Interleukin-2 and the Septohippocampal System: An Update on Intrinsic Actions and Autoimmune Processes Relevant to Neuropsychiatric Disorders

  • Samer El Hayek
  • Farah Allouch
  • Luna Geagea
  • Farid TalihEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 2011)


Recent research suggests that lymphocytes can secrete classic neuropeptides, whereas peripheral immunization may signal hypothalamic neuronal cells. These results have led to more analysis of the function of cytokines as modulators of the peripheral and central nervous systems. In the past, the role of brain cytokines was thought to be a mere redundancy of their activity within the peripheral immune system. Nevertheless, it is currently appreciated that central nervous system (CNS) cytokines have selective effects on neuronal cells. Furthermore, recent research has revealed the involvement of various cytokines in the pathophysiologic processes of neurologic and neuropsychiatric diseases. Yet, despite a plethora of published literature, most of this clinical knowledge remains correlative, and much of the basic research has understandably relied on in vitro experimental designs. However, animal knockout models have provided valuable insight into the complex biology of cytokines, mainly of interleukin-2 (IL-2). Indeed, research has tried to unveil the effects of IL-2 on the septohippocampal system and its associated pathways that regulate learning, memory, and other processes. In this chapter, we provide a comprehensive summary of the studies investigating the role of intrinsic and extrinsic IL-2 in the CNS, particularly at the level of the septohippocampal system. We also discuss the function of other cytokines in this system and propose possible clinical correlates.

Key words

Interleukin-2 Cytokines Septohippocampal system Animal models Neuropsychiatric disorders 


  1. 1.
    Besedovsky HO, Del Rey A, Klusman I, Furukawa H, Monge Arditi G, Kabiersch A (1991) Cytokines as modulators of the hypothalamus-pituitary-adrenal axis. J Steroid Biochem Mol Biol 40:613–618PubMedGoogle Scholar
  2. 2.
    Blalock JE (1994) The syntax of immune-neuroendocrine communication. Immunol Today 15:504–511PubMedGoogle Scholar
  3. 3.
    Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, Greenberg AH (1994) Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res 643:40–49PubMedGoogle Scholar
  4. 4.
    Jankowsky JL, Patterson PH (1999) Cytokine and growth factor involvement in long-term potentiation. Mol Cell Neurosci 14:273–286PubMedGoogle Scholar
  5. 5.
    Cose S, Brammer C, Khanna KM, Masopust D, Lefrancois L (2006) Evidence that a significant number of naive T cells enter non-lymphoid organs as part of a normal migratory pathway. Eur J Immunol 36:1423–1433PubMedGoogle Scholar
  6. 6.
    Hickey WF, Hsu BL, Kimura H (1991) T-lymphocyte entry into the central nervous system. J Neurosci Res 28:254–260PubMedGoogle Scholar
  7. 7.
    Pan W, Kastin AJ (1999) Penetration of neurotrophins and cytokines across the blood-brain/blood-spinal cord barrier. Adv Drug Deliv Rev 36:291–298PubMedGoogle Scholar
  8. 8.
    Goehler LE, Erisir A, Gaykema RP (2006) Neural-immune interface in the rat area postrema. Neuroscience 140:1415–1434PubMedGoogle Scholar
  9. 9.
    Goehler LE, Lyte M, Gaykema RP (2007) Infection-induced viscerosensory signals from the gut enhance anxiety: implications for psychoneuroimmunology. Brain Behav Immun 21:721–726PubMedPubMedCentralGoogle Scholar
  10. 10.
    Maier SF, Watkins LR (1998) Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 105:83–107PubMedGoogle Scholar
  11. 11.
    Martino G, Hartung HP (1999) Immunopathogenesis of multiple sclerosis: the role of T cells. Curr Opin Neurol 12:309–321PubMedGoogle Scholar
  12. 12.
    Vogt J, Paul F, Aktas O, Muller-Wielsch K, Dorr J, Dorr S, Bharathi BS, Glumm R, Schmitz C, Steinbusch H, Raine CS, Tsokos M, Nitsch R, Zipp F (2009) Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis. Ann Neurol 66:310–322PubMedGoogle Scholar
  13. 13.
    Cunningham ET Jr, Wada E, Carter DB, Tracey DE, Battey JF, De Souza EB (1992) In situ histochemical localization of type I interleukin-1 receptor messenger RNA in the central nervous system, pituitary, and adrenal gland of the mouse. J Neurosci 12:1101–1114PubMedPubMedCentralGoogle Scholar
  14. 14.
    Licinio J, Wong ML, Gold PW (1991) Localization of interleukin-1 receptor antagonist mRNA in rat brain. Endocrinology 129:562–564PubMedGoogle Scholar
  15. 15.
    Schobitz B, Voorhuis DA, De Kloet ER (1992) Localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain. Neurosci Lett 136:189–192PubMedGoogle Scholar
  16. 16.
    Petitto JM, Huang Z (2001) Cloning the full-length IL-2/15 receptor-beta cDNA sequence from mouse brain: evidence of enrichment in hippocampal formation neurons. Regul Pept 98:77–87PubMedGoogle Scholar
  17. 17.
    Petitto JM, Huang Z (1994) Molecular cloning of a partial cDNA of the interleukin-2 receptor-beta in normal mouse brain: in situ localization in the hippocampus and expression by neuroblastoma cells. Brain Res 650:140–145PubMedGoogle Scholar
  18. 18.
    Petitto JM, Huang Z, Raizada MK, Rinker CM, McCarthy DB (1998) Molecular cloning of the cDNA coding sequence of IL-2 receptor-gamma (gammac) from human and murine forebrain: expression in the hippocampus in situ and by brain cells in vitro. Brain Res Mol Brain Res 53:152–162PubMedGoogle Scholar
  19. 19.
    Lapchak PA (1992) A role for interleukin-2 in the regulation of striatal dopaminergic function. Neuroreport 3:165–168PubMedGoogle Scholar
  20. 20.
    Hanisch UK, Quirion R (1995) Interleukin-2 as a neuroregulatory cytokine. Brain Res Brain Res Rev 21:246–284PubMedGoogle Scholar
  21. 21.
    Jiang CL, Lu CL (1998) Interleukin-2 and its effects in the central nervous system. Biol Signals Recept 7:148–156Google Scholar
  22. 22.
    Malek TR, Yu A, Zhu L, Matsutani T, Adeegbe D, Bayer AL (2008) IL-2 family of cytokines in T regulatory cell development and homeostasis. J Clin Immunol 28:635–639PubMedGoogle Scholar
  23. 23.
    Turka LA, Walsh PT (2008) IL-2 signaling and CD4+ CD25+ Foxp3+ regulatory T cells. Front Biosci 13:1440–1446PubMedGoogle Scholar
  24. 24.
    Nelson BH (2004) IL-2, regulatory T cells, and tolerance. J Immunol 172:3983–3988PubMedGoogle Scholar
  25. 25.
    Waguespack PJ, Banks WA, Kastin AJ (1994) Interleukin-2 does not cross the blood-brain barrier by a saturable transport system. Brain Res Bull 34:103–109PubMedGoogle Scholar
  26. 26.
    Banks WA, Niehoff ML, Zalcman SS (2004) Permeability of the mouse blood-brain barrier to murine interleukin-2: predominance of a saturable efflux system. Brain Behav Immun 18:434–442PubMedGoogle Scholar
  27. 27.
    Eizenberg O, Faber-Elman A, Lotan M, Schwartz M (1995) Interleukin-2 transcripts in human and rodent brains: possible expression by astrocytes. J Neurochem 64:1928–1936PubMedGoogle Scholar
  28. 28.
    Lapchak PA, Araujo DM, Quirion R, Beaudet A (1991) Immunoautoradiographic localization of interleukin 2-like immunoreactivity and interleukin 2 receptors (Tac antigen-like immunoreactivity) in the rat brain. Neuroscience 44:173–184PubMedGoogle Scholar
  29. 29.
    Hanisch UK, Neuhaus J, Rowe W, Van Rossum D, Moller T, Kettenmann H, Quirion R (1997) Neurotoxic consequences of central long-term administration of interleukin-2 in rats. Neuroscience 79:799–818PubMedGoogle Scholar
  30. 30.
    Labuzek K, Kowalski J, Gabryel B, Herman ZS (2005) Chlorpromazine and loxapine reduce interleukin-1beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Eur Neuropsychopharmacol 15:23–30PubMedGoogle Scholar
  31. 31.
    Araujo DM, Lapchak PA (1994) Induction of immune system mediators in the hippocampal formation in Alzheimer’s and Parkinson’s diseases: selective effects on specific interleukins and interleukin receptors. Neuroscience 61:745–754PubMedGoogle Scholar
  32. 32.
    Awatsuji H, Furukawa Y, Nakajima M, Furukawa S, Hayashi K (1993) Interleukin-2 as a neurotrophic factor for supporting the survival of neurons cultured from various regions of fetal rat brain. J Neurosci Res 35:305–311PubMedGoogle Scholar
  33. 33.
    Sarder M, Saito H, Abe K (1993) Interleukin-2 promotes survival and neurite extension of cultured neurons from fetal rat brain. Brain Res 625:347–350PubMedGoogle Scholar
  34. 34.
    Dansokho C, Ait Ahmed D, Aid S, Toly-Ndour C, Chaigneau T, Calle V, Cagnard N, Holzenberger M, Piaggio E, Aucouturier P, Dorothee G (2016) Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139:1237–1251PubMedGoogle Scholar
  35. 35.
    Lacosta S, Merali Z, Anisman H (1999) Influence of acute and repeated interleukin-2 administration on spatial learning, locomotor activity, exploratory behaviors, and anxiety. Behav Neurosci 113:1030–1041PubMedGoogle Scholar
  36. 36.
    Sarder M, Abe K, Saito H, Nishiyama N (1996) Comparative effect of IL-2 and IL-6 on morphology of cultured hippocampal neurons from fetal rat brain. Brain Res 715:9–16PubMedGoogle Scholar
  37. 37.
    Shen Y, Liu SS, Zhan MY, Luo JH, Zhu LJ (2010) Interleukin-2 enhances dendritic development and spinogenesis in cultured hippocampal neurons. Anat Rec (Hoboken) 293:1017–1023Google Scholar
  38. 38.
    Seto D, Kar S, Quirion R (1997) Evidence for direct and indirect mechanisms in the potent modulatory action of interleukin-2 on the release of acetylcholine in rat hippocampal slices. Br J Pharmacol 120:1151–1157PubMedPubMedCentralGoogle Scholar
  39. 39.
    Meola D, Huang Z, Petitto JM (2013) Selective neuronal and brain regional expression of IL-2 in IL2P 8-GFP transgenic mice: relation to sensorimotor gating. J Alzheimers Dis Parkinsonism 3:1000127PubMedPubMedCentralGoogle Scholar
  40. 40.
    Yui MA, Hernandez-Hoyos G, Rothenberg EV (2001) A new regulatory region of the IL-2 locus that confers position-independent transgene expression. J Immunol 166:1730–1739PubMedGoogle Scholar
  41. 41.
    Girard S, Larouche A, Kadhim H, Rola-Pleszczynski M, Gobeil F, Sebire G (2008) Lipopolysaccharide and hypoxia/ischemia induced IL-2 expression by microglia in neonatal brain. Neuroreport 19:997–1002PubMedGoogle Scholar
  42. 42.
    Kowalski J, Labuzek K, Herman ZS (2004) Flupentixol and trifluperidol reduce interleukin-1 beta and interleukin-2 release by rat mixed glial and microglial cell cultures. Pol J Pharmacol 56:563–570PubMedGoogle Scholar
  43. 43.
    Horak I, Lohler J, Ma A, Smith KA (1995) Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance. Immunol Rev 148:35–44PubMedGoogle Scholar
  44. 44.
    Kundig TM, Schorle H, Bachmann MF, Hengartner H, Zinkernagel RM, Horak I (1993) Immune responses in interleukin-2-deficient mice. Science 262:1059–1061PubMedGoogle Scholar
  45. 45.
    Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I (1991) Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352:621–624PubMedGoogle Scholar
  46. 46.
    Horak I (1995) Immunodeficiency in IL-2-knockout mice. Clin Immunol Immunopathol 76:S172–S173PubMedGoogle Scholar
  47. 47.
    Denicoff KD, Rubinow DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, Chang AE, Rosenstein D, Rosenberg SA (1987) The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 107:293–300PubMedGoogle Scholar
  48. 48.
    West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Oldham RK (1987) Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316:898–905PubMedGoogle Scholar
  49. 49.
    Beck RD Jr, King MA, Ha GK, Cushman JD, Huang Z, Petitto JM (2005) IL-2 deficiency results in altered septal and hippocampal cytoarchitecture: relation to development and neurotrophins. J Neuroimmunol 160:146–153PubMedGoogle Scholar
  50. 50.
    Cardona AE, Li M, Liu L, Savarin C, Ransohoff RM (2008) Chemokines in and out of the central nervous system: much more than chemotaxis and inflammation. J Leukoc Biol 84:587–594PubMedPubMedCentralGoogle Scholar
  51. 51.
    Huang Z, Dauer DJ, Ha GK, Lewis MH, Petitto JM (2009) Interleukin-2 deficiency-induced T cell autoimmunity in the mouse brain. Neurosci Lett 463:44–48PubMedPubMedCentralGoogle Scholar
  52. 52.
    Petitto JM, McNamara RK, Gendreau PL, Huang Z, Jackson AJ (1999) Impaired learning and memory and altered hippocampal neurodevelopment resulting from interleukin-2 gene deletion. J Neurosci Res 56:441–446PubMedGoogle Scholar
  53. 53.
    Petitto JM, Cushman JD, Huang Z (2015) Effects of brain-derived IL-2 deficiency and the development of autoimmunity on spatial learning and fear conditioning. J Neurol Disord 3:196PubMedGoogle Scholar
  54. 54.
    Petitto JM, Meola D, Huang Z (2012) Interleukin-2 and the brain: dissecting central versus peripheral contributions using unique mouse models. Methods Mol Biol 934:301–311PubMedGoogle Scholar
  55. 55.
    Merrill JE (1990) Interleukin-2 effects in the central nervous system. Ann N Y Acad Sci 594:188–199PubMedGoogle Scholar
  56. 56.
    Hanisch UK, Seto D, Quirion R (1993) Modulation of hippocampal acetylcholine release: a potent central action of interleukin-2. J Neurosci 13:3368–3374PubMedPubMedCentralGoogle Scholar
  57. 57.
    Tancredi V, Zona C, Velotti F, Eusebi F, Santoni A (1990) Interleukin-2 suppresses established long-term potentiation and inhibits its induction in the rat hippocampus. Brain Res 525:149–151PubMedGoogle Scholar
  58. 58.
    Bianchi M, Ferrario P, Zonta N, Panerai AE (1995) Effects of interleukin-1 beta and interleukin-2 on amino acids levels in mouse cortex and hippocampus. Neuroreport 6:1689–1692PubMedGoogle Scholar
  59. 59.
    Bianchi M, Panerai AE (1993) Interleukin-2 enhances scopolamine-induced amnesia and hyperactivity in the mouse. Neuroreport 4:1046–1048PubMedGoogle Scholar
  60. 60.
    Mennicken F, Quirion R (1997) Interleukin-2 increases choline acetyltransferase activity in septal-cell cultures. Synapse 26:175–183PubMedGoogle Scholar
  61. 61.
    Nemni R, Iannaccone S, Quattrini A, Smirne S, Sessa M, Lodi M, Erminio C, Canal N (1992) Effect of chronic treatment with recombinant interleukin-2 on the central nervous system of adult and old mice. Brain Res 591:248–252PubMedGoogle Scholar
  62. 62.
    Petitto JM, Huang Z, Hartemink DA, Beck R Jr (2002) IL-2/15 receptor-beta gene deletion alters neurobehavioral performance. Brain Res 929:218–225PubMedGoogle Scholar
  63. 63.
    Petitto JM, McCarthy DB, Rinker CM, Huang Z, Getty T (1997) Modulation of behavioral and neurochemical measures of forebrain dopamine function in mice by species-specific interleukin-2. J Neuroimmunol 73:183–190PubMedGoogle Scholar
  64. 64.
    Beck RD Jr, Wasserfall C, Ha GK, Cushman JD, Huang Z, Atkinson MA, Petitto JM (2005) Changes in hippocampal IL-15, related cytokines, and neurogenesis in IL-2 deficient mice. Brain Res 1041:223–230PubMedGoogle Scholar
  65. 65.
    Huang Z, Meola D, Petitto JM (2012) Dissecting the effects of endogenous brain IL-2 and normal versus autoreactive T lymphocytes on microglial responsiveness and T cell trafficking in response to axonal injury. Neurosci Lett 526:138–143PubMedPubMedCentralGoogle Scholar
  66. 66.
    Huang Z, Ha GK, Petitto JM (2007) IL-15 and IL-15R alpha gene deletion: effects on T lymphocyte trafficking and the microglial and neuronal responses to facial nerve axotomy. Neurosci Lett 417:160–164PubMedPubMedCentralGoogle Scholar
  67. 67.
    Ransohoff RM (2009) Chemokines and chemokine receptors: standing at the crossroads of immunobiology and neurobiology. Immunity 31:711–721PubMedPubMedCentralGoogle Scholar
  68. 68.
    Wilkinson PC, Liew FY (1995) Chemoattraction of human blood T lymphocytes by interleukin-15. J Exp Med 181:1255–1259PubMedGoogle Scholar
  69. 69.
    Huang Z, Meola D, Petitto JM (2011) Loss of CNS IL-2 gene expression modifies brain T lymphocyte trafficking: response of normal versus autoreactive Treg-deficient T cells. Neurosci Lett 499:213–218PubMedPubMedCentralGoogle Scholar
  70. 70.
    Beck RD Jr, King MA, Huang Z, Petitto JM (2002) Alterations in septohippocampal cholinergic neurons resulting from interleukin-2 gene knockout. Brain Res 955:16–23PubMedGoogle Scholar
  71. 71.
    Altman J, Bayer SA (1990) Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J Comp Neurol 301:365–381PubMedGoogle Scholar
  72. 72.
    Cameron HA, McKay RD (2001) Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol 435:406–417PubMedGoogle Scholar
  73. 73.
    Schwegler H, Crusio WE, Lipp HP, Brust I, Mueller GG (1991) Early postnatal hyperthyroidism alters hippocampal circuitry and improves radial-maze learning in adult mice. J Neurosci 11:2102–2106PubMedPubMedCentralGoogle Scholar
  74. 74.
    Alderson RF, Alterman AL, Barde YA, Lindsay RM (1990) Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron 5:297–306PubMedGoogle Scholar
  75. 75.
    Morse JK, Wiegand SJ, Anderson K, You Y, Cai N, Carnahan J, Miller J, DiStefano PS, Altar CA, Lindsay RM et al (1993) Brain-derived neurotrophic factor (BDNF) prevents the degeneration of medial septal cholinergic neurons following fimbria transection. J Neurosci 13:4146–4156PubMedPubMedCentralGoogle Scholar
  76. 76.
    Ward NL, Hagg T (2000) BDNF is needed for postnatal maturation of basal forebrain and neostriatum cholinergic neurons in vivo. Exp Neurol 162:297–310PubMedGoogle Scholar
  77. 77.
    Knipper M, da Penha Berzaghi M, Blochl A, Breer H, Thoenen H, Lindholm D (1994) Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci 6:668–671PubMedGoogle Scholar
  78. 78.
    Larsson E, Mandel RJ, Klein RL, Muzyczka N, Lindvall O, Kokaia Z (2002) Suppression of insult-induced neurogenesis in adult rat brain by brain-derived neurotrophic factor. Exp Neurol 177:1–8PubMedGoogle Scholar
  79. 79.
    Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375PubMedGoogle Scholar
  80. 80.
    Besser M, Wank R (1999) Cutting edge: clonally restricted production of the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors. J Immunol 162:6303–6306PubMedGoogle Scholar
  81. 81.
    Canossa M, Griesbeck O, Berninger B, Campana G, Kolbeck R, Thoenen H (1997) Neurotrophin release by neurotrophins: implications for activity-dependent neuronal plasticity. Proc Natl Acad Sci U S A 94:13279–13286PubMedPubMedCentralGoogle Scholar
  82. 82.
    Saarelainen T, Vaittinen S, Castren E (2001) trkB-receptor activation contributes to the kainate-induced increase in BDNF mRNA synthesis. Cell Mol Neurobiol 21:429–435PubMedGoogle Scholar
  83. 83.
    Hellweg R, Humpel C, Lowe A, Hortnagl H (1997) Moderate lesion of the rat cholinergic septohippocampal pathway increases hippocampal nerve growth factor synthesis: evidence for long-term compensatory changes? Brain Res Mol Brain Res 45:177–181PubMedGoogle Scholar
  84. 84.
    Hock C, Heese K, Hulette C, Rosenberg C, Otten U (2000) Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 57:846–851PubMedGoogle Scholar
  85. 85.
    Luo JH, Fu ZY, Losi G, Kim BG, Prybylowski K, Vissel B, Vicini S (2002) Functional expression of distinct NMDA channel subunits tagged with green fluorescent protein in hippocampal neurons in culture. Neuropharmacology 42:306–318PubMedGoogle Scholar
  86. 86.
    Ye JH, Tao L, Zalcman SS (2001) Interleukin-2 modulates N-methyl-D-aspartate receptors of native mesolimbic neurons. Brain Res 894:241–248PubMedGoogle Scholar
  87. 87.
    Shen Y, Zhu LJ, Liu SS, Zhou SY, Luo JH (2006) Interleukin-2 inhibits NMDA receptor-mediated currents directly and may differentially affect subtypes. Biochem Biophys Res Commun 351:449–454PubMedGoogle Scholar
  88. 88.
    Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39PubMedPubMedCentralGoogle Scholar
  89. 89.
    Morris RG, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319:774–776PubMedGoogle Scholar
  90. 90.
    Sharma R, Ju AC, Kung JT, Fu SM, Ju ST (2008) Rapid and selective expansion of nonclonotypic T cells in regulatory T cell-deficient, foreign antigen-specific TCR-transgenic scurfy mice: antigen-dependent expansion and TCR analysis. J Immunol 181:6934–6941PubMedPubMedCentralGoogle Scholar
  91. 91.
    Petitto JM, Huang Z, Lo J, Beck RD, Rinker C, Hartemink DA (2002) Relationship between the development of autoimmunity and sensorimotor gating in MRL-lpr mice with reduced IL-2 production. Neurosci Lett 328:304–308PubMedGoogle Scholar
  92. 92.
    Petitto JM, Huang Z, Lo J, Streit WJ (2003) IL-2 gene knockout affects T lymphocyte trafficking and the microglial response to regenerating facial motor neurons. J Neuroimmunol 134:95–103Google Scholar
  93. 93.
    Quirion R, Aubert I, Robitaille Y, Gauthier S, Araujo DM, Chabot JG (1990) Neurochemical deficits in pathological brain aging: specificity and possible relevance for treatment strategies. Clin Neuropharmacol 13(Suppl 3):S73–S80PubMedGoogle Scholar
  94. 94.
    Zalcman SS (2002) Interleukin-2-induced increases in climbing behavior: inhibition by dopamine D-1 and D-2 receptor antagonists. Brain Res 944:157–164PubMedGoogle Scholar
  95. 95.
    Klatzmann D, Abbas AK (2015) The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 15:283–294PubMedGoogle Scholar
  96. 96.
    Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, Sene D, Cacoub P, Klatzmann D (2011) Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 365:2067–2077PubMedGoogle Scholar
  97. 97.
    Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, Fonfrede M, Rosenzwajg M, Bernard C, Klatzmann D (2013) Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 1:295–305PubMedGoogle Scholar
  98. 98.
    Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P, Lacour JP, Passeron T (2014) Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol 150:748–751PubMedGoogle Scholar
  99. 99.
    He J, Zhang X, Wei Y, Sun X, Chen Y, Deng J, Jin Y, Gan Y, Hu X, Jia R, Xu C, Hou Z, Leong YA, Zhu L, Feng J, An Y, Jia Y, Li C, Liu X, Ye H, Ren L, Li R, Yao H, Li Y, Chen S, Zhang X, Su Y, Guo J, Shen N, Morand EF, Yu D, Li Z (2016) Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med 22:991–993PubMedGoogle Scholar
  100. 100.
    Curry AE, Vogel I, Skogstrand K, Drews C, Schendel DE, Flanders WD, Hougaard DM, Thorsen P (2008) Maternal plasma cytokines in early- and mid-gestation of normal human pregnancy and their association with maternal factors. J Reprod Immunol 77:152–160PubMedGoogle Scholar
  101. 101.
    Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M (2015) Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer’s disease pathology. Nat Commun 6:7967PubMedPubMedCentralGoogle Scholar
  102. 102.
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787PubMedGoogle Scholar
  103. 103.
    Wing K, Sakaguchi S (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11:7–13PubMedGoogle Scholar
  104. 104.
    Birch AM, Katsouri L, Sastre M (2014) Modulation of inflammation in transgenic models of Alzheimer’s disease. J Neuroinflammation 11:25PubMedPubMedCentralGoogle Scholar
  105. 105.
    Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG, Peters O, Winter Y, Becher B, Heppner FL (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 18:1812–1819PubMedGoogle Scholar
  106. 106.
    Kiyota T, Okuyama S, Swan RJ, Jacobsen MT, Gendelman HE, Ikezu T (2010) CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J 24:3093–3102PubMedPubMedCentralGoogle Scholar
  107. 107.
    Kiyota T, Ingraham KL, Swan RJ, Jacobsen MT, Andrews SJ, Ikezu T (2012) AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther 19:724–733PubMedGoogle Scholar
  108. 108.
    Latta CH, Sudduth TL, Weekman EM, Brothers HM, Abner EL, Popa GJ, Mendenhall MD, Gonzalez-Oregon F, Braun K, Wilcock DM (2015) Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-beta using BV2 microglial cells and APP/PS1 transgenic mice. J Neuroinflammation 12:41PubMedPubMedCentralGoogle Scholar
  109. 109.
    Beloosesky Y, Salman H, Bergman M, Bessler H, Djaldetti M (2002) Cytokine levels and phagocytic activity in patients with Alzheimer’s disease. Gerontology 48:128–132PubMedGoogle Scholar
  110. 110.
    Alves S, Churlaud G, Audrain M, Michaelsen-Preusse K, Fol R, Souchet B, Braudeau J, Korte M, Klatzmann D, Cartier N (2017) Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice. Brain 140:826–842PubMedGoogle Scholar
  111. 111.
    Gage FH, Olejniczak P, Armstrong DM (1988) Astrocytes are important for sprouting in the septohippocampal circuit. Exp Neurol 102:2–13PubMedGoogle Scholar
  112. 112.
    Takao T, Tracey DE, Mitchell WM, De Souza EB (1990) Interleukin-1 receptors in mouse brain: characterization and neuronal localization. Endocrinology 127:3070–3078PubMedPubMedCentralGoogle Scholar
  113. 113.
    Ban E, Milon G, Prudhomme N, Fillion G, Haour F (1991) Receptors for interleukin-1 (alpha and beta) in mouse brain: mapping and neuronal localization in hippocampus. Neuroscience 43:21–30PubMedGoogle Scholar
  114. 114.
    Rada P, Mark GP, Vitek MP, Mangano RM, Blume AJ, Beer B, Hoebel BG (1991) Interleukin-1 beta decreases acetylcholine measured by microdialysis in the hippocampus of freely moving rats. Brain Res 550:287–290PubMedGoogle Scholar
  115. 115.
    Matsumoto Y, Yoshida M, Watanabe S, Yamamoto T (2001) Involvement of cholinergic and glutamatergic functions in working memory impairment induced by interleukin-1beta in rats. Eur J Pharmacol 430:283–288PubMedGoogle Scholar
  116. 116.
    Pugh CR, Kumagawa K, Fleshner M, Watkins LR, Maier SF, Rudy JW (1998) Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning. Brain Behav Immun 12:212–229PubMedGoogle Scholar
  117. 117.
    Laye S, Parnet P, Goujon E, Dantzer R (1994) Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. Brain Res Mol Brain Res 27:157–162PubMedGoogle Scholar
  118. 118.
    Gibertini M, Newton C, Klein TW, Friedman H (1995) Legionella pneumophila-induced visual learning impairment reversed by anti-interleukin-1 beta. Proc Soc Exp Biol Med 210:7–11PubMedGoogle Scholar
  119. 119.
    Aubert A, Vega C, Dantzer R, Goodall G (1995) Pyrogens specifically disrupt the acquisition of a task involving cognitive processing in the rat. Brain Behav Immun 9:129–148PubMedGoogle Scholar
  120. 120.
    Dantzer R, Bluthe RM, Gheusi G, Cremona S, Laye S, Parnet P, Kelley KW (1998) Molecular basis of sickness behavior. Ann N Y Acad Sci 856:132–138PubMedGoogle Scholar
  121. 121.
    Cacabelos R, Alvarez XA, Fernandez-Novoa L, Franco A, Mangues R, Pellicer A, Nishimura T (1994) Brain interleukin-1 beta in Alzheimer’s disease and vascular dementia. Methods Find Exp Clin Pharmacol 16:141–151PubMedGoogle Scholar
  122. 122.
    Kamegai M, Niijima K, Kunishita T, Nishizawa M, Ogawa M, Araki M, Ueki A, Konishi Y, Tabira T (1990) Interleukin 3 as a trophic factor for central cholinergic neurons in vitro and in vivo. Neuron 4:429–436PubMedGoogle Scholar
  123. 123.
    Li DD, Chien YK, Gu MZ, Richardson A, Cheung HT (1988) The age-related decline in interleukin-3 expression in mice. Life Sci 43:1215–1222PubMedGoogle Scholar
  124. 124.
    Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, Oldstone MB, Mucke L (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A 90:10061–10065PubMedPubMedCentralGoogle Scholar
  125. 125.
    Steffensen SC, Campbell IL, Henriksen SJ (1994) Site-specific hippocampal pathophysiology due to cerebral overexpression of interleukin-6 in transgenic mice. Brain Res 652:149–153PubMedGoogle Scholar
  126. 126.
    Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, Yolk B, Berger M (1991) Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer’s disease cortices. FEBS Lett 285:111–114PubMedGoogle Scholar
  127. 127.
    Vandenabeele P, Fiers W (1991) Is amyloidogenesis during Alzheimer’s disease due to an IL-1-/IL-6-mediated ‘acute phase response’ in the brain? Immunol Today 12:217–219PubMedGoogle Scholar
  128. 128.
    Maimone D, Gregory S, Arnason BG, Reder AT (1991) Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J Neuroimmunol 32:67–74PubMedGoogle Scholar
  129. 129.
    Gallo P, Frei K, Rordorf C, Lazdins J, Tavolato B, Fontana A (1989) Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system: an evaluation of cytokines in cerebrospinal fluid. J Neuroimmunol 23:109–116PubMedGoogle Scholar
  130. 130.
    Tyor WR, Glass JD, Griffin JW, Becker PS, McArthur JC, Bezman L, Griffin DE (1992) Cytokine expression in the brain during the acquired immunodeficiency syndrome. Ann Neurol 31:349–360PubMedGoogle Scholar
  131. 131.
    Ikiz B, Przedborski S (2008) A sequel to the tale of p25/Cdk5 in neurodegeneration. Neuron 60:731–732PubMedGoogle Scholar
  132. 132.
    Koyama Y, Adachi M, Sekiya M, Takekawa M, Imai K (2000) Histone deacetylase inhibitors suppress IL-2-mediated gene expression prior to induction of apoptosis. Blood 96:1490–1495PubMedGoogle Scholar
  133. 133.
    Lam E, Pareek TK, Letterio JJ (2015) Cdk5 controls IL-2 gene expression via repression of the mSin3a-HDAC complex. Cell Cycle 14:1327–1336PubMedPubMedCentralGoogle Scholar
  134. 134.
    Bignante EA, Rodriguez Manzanares PA, Mlewski EC, Bertotto ME, Bussolino DF, Paglini G, Molina VA (2008) Involvement of septal Cdk5 in the emergence of excessive anxiety induced by stress. Eur Neuropsychopharmacol 18:578–588PubMedGoogle Scholar
  135. 135.
    Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J (2002) Cyclin-dependent kinase 5 is required for associative learning. J Neurosci 22:3700–3707PubMedPubMedCentralGoogle Scholar
  136. 136.
    Smith DS, Greer PL, Tsai LH (2001) Cdk5 on the brain. Cell Growth Differ 12:277–283PubMedGoogle Scholar
  137. 137.
    Nikolic M, Chou MM, Lu W, Mayer BJ, Tsai LH (1998) The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 395:194–198PubMedGoogle Scholar
  138. 138.
    Pareek TK, Lam E, Zheng X, Askew D, Kulkarni AB, Chance MR, Huang AY, Cooke KR, Letterio JJ (2010) Cyclin-dependent kinase 5 activity is required for T cell activation and induction of experimental autoimmune encephalomyelitis. J Exp Med 207:2507–2519PubMedPubMedCentralGoogle Scholar
  139. 139.
    Matsubara M, Kusubata M, Ishiguro K, Uchida T, Titani K, Taniguchi H (1996) Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions. J Biol Chem 271:21108–21113PubMedGoogle Scholar
  140. 140.
    Fletcher AI, Shuang R, Giovannucci DR, Zhang L, Bittner MA, Stuenkel EL (1999) Regulation of exocytosis by cyclin-dependent kinase 5 via phosphorylation of Munc18. J Biol Chem 274:4027–4035PubMedGoogle Scholar
  141. 141.
    Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna, Pant HC, Brady RO, Martin LJ, Kulkarni AB (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci U S A 93:11173–11178PubMedPubMedCentralGoogle Scholar
  142. 142.
    Chae T, Kwon YT, Bronson R, Dikkes P, Li E, Tsai LH (1997) Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18:29–42PubMedGoogle Scholar
  143. 143.
    Bencherif M, Lukas RJ (1993) Cytochalasin modulation of nicotinic cholinergic receptor expression and muscarinic receptor function in human TE671/RD cells: a possible functional role of the cytoskeleton. J Neurochem 61:852–864PubMedGoogle Scholar
  144. 144.
    Dhavan R, Tsai LH (2001) A decade of CDK5. Nat Rev Mol Cell Biol 2:749–759PubMedGoogle Scholar
  145. 145.
    Fischer A, Sananbenesi F, Spiess J, Radulovic J (2003) Cdk5: a novel role in learning and memory. Neurosignals 12:200–208PubMedGoogle Scholar
  146. 146.
    Angelo M, Plattner F, Giese KP (2006) Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. J Neurochem 99:353–370PubMedGoogle Scholar
  147. 147.
    Ohshima T, Ogura H, Tomizawa K, Hayashi K, Suzuki H, Saito T, Kamei H, Nishi A, Bibb JA, Hisanaga S, Matsui H, Mikoshiba K (2005) Impairment of hippocampal long-term depression and defective spatial learning and memory in p35 mice. J Neurochem 94:917–925PubMedGoogle Scholar
  148. 148.
    Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622PubMedGoogle Scholar
  149. 149.
    Alvarez A, Munoz JP, Maccioni RB (2001) A Cdk5-p35 stable complex is involved in the beta-amyloid-induced deregulation of Cdk5 activity in hippocampal neurons. Exp Cell Res 264:266–274PubMedGoogle Scholar
  150. 150.
    Morrison JH, Hof PR (1997) Life and death of neurons in the aging brain. Science 278:412–419PubMedGoogle Scholar
  151. 151.
    Muller N (1997) Role of the cytokine network in the CNS and psychiatric disorders. Nervenarzt 68(1):11–20PubMedGoogle Scholar
  152. 152.
    Kronfol Z, Remick DG (2000) Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 157(5):683–694PubMedGoogle Scholar
  153. 153.
    Talih F et al (2018) Delayed sleep phase syndrome and bipolar disorder: pathogenesis and available common biomarkers. Sleep Med RevGoogle Scholar
  154. 154.
    Waheed A et al (2018) A systematic review of interleukin (IL) -1β in post-traumatic stress disorder: evidence from human and animal studies. J Interferon Cytokine ResGoogle Scholar
  155. 155.
    Tükel R et al (2012) Decreased IFN-γ and IL-12 levels in panic disorder. J Psychosom Res 73(1):63–67PubMedGoogle Scholar
  156. 156.
    Rao NP et al (2015) Plasma cytokine abnormalities in drug-naïve, comorbidity-free obsessive–compulsive disorder. Psychiatry Res 229(3):949–952PubMedPubMedCentralGoogle Scholar
  157. 157.
    Boerrigter D et al (2017) Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflammation 14:188PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Samer El Hayek
    • 1
    • 2
  • Farah Allouch
    • 2
  • Luna Geagea
    • 1
  • Farid Talih
    • 1
    • 3
    Email author
  1. 1.Department of Psychiatry, Faculty of MedicineAmerican University of BeirutBeirutLebanon
  2. 2.Department of Biochemistry and Molecular Genetics, Faculty of MedicineAmerican University of BeirutBeirutLebanon
  3. 3.Psychiatry DepartmentAmerican University of Beirut Medical CenterBeirutLebanon

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