growth factor and other cytokines. Brain Research, 569, 14-25. doi:10.1016/0006-8993(92)90364-F
[5] Marchetti, B. (1997) Cross-talk signals in the CNS: Role of neurotrophic and Hormonal factors, adhesion molecules and intercellular signalling agents in leuteinizing hormone (LHRH)-astroglial interactive network. Frontiers in Bioscience, 1, 88-125.
[6] Friedman, W.J., Larkfors, L., Ayer-leliever, C., et al. (1990) Regulation of B-nerve growth factor expression by inflammatory mediators in hippocampal cultures. Journal of Neuroscience Research, 27, 374-382. doi:10.1002/jnr.490270316
[7] Liddell, J.R., Robinson, S.R., Dringen, R. and Bishop, G.M. (2010) Astrocytes retain their antioxidant capacity into advanced old age. Glia, 58, 1500-1509.
[8] McGraw, J., Hiebert, G.W. and Steeves, J.D. (2001) Modulating astrogliosis after neurotrauma. Journal of Neuroscience Research, 63, 109-115. doi:10.1002/1097-4547(20010115)63:2<109::AID-JNR1002>3.0.CO;2-J
[9] Morrison, R.S., DeVellis, J., Bradshaw, R.A. and Eng, L.F. (1985) Hormones and growth factors induce the synthesis of glial fibrillary acidic protein in the rat brain astrocytes. Journal of Neuroscience Research, 14, 167-176. doi:10.1002/jnr.490140202
[10] Laping, N.J., Teter, B., Nichols, N.R., Rozovsky, I. and Finch, C.E. (1994) Glial fibrillary acidic protein: Regulation by hormones, cytokines, and growth factors. Brain Pathology, 1, 259-275. doi:10.1111/j.1750-3639.1994.tb00841.x
[11] Wanner, I.B., Deik, A., Torres, M., et al. (2008) A new in vitro model of glial scar inhibits axon growth. Glia, 56, 1691-1709. doi:10.1002/glia.20721
[12] Sofroniew, M.V. (2005) Reactive astrocytes in neural repair and protection. Neuroscientist, 11, 400-707. doi:10.1177/1073858405278321
[13] Rolls, A., Shechter, R. and Schwartz, M. (2009) The bright side of the glial scar in CNS repair. Nature Reviews Neuroscience, 10, 235-241. doi:10.1038/nrn2591
[14] Lu, P., Jones, L.L. and Tuszynshi, M.H. (2007) Axon regeneration through scars and into sites of chronic spinal cord injury. Experimental Neurology, 203, 8-21. doi:10.1016/j.expneurol.2006.07.030
[15] Faulkner, J.R., Hermann, J.E., Woo, M.J., et al. (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. The Journal of Neuroscience, 24, 2143-2155. doi:10.1523/JNEUROSCI.3547-03.2004
[16] John, G.R., Lee, S.C., Song, X., Rivieccio, M. and Brosnan, C.F. (2005) IL-1-regulated responses in astrocytes: Relevance to injury and recovery. Glia, 49, 161-176. doi:10.1002/glia.20109
[17] Hopkins, S.J. and Rothwell, N.J. (1995) Cytokines and nervous system. I: Expression and recognition. Trends in Neurosciences, 18, 83-85. doi:10.1016/0166-2236(95)93881-W
[18] Benveniste, E.N. (1992) Inflammatory cytokines within the central nervous system: Sources, function and mechanism of action. American Journal of Physiology, 263, c1-c16.
[19] Neumann, H. (2001) Control of glial immune function by neurons. Glia, 36, 191-199. doi:10.1002/glia.1108
[20] Skaper, S.D. (2007) The brain as a target for inflammatory processes and neuroprotective strategies. Annals of the New York Academy of Sciences, 1122, 23-34. doi:10.1196/annals.1403.002
[21] Saha, R.N. and Pahan, K. (2003) Tumor necrosis factor-alpha at the crossroads of neuronal life and death during HIV-associated dementia. Journal of Neurochemistry, 86, 1057-1071. doi:10.1046/j.1471-4159.2003.01942.x
[22] Little, A.R. and O’Callagha, J.P. (2001) Astrogliosis in adult and developing CNS: Is there a role for poinflammatory cytokines? Neurotoxicology, 22, 607-618. doi:10.1016/S0161-813X(01)00032-8
[23] Park, K.M. and Bowers, W.J. (2010) Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal, 22, 977-983. doi:10.1016/j.cellsig.2010.01.010
[24] Abd-El-Basset, E.M., Kalnins, V.I., Subrahamanyan, L., Ahmed, I. and Fedoroff, S. (1988) 48 Kilodalton intermediate filament-associated protein in astrocytes. Journal of Neuroscience Research, 19, 1-13. doi:10.1002/jnr.490190102
[25] Zhang, S. and Fedoroff, S. (1996) Neuron-microglia interactions in vitro. Acta Neuropathologica, 91, 385-395. doi:10.1007/s004010050440
[26] Bradford, M.M. (1976) A rapid and sensitive method for quantification of microgram quantities of protein utilizing the principles of protein-dyebinding. Analytical Biochemistry, 72, 248-254. doi:10.1016/0003-2697(76)90527-3
[27] Laemmli, U.K. (1970) Cleavage of structural proteins during assembly of head of the bacteriophage T4. Nature, 227, 680-685. doi:10.1038/227680a0
[28] Towbin, H., Staehlin, T. and Gordon, J. (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications. Proceedings of the National Academy of Sciences, 76, 4350-4354. doi:10.1073/pnas.76.9.4350
[29] Medina, S., Martinez, M. and Hernanz., A. (2002) Antioxidants inhibit the human cortical neuron apoptosis induced by hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42. Free Radical Research, 36, 1179-1184. doi:10.1080/107157602100006445
[30] Miliani, D., Zauli, G., Rimondi, E., et al. (2003) Tumour necrosis factor-related apoptosis-inducing ligand sequentially activates pro-survival and pro-apoptotic pathway in SK-N-MC neuronal cells. Journal of Neurochemistry, 86, 126-135. doi:10.1046/j.1471-4159.2003.01805.x
[31] Neumann, H., Schweigreiter, R., Yamashita. T. et al., (2002) Tumour necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a Rh-dependent mechanism. The Journal of Neuroscience, 22, 854-862.
[32] Li, B., Xu, W., Luo, C., Gozal, D. and Liu, R. (2003) VEGF-induced activation of the P 23-K/Akt pathway reduces mutant SOD1-mediated motor neuron cell death. Molecular Brain Research, 17, 155-164. doi:10.1016/S0169-328X(03)00025-1
[33] Al-Gayyar, M.M. and Elsherbiny, N.M. (2013) Contribution of TNF-α to the development of retinal neurodegenerative disorders. European Cytokine Network, 24, 27-36.
[34] Brietzke, E. and Kapczinski, F. (2008) TNF-alpha as a molecular target in bipolar disorder. Progress in NeuroPsychopharmacology & Biological Psychiatry, 32, 1355-1361. doi:10.1016/j.pnpbp.2008.01.006
[35] Brabers, N.A. and Nottet, H.S. (2006) Role of the proinflammatory cytokines TNF-alpha and IL-1beta in HIVassociated dementia. European Journal of Clinical Investigation, 36, 447-458. doi:10.1111/j.1365-2362.2006.01657.x
[36] Lambertsen, K.L., Clausen, B.H., Babcock, A.A., et al. (2009) Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. The Journal of Neuroscience, 29, 1319-1330. doi:10.1523/JNEUROSCI.5505-08.2009
[37] Suzuki, T., Hide, I., Kohsaka, S., Inoue, K. and Nakata, Y. (2004) Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. The Journal of Neuroscience, 7, 1-7. doi:10.1523/JNEUROSCI.3792-03.2004
[38] Dolga, A.M., Grank, T., Knaus, H.G., et al. (2008) TNF-alpha-mediates neuroprotection against glutamate-induced excitotoxicity via NF-KappaB-dependent up-regulation of K2.2 channels. Journal of Neurochemistry, 107, 1158-1167.
[39] Barone, F.C., Arvin, B., White, R.F., Miller, A., Webb, C.L., Willette, R.N., Lysko, P.G. and Feuerstein, G.Z. (1997) Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke, 28, 1233-1244. doi:10.1161/01.STR.28.6.1233
[40] Dawson, D.A., Martin, D. and Hallenbeck, J.M. (1996) Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neuroscience Letters, 218, 41-44. doi:10.1016/0304-3940(96)13116-5
[41] Nawashiro, H., Martin. D. and Hallenbeck, J.M. (1997) Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Research, 778, 265-271. doi:10.1016/S0006-8993(97)00981-5
[42] Sairanen, T., Lindsberg, M., Paetau, A., Kaste, M. and Lindsberg, P. (2001) Evolution of cerebral tumor necrosis factor alpha production during human ischemic stroke. Stroke, 32, 1750-1773. doi:10.1161/01.STR.32.8.1750
[43] Bernardino, L., Agasse, F., Silva, B., Ferreira, R., Grade, S. and Malva, J.O. (2008) Tumor necrosis factor-alpha modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures. Stem Cells, 26, 2361-2371. doi:10.1634/stemcells.2007-0914
[44] Chertoff, M., Di Paolo, N., Schoeneberg, A., et al. (2011) Neuroprotective effects of chronic expression of tumor necrosis factor α in the nigrostriatal dopaminergic circuit of adult mice. Experimental Neurology, 227, 237-251. doi:10.1016/j.expneurol.2010.11.010
[45] Oldreive, C.E. and Doherty, G.H. (2010) Effect of tumour necrosis factor-alpha on developing cerebellar granule and purkinje neurons in vitro. Journal of Molecular Neuroscience, 42, 44-52. doi:10.1007/s12031-010-9370-9
[46] Lachman, L.B., Brown, D.C. and Dinarello, C.A. (1987) Growth promoting effect of recombinant interleukin-1 and tumor necrosis factor for a human astrocytoma cell line. Journal of Immunology, 138, 2913-2916.
[47] Giulian, D., Woodward, J., Young, D.G., Krebs, J.F. and Lachman, L.B. (1988) Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. Journal of Neuroscience, 8, 2485-2490.
[48] Abd-El-Basset, E.M. and Abd-El-Barr, M.M. (2011) Effect of interleukin-1ß on the expression of actin isoforms in cultured mouse astroglia. Anatomical Record, 294, 16-23. doi:10.1002/ar.21303
[49] Merrill, J.E. (1992) Tumor necrosis factor-α, interleukin-1 and related cytokines in brain development: Normal and pathological. Developmental Neuroscience, 14, 1-10. doi:10.1159/000111642
[50] Venters, H., Tang, Q., Liu, Q., et al. (1999) A new mechanism of neurodegeneration: A proinflammatory cytokine inhibits receptor signaling by a survival peptide. Neurobiology, 96, 9879-9884.
[51] McCoy, M.K. and Tansey, M.G. (2008) TNF signaling inhibition in the CNS: Implications for normal brain function and neurodegenerative disease. Journal of Neuroinflammation, 5, 45-57. doi:10.1186/1742-2094-5-45
[52] Tabakman, R., Lecht, S., Sephanova, S., Arien-Zakay, H. and Lazarovici, P. (2004) Interactions between the cells of the immune and nervous systems: Neurotrophins as neuroprotection mediators in CNS injury. Progress in Brain Research, 146, 387-401. doi:10.1016/S0079-6123(03)46024-X
[53] Marchetti, B. and Abbracchio, M.P. (2005) To be or not to be (inflamed)—Is that the question in anti-inflammatory drug therapy of neurodegenerative disorders? Trends in Pharmacological Science, 26, 517-525. doi:10.1016/
[54] Tweedie, D., Sambamurti, K. and Greig, N.H. (2007) TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: New drug candidates and targets. Current Alzheimer Research, 4, 378-385. doi:10.2174/156720507781788873

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.