The Role of Cytokines in the Regulation of Neurotransmission

Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped in several protein families, namely tumor necrosis factors, interleukins, interferons and colony-stimulating factors. In recent years, evidence has elucidated that some of these proteins as well as their receptors are also produced in the central nervous system (CNS) by specific neural cell lineages under physiological and pathological conditions. Cytokines regulate a variety of processes in the CNS, including neurotransmission. The current data let us to suggest that cytokines play an important role in the regulation of both excitatory and inhibitory neurotransmission in the CNS. This knowledge could be fundamental for the proposal of new therapeutic approaches to neurological and psychiatric disorders.

[1]  W. Jarvis,et al.  Somatostatin and Gamma-Aminobutyric Acid Inhibit Interleukin-1β-Stimulated Release of Interleukin-6 from Rat C6 Glioma Cells , 2004, Neuroimmunomodulation.

[2]  J. Diorio,et al.  Interleukin‐2 Modulates Evoked Release of [3H]Dopamine in Rat Cultured Mesencephalic Cells , 1993, Journal of neurochemistry.

[3]  V. Rettori,et al.  Role of Nitric Oxide in the Neuroendocrine Responses to Cytokines a , 1998, Annals of the New York Academy of Sciences.

[4]  M. Maes,et al.  Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor α and interleukin-6 , 2005, Psychiatry Research.

[5]  E. Parati,et al.  Neural stem cells. Biological features and therapeutic potential in Parkinson's disease. , 2003, Journal of neurosurgical sciences.

[6]  M. Huleihel,et al.  Involvement of tumor necrosis factor alpha in hippocampal development and function. , 2004, Cerebral cortex.

[7]  Hugo O Besedovsky,et al.  Introduction: immune-neuroendocrine network. , 2002, Frontiers of hormone research.

[8]  J. Haddad,et al.  Cytokines and neuro–immune–endocrine interactions: a role for the hypothalamic–pituitary–adrenal revolving axis , 2002, Journal of Neuroimmunology.

[9]  Jia-Yi Wang,et al.  Hypoxia/Reoxygenation induces nitric oxide and TNF-alpha release from cultured microglia but not astrocytes of the rat. , 2007, The Chinese journal of physiology.

[10]  A. Vercelli,et al.  Macrophage stimulating protein is a novel neurotrophic factor. , 2001, Molecular biology of the cell.

[11]  E. Benveniste,et al.  Differential modulation of astrocyte cytokine gene expression by TGF-beta. , 1994, Journal of immunology.

[12]  H. Besedovsky,et al.  Immune-neuro-endocrine interactions: facts and hypotheses. , 1996, Endocrine reviews.

[13]  J. Morales-Montor,et al.  HOST GENDER IN PARASITIC INFECTIONS OF MAMMALS: AN EVALUATION OF THE FEMALE HOST SUPREMACY PARADIGM , 2004, The Journal of parasitology.

[14]  A. Panerai,et al.  GM‐CSF affects hypothalamic neurotransmitter levels in mice: involvement of interleukin‐1 , 1997, Neuroreport.

[15]  C. Dinarello,et al.  Interleukin-1 augments gamma-aminobutyric acidA receptor function in brain. , 1991, Molecular pharmacology.

[16]  A. Ho,et al.  Induction of Interleukin-1 Associated with Compensatory Dopaminergic Sprouting in the Denervated Striatum of Young Mice: Model of Aging and Neurodegenerative Disease , 1998 .

[17]  D. Gruol,et al.  Altered physiology of purkinje neurons in cerebellar slices from transgenic mice with chronic central nervous system expression of interleukin-6 , 1999, Neuroscience.

[18]  M. Chao,et al.  Oligodendrocyte Apoptosis Mediated by Caspase Activation , 1999, The Journal of Neuroscience.

[19]  H. Neumann,et al.  Tumor Necrosis Factor Inhibits Neurite Outgrowth and Branching of Hippocampal Neurons by a Rho-Dependent Mechanism , 2002, The Journal of Neuroscience.

[20]  N. Rothwell,et al.  Brain TNF: Damage limitation or damaged reputation? , 1996, Nature Medicine.

[21]  A. Davies,et al.  Cytokines promote the survival of mouse cranial sensory neurones at different developmental stages , 1998, The European journal of neuroscience.

[22]  G. D’Arcangelo,et al.  The Inhibitory Effects of Interleukin‐6 on Synaptic Plasticity in the Rat Hippocampus Are Associated with an Inhibition of Mitogen‐Activated Protein Kinase ERK , 2000, Journal of neurochemistry.

[23]  I. Kimber,et al.  Interleukin‐1‐induced interleukin‐6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones , 2008, British journal of pharmacology.

[24]  W. Friedman.  Cytokines Regulate Expression of the Type 1 Interleukin-1 Receptor in Rat Hippocampal Neurons and Glia , 2001, Experimental Neurology.

[25]  F. Gage,et al.  Cytokine Regulation of Nerve Growth Factor‐Mediated Cholinergic Neurotrophic Activity Synthesized by Astrocytes and Fibroblasts , 1992, Journal of neurochemistry.

[26]  B. Brew,et al.  Expression of chemokines and their receptors in human and simian astrocytes: Evidence for a central role of TNFα and IFNγ in CXCR4 and CCR5 modulation , 2003 .

[27]  S. Henriksen,et al.  Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha. , 1999, Brain research.

[28]  H. Neumann,et al.  Interferon γ Gene Expression in Sensory Neurons: Evidence for Autocrine Gene Regulation , 1997, The Journal of experimental medicine.

[29]  T. Tabira,et al.  Interleukin‐3 and Interleukin‐3 Receptors in the Brain a , 1998, Annals of the New York Academy of Sciences.

[30]  S. Henriksen,et al.  Profound increase in sensitivity to glutamatergic‐ but not cholinergic agonist‐induced seizures in transgenic mice with astrocyte production of IL‐6 , 2003, Journal of neuroscience research.

[31]  A. Panerai,et al.  Effects of interleukin-1 beta and interleukin-2 on amino acids levels in mouse cortex and hippocampus. , 1995, Neuroreport.

[32]  M. Millan,et al.  Dopamine D2 receptor-mediated G-protein activation in rat striatum: functional autoradiography and influence of unilateral 6-hydroxydopamine lesions of the substantia nigra , 2001, Brain Research.

[33]  R. Hill,et al.  Exposure to interferon-gamma during synaptogenesis increases inhibitory activity after a latent period in cultured rat hippocampal neurons. , 2004, The European journal of neuroscience.

[34]  F. Gage,et al.  Expression of cytokines by multipotent neural progenitor cells. , 2003, Cytokine.

[35]  A. Grossman,et al.  Reciprocal interactions between the neuroendocrine and immune systems during inflammation. , 2000, Rheumatic diseases clinics of North America.

[36]  R. Dantzer,et al.  Expression of type I and type II interleukin-1 receptors in mouse brain. , 1994, Brain research. Molecular brain research.

[37]  S. Malik,et al.  Interleukin-1beta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. , 2000, The Journal of pharmacology and experimental therapeutics.

[38]  Detlef Balschun,et al.  A neuromodulatory role of interleukin-1β in the hippocampus , 1998 .

[39]  L. Vitković,et al.  Transforming growth factor-beta 1 (TGF-β1) expression and regulation in rat cortical astrocytes , 1992, Journal of Neuroimmunology.

[40]  M. Horne,et al.  The Role of Interleukin-1, Interleukin-6, and Glia in Inducing Growth of Neuronal Terminal Arbors in Mice , 2002, The Journal of Neuroscience.

[41]  F. Holsboer,et al.  Cellular Localization of Interleukin 6 mRNA and Interleukin 6 Receptor mRNA in Rat Brain , 1993, The European journal of neuroscience.

[42]  H. Besedovsky,et al.  The cytokine-HPA axis feed-back circuit , 2000, Zeitschrift für Rheumatologie.

[43]  H. Thoenen,et al.  Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve , 1987, Nature.

[44]  P. Grob,et al.  Astrocyte-derived interleukin-1-like factors. , 1984, Lymphokine research.

[45]  J. Weiss,et al.  Alteration of Locus coeruleus Neuronal Activity by Interleukin-1 and the Involvement of Endogenous Corticotropin-Releasing Hormone , 2002, Neuroimmunomodulation.

[46]  R. Andrew,et al.  Interferon-α inhibits long-term potentiation and unmasks a long-term depression in the rat hippocampus , 2000, Brain Research.

[47]  J. Petitto,et al.  Molecular cloning of a partial cDNA of the interleukin-2 receptor-β in normal mouse brain: in situ localization in the hippocampus and expression by neuroblastoma cells , 1994, Brain Research.

[48]  A. Martella,et al.  Role of cytokines in lipopolysaccharide‐induced functional and structural abnormalities of astrocytes , 1994, Glia.

[49]  Shuxian Hu,et al.  Cytokine Effects on Glutamate Uptake by Human Astrocytes , 2000, Neuroimmunomodulation.

[50]  E. Aronica,et al.  Activation of metabotropic glutamate receptor 3 enhances interleukin (IL)-1β-stimulated release of IL-6 in cultured human astrocytes , 2005, Neuroscience.

[51]  Klaus Pfeffer,et al.  Biological functions of tumor necrosis factor cytokines and their receptors. , 2003, Cytokine & growth factor reviews.

[52]  E. Benveniste,et al.  Cytokine actions in the central nervous system. , 1998, Cytokine & growth factor reviews.

[53]  C. Dinarello,et al.  Interleukin-1 beta stimulates somatostatin biosynthesis in primary cultures of fetal rat brain. , 1989, Endocrinology.

[54]  J. G. Netzeband,et al.  Chronic interleukin‐6 exposure alters metabotropic glutamate receptor‐activated calcium signalling in cerebellar Purkinje neurons , 2004, The European journal of neuroscience.

[55]  N. Rothwell,et al.  Cytokines and fever. , 1996, International archives of allergy and immunology.

[56]  Rodney W. Johnson,et al.  An Age-Related Decline in Interleukin-10 May Contribute to the Increased Expression of Interleukin-6 in Brain of Aged Mice , 2002, Neuroimmunomodulation.

[57]  P. Blumbergs,et al.  Early Expression and Cellular Localization of Proinflammatory Cytokines Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor-&agr; in Human Traumatic Spinal Cord Injury , 2004, Spine.

[58]  S. Levison,et al.  Mini review , 2004 .

[59]  N. Nishimoto,et al.  The blockade of IL-6 signaling in rational drug design. , 2008, Current pharmaceutical design.

[60]  G. Levi,et al.  Interferon gamma gene expression in rat central nervous system glial cells. , 1998, Cytokine.

[61]  M. Schwaninger,et al.  Induction of Interleukin-6 by Depolarization of Neurons , 2000, The Journal of Neuroscience.

[62]  J. Morales-Montor,et al.  The role of sex steroids in the complex physiology of the host-parasite relationship: the case of the larval cestode of Taenia crassiceps , 2005, Parasitology.

[63]  U. Otten,et al.  Differential expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat hypothalamus , 1993, Neuroscience Letters.

[64]  M. Kimura,et al.  The Mechanism of Action of Cytokines to Control the Release of Hypothalamic and Pituitary Hormones in Infection , 2000, Annals of the New York Academy of Sciences.

[65]  Jae-Wook Oh,et al.  Interleukin-6 (IL-6) Production by Astrocytes: Autocrine Regulation by IL-6 and the Soluble IL-6 Receptor , 1999, The Journal of Neuroscience.

[66]  S. Tsuji,et al.  Effects of interferon-beta on the cytokine production of astrocytes. , 2005, Journal of neuroimmunology.

[67]  M. Diener,et al.  TNF-alpha hyperpolarizes membrane potential and potentiates the response to nicotinic receptor stimulation in cultured rat myenteric neurones. , 2004, Acta physiologica Scandinavica.

[68]  E. Ponomarev,et al.  CNS-Derived Interleukin-4 Is Essential for the Regulation of Autoimmune Inflammation and Induces a State of Alternative Activation in Microglial Cells , 2007, The Journal of Neuroscience.

[69]  S. Henriksen,et al.  Structural and functional neuropathology in transgenic mice with CNS expression of IFN-α 1 Published on the World Wide Web on 17 March 1999. 1 , 1999, Brain Research.

[70]  C. Saper,et al.  Interleukin-1 immunoreactive innervation of the human hypothalamus. , 1988, Science.

[71]  Kohji Sato,et al.  Interleukin 3 Prevents Delayed Neuronal Death in the Hippocampal CA1 Field , 1998, The Journal of experimental medicine.

[72]  F. Shi,et al.  Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis? , 2006, International immunology.

[73]  M. Cuzner,et al.  Macrophages in CNS Remyelination: Friend or Foe? , 1998, Neurochemical Research.

[74]  U. Otten,et al.  Identification of interleukin-6 (IL-6)-expressing neurons in the cerebellum and hippocampus of normal adult rats , 1994, Neuroscience Letters.

[75]  D. Giulian,et al.  Interleukin-1 is an astroglial growth factor in the developing brain , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[76]  B. Duvilanski,et al.  Effect of Interleukin-6 and Tumor Necrosis Factor-α on GABA Release from Mediobasal Hypothalamus and Posterior Pituitary , 1999, Neuroimmunomodulation.

[77]  T. Kielian,et al.  Tumor necrosis factor-alpha (TNF-alpha) regulates Toll-like receptor 2 (TLR2) expression in microglia. , 2007, Journal of neurochemistry.

[78]  P. Ricciardi-Castagnoli,et al.  DHEAS inhibits TNF production in monocytes, astrocytes and microglial cells. , 1996, Neuroimmunomodulation.

[79]  D. Gruol,et al.  Chronic interleukin-6 exposure alters electrophysiological properties and calcium signaling in developing cerebellar purkinje neurons in culture. , 2002, Journal of neurophysiology.

[80]  C. Dinarello,et al.  INTERLEUKIN-1β STIMULATES SOMATOSTATIN BIOSYNTHESIS IN PRIMARY CULTURES OF FETAL RAT BRAIN , 1989 .

[81]  M. Mattson,et al.  The Transcription Factor NF‐κB Mediates Increases in Calcium Currents and Decreases in NMDA‐ and AMPA/Kainate‐Induced Currents Induced by Tumor Necrosis Factor‐α in Hippocampal Neurons , 1998, Journal of neurochemistry.

[82]  H. Hatanaka,et al.  Interleukin-6 as a neurotrophic factor for promoting the survival of cultured catecholaminergic neurons in a chemically defined medium from fetal and postnatal rat midbrains , 1992, Neuroscience Research.

[83]  A. Reeve,et al.  Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat , 2000, European journal of pain.

[84]  A. Dickenson,et al.  Nerve injury alters the effects of interleukin-6 on nociceptive transmission in peripheral afferents. , 2004, European journal of pharmacology.

[85]  W. Pan,et al.  Brain proteome of mice lacking the receptors for tumor necrosis factor α , 2004, Proteomics.

[86]  M. A. Colivicchi,et al.  Interleukin-1β activates forebrain glial cells and increases nitric oxide production and cortical glutamate and GABA release in vivo: implications for Alzheimer's disease , 1999, Neuroscience.

[87]  M. Mostarica‐Stojković,et al.  Astrocytes stimulate interleukin‐17 and interferon‐γ production in vitro , 2007, Journal of neuroscience research.

[88]  S. Barger,et al.  Differential Transcriptional Control of the Superoxide Dismutase-2 κB Element in Neurons and Astrocytes* , 2006, Journal of Biological Chemistry.

[89]  P. Lazarovici,et al.  Interactions between the cells of the immune and nervous system: neurotrophins as neuroprotection mediators in CNS injury. , 2004, Progress in brain research.

[90]  D. Lawrence,et al.  Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[91]  D. Gruol,et al.  Physiological and pathological roles of interleukin-6 in the central nervous system , 1997, Molecular Neurobiology.

[92]  M. Syed,et al.  Tumor necrosis factor‐alpha (TNF‐α) regulates Toll‐like receptor 2 (TLR2) expression in microglia , 2007 .

[93]  N. Nishiyama,et al.  Interleukin‐1β abrogates long‐term depression of hippocampal CA1 synaptic transmission , 2003, Synapse.

[94]  F. Gage,et al.  Reduced Hippocampal Neurogenesis in Adult Transgenic Mice with Chronic Astrocytic Production of Interleukin-6 , 2002, The Journal of Neuroscience.

[95]  P. Neveu,et al.  Treatment of cytokine-induced depression , 2002, Brain, Behavior, and Immunity.

[96]  S. Brull,et al.  Increased sensitivity of sensory neurons to tumor necrosis factor alpha in rats with chronic compression of the lumbar ganglia. , 2002, Journal of neurophysiology.

[97]  R. Heumann,et al.  [Corticoids protect oligodentrocyte precursor cells against cytokine-induced damage]. , 2004, Zentralblatt für Gynäkologie.

[98]  Sunil Kumar,et al.  Interleukin‐1β modulates state‐dependent discharge activity of preoptic area and basal forebrain neurons: role in sleep regulation , 2004, The European journal of neuroscience.

[99]  M. O’Banion,et al.  Chronic Interleukin-1β Expression in Mouse Brain Leads to Leukocyte Infiltration and Neutrophil-Independent Blood–Brain Barrier Permeability without Overt Neurodegeneration , 2007, The Journal of Neuroscience.

[100]  H. Schaible,et al.  Sensitization of unmyelinated sensory fibers of the joint nerve to mechanical stimuli by interleukin-6 in the rat: an inflammatory mechanism of joint pain. , 2007, Arthritis and rheumatism.

[101]  L. G. Miller,et al.  Interleukin‐1 Modulates GABAergic and Glutamatergic Function in Brain a , 1994, Annals of the New York Academy of Sciences.

[102]  U. Otten,et al.  Postnatal expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) mRNAs in rat sympathetic and sensory ganglia , 1996, Brain Research.

[103]  M. Yokoyama,et al.  Chronic intraperitoneal injection of interferon‐α reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate , 2006, Psychiatry and clinical neurosciences.

[104]  N. de Tribolet,et al.  Glioblastoma cells release interleukin 1 and factors inhibiting interleukin 2-mediated effects. , 1984, Journal of immunology.

[105]  D. Refojo,et al.  Interleukin-1 Inhibits NMDA-Stimulated GnRH Secretion: Associated Effects on the Release of Hypothalamic Inhibitory Amino Acid Neurotransmitters , 1999, Neuroimmunomodulation.

[106]  S. Tsuji,et al.  Effects of interferon-β on the cytokine production of astrocytes , 2005, Journal of Neuroimmunology.

[107]  A. da Cunha,et al.  Transforming growth factor-beta 1 (TGF-beta 1) expression and regulation in rat cortical astrocytes. , 1992, Journal of neuroimmunology.

[108]  R. Hill,et al.  Exposure to interferon‐γ during synaptogenesis increases inhibitory activity after a latent period in cultured rat hippocampal neurons , 2004 .

[109]  R. Hill,et al.  Interferon-γ-induced changes in synaptic activity and AMPA receptor clustering in hippocampal cultures , 2001, Brain Research.

[110]  S. Zalcman,et al.  Interleukin-2 modulates N-methyl-d-aspartate receptors of native mesolimbic neurons , 2001, Brain Research.

[111]  M. Ichinose,et al.  Interleukin‐2 inhibits the GABA‐induced Cl‐ current in identified Aplysia neurons , 1992, Journal of neuroscience research.

[112]  H. Besedovsky,et al.  Immune-neuro-endocrine interactions: facts and hypotheses. , 1996, Endocrine reviews.

[113]  M. Racke,et al.  Peroxisome proliferator‐activated receptor‐α agonist fenofibrate regulates IL‐12 family cytokine expression in the CNS: relevance to multiple sclerosis , 2007, Journal of neurochemistry.

[114]  F. Aloisi,et al.  Norepinephrine and vasoactive intestinal peptide induce IL-6 secretion by astrocytes: Synergism with IL-1β and TNFα , 1993, Journal of Neuroimmunology.

[115]  I. Mazzoni,et al.  Microglia from the developing rat medial septal area can affect cholinergic and GABAergic neuronal differentiation in vitro , 1996, Neuroscience.

[116]  S. Maier,et al.  A novel immune-to-CNS communication pathway: Cells of the meninges surrounding the spinal cord CSF space produce proinflammatory cytokines in response to an inflammatory stimulus , 2007, Brain, Behavior, and Immunity.

[117]  R. Quirion,et al.  Evidence for direct and indirect mechanisms in the potent modulatory action of interleukin‐2 on the release of acetylcholine in rat hippocampal slices , 1997, British journal of pharmacology.

[118]  D. Refojo,et al.  Interleukin-1 Stimulates Hypothalamic Inhibitory Amino Acid Neurotransmitter Release , 1998, Neuroimmunomodulation.

[119]  C. Rivier.  Neuroendocrine Effects of Cytokines in the Rat , 1993, Reviews in the neurosciences.

[120]  G. Kollias,et al.  Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy. , 1998, The American journal of pathology.