Functional Role of Proinflammatory and Anti-Inflammatory Cytokines in Seizures

  • Annamaria Vezzani
  • Daniela Moneta
  • Cristina Richichi
  • Carlo Perego
  • Maria G. De Simoni
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 548)


Recent evidence has shown that proinflammatory and anti-inflammatory molecules are synthesized during epileptic activity in glial cells in CNS regions where seizures initiate d spread. These molecules are released and interact with specific receptors on neurons. Since various cytokines have been shown to affect neuronal excitability, this led to the hypothesis that they may have a role in altering synaptic transmission in epileptic conditions. Indeed, intracerebral application of IL-1β enhances epileptic activity in experimental models while its naturally occurring receptor antagonist (IL-1Ra) mediates anticonvulsant actions. Transgenic mice overexpressing IL-1Ra in astrocytes are less susceptible to seizures, indicating that endogenous IL-1 has proconvulsant activity. Several studies indicate a central role of IL-1β for the exacerbation of brain damage after ischemic, traumatic or excitotoxic insults, suggesting that it may also contribute to neuronal cell injury associated with seizures. Finally, a functional polymorphism in the IL-1β gene promoter, possibly associated with enhanced ability to produce this cytokine, has been specifically found in temporal lobe epilepsy patients with hippocampal sclerosis and in children with febrile seizures. Thus, the IL-1 system may represent a novel target for controlling seizure activity and/or the associated long-term sequelae. Furthermore, these studies suggest that other inflammatory and anti-inflammatory molecules produced in the CNS may have a role in the pathophysiology of seizure disorders.


Temporal Lobe Epilepsy Kainic Acid Febrile Seizure Anticonvulsant Action Epileptic Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Schöbitz B, Ron De Kloet E, Holsboer F. Gene expression and function of interleukin-1, interleukin-6 and tumor necrosis factor in the brain. Prog Neurobiol 1994; 44: 397 - 432.PubMedCrossRefGoogle Scholar
  2. 2.
    Hopkins SJ, Rothwell NJ. Cytokines and the nervous system I. Expression and recognition. Trends Neurosci 1995; 18: 83 - 88.PubMedCrossRefGoogle Scholar
  3. 3.
    Rothwell NJ, Hopkins SJ. Cytokines and the nervous system II: Actions and mechanisms of action. Trends Neurosci 1995; 18: 130 - 136.PubMedCrossRefGoogle Scholar
  4. 4.
    De Simoni MG, Imeri L. Cytokine-neurotransmitter interactions in the brain. Biol Signals 1998; 7: 33 - 44.PubMedCrossRefGoogle Scholar
  5. 5.
    Scarborough DE, Lee SL, Dinarello CA et al. Interleukin-113 stimulates somatostatin biosynthesis in primary cultures of fetal rat brain. Endocrinology 1986; 124: 549 - 551.CrossRefGoogle Scholar
  6. 6.
    Spranger M, Lindholm D, Bandtlow C et al. Regulation of nerve growth factor (NGF) synthesis in the rat central nervous system: comparison between the effects of interleukin-1 and various growth factors in astrocyte cultures and in vivo. Eur J Neurosci 1990; 2: 69 - 76.PubMedCrossRefGoogle Scholar
  7. 7.
    Lapchak PA, Araujo DM. Hippocampal interleukin-2 regulates monoamine and opioid peptide release from the hippocampus. Neuroreport 1993; 4: 303 - 306.PubMedCrossRefGoogle Scholar
  8. 8.
    Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nature Rev Neurosci 2001; 2: 734 - 744.CrossRefGoogle Scholar
  9. 9.
    Katsuki H, Nakai S, Hirai Y et al. Interleukin-113 inhibits long-term potentiation in the CA3 region of the mouse hippocampal slice. Eur J Pharmacol 1990; 181: 323 - 326.PubMedCrossRefGoogle Scholar
  10. 10.
    Bellinger FP, Madamba S, Siggins GR. Interleukin 113 inhibits synaptic strength and long-term potentiation in the rat CAl hippocampus. Brain Res 1993; 628: 227 - 234.PubMedCrossRefGoogle Scholar
  11. 11.
    Cunningham AJ, Murray CA, O’Neil LAJ et al. Interleukin 113 and tumor necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci Lett 1996; 203: 17 - 20.PubMedCrossRefGoogle Scholar
  12. 12.
    Coogan A, O’Connor JJ. Inhibition of NMDA receptor-mediated synaptic transmission in the rat dentate gyrus in vitro by IL-113. Neuroreport 1997; 8: 2107 - 2110.PubMedCrossRefGoogle Scholar
  13. 13.
    D’Arcangelo G, Dodt H, Zieglgansberger W. Reduction of excitation by interleukin-113 in rat neocortical slices visualized using infrared darkfield videomicroscopy. Neuroreport 1997; 8: 2079 - 2083.PubMedCrossRefGoogle Scholar
  14. 14.
    Zeise ML, Espinoza J, Morales P et al. Interleukin-113 does not increase synaptic inhibition in hippocampal CA3 pyramidal and dentate gyrus granule cells of the rat in vitro. Brain Res 1997; 768: 341 - 344.PubMedCrossRefGoogle Scholar
  15. 15.
    Wang S, Cheng Q, Malik S. Interleukin-113 inhibits ’-amino butyric acid type A (GABAA) receptor current in cultured hippocampal neurons. J Pharmacol Exp Ther 2000; 292: 497 - 504.PubMedGoogle Scholar
  16. 16.
    Miller LG, Galpern WG, Lumpkin M et al. Interleukin-1 (IL-1) augments gamma-aminobutyric acid receptor function in the brain. Mol Pharmacol 1991; 39: 105 - 108.PubMedGoogle Scholar
  17. 17.
    Plata-Salaman CR, French-Mullen JMH. Interleukin-113 depresses calcium current in CAl hippocampal neurons at pathophysiological concentrations. Brain Res Bull 1992; 29: 221 - 223.PubMedCrossRefGoogle Scholar
  18. 18.
    Minami M, Kuraishi Y, Satoh M. Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain. Biochem Biophys Res Commun 1991; 176: 593 - 598.PubMedCrossRefGoogle Scholar
  19. 19.
    Yabuuchi K, Minami M, Katsumata S et al. In situ hybridization study of interleukin-113 mRNA induced by kainic acid in the rat brain. Brain Res Mol Brain Res 1993; 20: 153 - 161.PubMedCrossRefGoogle Scholar
  20. 20.
    Nishiyori A, Minami M, Takami S et al. Type 2 interleukin-1 receptor mRNA is induced by kainic acid in the rat brain. Mol Brain Res 1997; 50: 237 - 245.PubMedCrossRefGoogle Scholar
  21. 21.
    Gahring LC, White SH, Skradski SL et al. Interleukin-la in the brain is induced by audiogenic seizure. Neurobiol Dis 1997; 3: 263 - 269.PubMedCrossRefGoogle Scholar
  22. 22.
    Eriksson C, Winblad B, Schultzberg M. Immunohistochemical localization of interleukin-lbeta, interleukin-1 receptor antagonist and interleukin-lbeta converting enzyme/caspase-1 in the rat brain after peripheral administration of kainic acid. Neuroscience 1999; 93: 915 - 930.PubMedCrossRefGoogle Scholar
  23. 23.
    Vezzani A, Conti M, De Luigi A et al. Interleukin-113 immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures. J Neurosci 1999; 19: 5054 - 5065.PubMedGoogle Scholar
  24. 24.
    De Simoni MG, Perego C, Ravizza T et al. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci 2000; 12: 2623 - 2633.PubMedCrossRefGoogle Scholar
  25. 25.
    Vezzani A, Moneta D, Conti M et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci USA 2000; 97: 11534 - 11539.PubMedCrossRefGoogle Scholar
  26. 26.
    Benveniste EN. Inflammatory cytokines within the central nervous system: sources, function and mechanism of action. Am J Physiol 1992; 263: C1 - C16.PubMedGoogle Scholar
  27. 27.
    Bartfai T, Shultzberg M. Cytokines in neuronal cell types. Neurochem Int 1993; 22: 435 - 444.PubMedCrossRefGoogle Scholar
  28. 28.
    Perry VH, Andersson PB, Gordon S. Macrophages and inflammation in the central nervous system. Trends Neurosci 1993; 16 (7): 268 - 273.PubMedCrossRefGoogle Scholar
  29. 29.
    Montero-Menei CN, Sindji L, Garcion E et al. Early events of the inflammatory reaction induced in rat brain by lipolysaccharide intracerebral injection: relative contribution of peripheral monocytes and activated microglia. Brain Res 1996; 724: 55 - 66.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhao B, Schwartz JP. Involvement of cytokines in normal CNS development and neurological diseases: recent progress and perspective. J Neurosci Res 1998; 52: 7 - 16.PubMedCrossRefGoogle Scholar
  31. 31.
    Nitsch C, Goping G, Klatzo I. Pathophysiological aspects of blood brain barrier permeability in epileptic seizures. In: Schwarcz R, Ben-Ari Y, eds. Advances in Experimental Medicine and Biology. New York, London: 1986: 175 - 184.Google Scholar
  32. 32.
    Jander S, Schroeter M, Stoll G. Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia. J Neuroimmunol 2000; 109: 181 - 187.PubMedCrossRefGoogle Scholar
  33. 33.
    Kamikawa H, Hon T, Nakane H et al. IL-1(3 increases norepinephrine level in the rat frontal cortex: involvement of prostanoids, NO, and glutamate: Am J Physiol 1998; 275: R806 - R810.Google Scholar
  34. 34.
    Ye ZC, Sontheimer H. Cytokine modulation of glial glutamate uptake: a possible involvement of nitric oxide. Neuroreport 1996; 72: 181 - 2185.Google Scholar
  35. 35.
    Luk WP, Zhang Y, White TD et al. Adenosine: a mediator of interleukin-1(3 induced hippocampal synaptic inhibition. J Neurosci 1999; 19: 4238 - 4244.PubMedGoogle Scholar
  36. 36.
    Campbell IL, Abraham CR, Masliah E et al. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci USA 1993; 90: 10061 - 10065.PubMedCrossRefGoogle Scholar
  37. 37.
    Akassoglou K, Probert L, Kontogeorgos G et al. Astrocyte-specific but not neuron specific trans-membrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice. J Immunol 1997; 158: 438 - 445.PubMedGoogle Scholar
  38. 38.
    Vezzani A, Moneta D, Richichi C et al. Functional role of TNF-a and IL-113 systems in seizure susceptibility and epileptogenesis. 31st Annual meeting Society for Neuroscience Nov 10-15 2001; 557: 18.Google Scholar
  39. 39.
    Bruce AJ, Boling W, Kindy MS. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Med 1996; 2: 788 - 794.PubMedCrossRefGoogle Scholar
  40. 40.
    Sheng JG, Boop FA, Mrak RE et al. Increased neuronal 13-amyloid precursor protein expression in human temporal lobe epilepsy: association with interleukin-la immunoreactivity. J Neurochem 1994; 63: 1872 - 1879.PubMedCrossRefGoogle Scholar
  41. 41.
    Barres BA. New roles for microglia. J Neurosci 1991; 11: 3685 - 3694.PubMedGoogle Scholar
  42. 42.
    Peltola J, Palmio J, Korhonen L. Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures. Epilepsy Res 2000; 41: 205 - 211.PubMedCrossRefGoogle Scholar
  43. 43.
    Lahat E, Livine M, Barr J. Interleukin-1 levels in serum and cerebrospinal fluid of children with febrile seizures. Pediatr Neurol 1997; 17: 34 - 36.PubMedCrossRefGoogle Scholar
  44. 44.
    Ichiyama T, Nishikawa M, Yoshitomi T. Tumor necrosis factor-a, interleukin-1, and interleukin-6 in cerebrospinal fluid from children with prolonged seizures. Neurology 1998; 50: 407 - 411.PubMedCrossRefGoogle Scholar
  45. 45.
    Kanemoto K, Kawasaki J, Miyamoto T. Interleukin(IL)-113, IL-1 a, and IL-1 receptor antagonist gene polymorphisms in patients with temporal lobe epilepsy. Ann Neurol 2000; 47: 571 - 574.PubMedCrossRefGoogle Scholar
  46. 46.
    Hurme VM, Helminen M. Increased frequency of interleukin-lbeta (-511) allele 2 in febrile seizures. Pediatr Neurol 2002; 26: 192 - 195.PubMedCrossRefGoogle Scholar
  47. 47.
    de Bock F, Dornand J, Rondouin G. Release of TNF in the rat hippocampus following epileptic seizures and excitotoxic neuronal damage. Neuroreport 1996; 7: 1125 - 1129.PubMedCrossRefGoogle Scholar
  48. 48.
    Takao T, Tracey DE, Mitchell WM. Interleukin-1 receptors in mouse brain: Characterization and neuronal localization Endocrinology 1990; 127: 3070 - 3078.Google Scholar
  49. 49.
    Ban E, Milon G, Prudhomme N et al. Receptors for interleukin-1 (alpha and beta) in mouse brain: Mapping and neuronal localization in hippocampus. Neuroscience 1991; 43: 21 - 30.PubMedCrossRefGoogle Scholar
  50. 50.
    Dinarello CA. Biological basis for interleukin-1 in disease. Blood 1996; 87: 2095 - 2147.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Annamaria Vezzani
  • Daniela Moneta
  • Cristina Richichi
  • Carlo Perego
  • Maria G. De Simoni

There are no affiliations available

Personalised recommendations