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Cytokine signals propagate through the brain

A Corrigendum to this article was published on 17 April 2001

Abstract

Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFα) are proinflammatory cytokines that are constitutively expressed in healthy, adult brain where they mediate normal neural functions such as sleep. They are neuromodulators expressed by and acting on neurons and glia. IL-1 and TNFα expression is upregulated in several important diseases/disorders. Upregulation of IL-1 and/or TNFα expression, elicited centrally or systemically, propagates through brain parenchyma following specific spatio-temporal patterns. We propose that cytokine signals propagate along neuronal projections and extracellular diffusion pathways by molecular cascades that need to be further elucidated. This elucidation is a prerequisite for better understanding of reciprocal interactions between nervous, endocrine and immune systems.

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References

  1. Breder C, Dinarello C, Saper C . Interleukin-1 immunoreactive innervation of the human hypothalamus Science 1988; 240: 321–324

    CAS  PubMed  Google Scholar 

  2. Cunningham ET Jr, Wada E, Carter DB, Tracey DE, Battey JF, De Souza EB . Localization of interleukin-1 receptor messenger RNA in murine hippocampus Endocrinology 1991; 128: 2666–2668

    PubMed  Google Scholar 

  3. Farrar W, Kilian P, Ruff M, Hill J, Pert C . Visualization and characterization of interleukin-1 in the brain J Immunol 1987; 139: 459–463

    CAS  PubMed  Google Scholar 

  4. Ban E, Milon G, Prudhomme N, Fillion G, Haour F . Receptors for interleukin-1 (alpha and beta) in mouse brain: mapping and neuronal localization in hippocampus Neuroscience 1991; 43: 21–30

    CAS  PubMed  Google Scholar 

  5. Tazi A, Dantzer R, Crestani F, Le Moal M . Interleukin-1 induces conditioned taste aversion in rats: a possible explanation for its pituitary-adrenal stmulating activity Brain Res 1988; 473: 369–371

    CAS  PubMed  Google Scholar 

  6. Plata-Salaman CR, Oomura Y, Kai Y . Tumor necrosis factor and interleukin-1 beta: suppression of food intake by direct action in the central nervous system Brain Res 1988; 448: 106–114

    CAS  PubMed  Google Scholar 

  7. van Dam AM, Brouns M, Louisse S, Berkenbosch F . Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness? Brain Res 1992; 588: 291–296

    CAS  PubMed  Google Scholar 

  8. Dantzer R, Bluthe RM, Gheusi G et al. Molecular basis of sickness behavior Ann NY Acad Sci 1998; 856: 132–138

    CAS  PubMed  Google Scholar 

  9. Kluger M, Kozak W, Leon L, Conn C . The use of knockout mice to understand the role of cytokines in fever Clin Exp Pharmacol Physiol 1998; 25: 141–144

    CAS  PubMed  Google Scholar 

  10. Saper CB . Neurobiological basis of fever Ann NY Acad Sci 1998; 856: 90–94

    CAS  PubMed  Google Scholar 

  11. Plata-Salaman CR . Cytokine-induced anorexia. Behavioral, cellular, and molecular mechanisms Ann NY Acad Sci 1998; 856: 160–170

    CAS  PubMed  Google Scholar 

  12. Watkins LR, Goehler LE, Relton J, Brewer MT, Maier SF . Mechanisms of tumor necrosis factor-alpha (TNF-alpha) hyperalgesia Brain Res 1995; 692: 244–250

    CAS  PubMed  Google Scholar 

  13. Turnbull AV, Rivier CL . Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action Physiol Rev 1999; 79: 1–71

    CAS  PubMed  Google Scholar 

  14. Vitkovic L, Bockaert J, Jacque C . ‘Inflammatory’ cytokines: neuroímodulators in normal brain? J Neurochem 2000; 74: 457–471

    CAS  PubMed  Google Scholar 

  15. da Cunha A, Jefferson JA, Jackson RW, Vitkovic L . Glial cell-specific mechanisms of TGF-beta 1 induction by IL-1 in cerebral cortex J Neuroimmunol 1993; 42: 71–85

    CAS  PubMed  Google Scholar 

  16. Brew BJ, Rosenblum M, Cronin K, Price RW . AIDS dementia complex and HIV-1 brain infection: clinical-virological correlations Ann Neurol 1995; 38: 563–570

    CAS  PubMed  Google Scholar 

  17. Licinio J, Wong ML . Pathways and mechanisms for cytokine signaling of the central nervous system J Clin Invest 1997; 100: 2941–2947

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Vitkovic L, da Cunha A, Tyor WR . Cytokine expression and pathogenesis in AIDS brain Res Publ Assoc Res Nerv Ment Dis 1994; 72: 203–222

    CAS  PubMed  Google Scholar 

  19. Emilie D, Fior R, Jarrousse B et al. Cytokines in HIV infection Int J Immunopharmacol 1994; 16: 391–396

    CAS  PubMed  Google Scholar 

  20. Wahl SM, Allen JB, Weeks BS, Wong HL, Klotman PE . Transforming growth factor beta enchances integrin expression and type IV collagenase secretion in human monocytes Proc Natl Acad Sci USA 1993; 90: 4577–4581

    CAS  PubMed  Google Scholar 

  21. Fiala M, Looney DJ, Stins M et al. TNF-alpha opens a paracellular route for HIV-1 invasion across the blood–brain barrier Mol Med 1997; 3: 553–564

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Persidsky Y, Stins M, Way D et al. A model for monocyte migration through the blood–brain barrier during HIV-1 encephalitis J Immunol 1997; 158: 3499–3510

    CAS  PubMed  Google Scholar 

  23. Lee SC, Liu W, Dickson DW, Brosnan CF, Berman JW . Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta J Immunol 1993; 150: 2659–2667

    CAS  PubMed  Google Scholar 

  24. Pearson VL, Rothwell NJ, Toulmond S . Excitotoxic brain damage in the rat induces interleukin-1beta protein in microglia and astrocytes: correlation with the progression of cell death Glia 1999; 25: 311–323

    CAS  PubMed  Google Scholar 

  25. da Cunha A, Jefferson JJ, Tyor WR, Glass JD, Jannotta FS, Vitkovic L . Control of astrocytosis by interleukin-1 and transforming growth factor-beta 1 in human brain Brain Res 1993; 631: 39–45

    CAS  PubMed  Google Scholar 

  26. Vitkovic L . Neuropathogenesis of HIV-1 infection: interactions between interleukin-1 and transforming growth factor-beta 1 Mol Psychiatry 1997; 2: 111–112

    CAS  PubMed  Google Scholar 

  27. Sheng JG, Boop FA, Mrak RE, Griffin WS . Increased neuronal beta-amyloid precursor protein expression in human temporal lobe epilepsy: association with interleukin-1 alpha immunoreactivity J Neurochem 1994; 63: 1872–1879

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gahring LC, White HS, Skradski SL, Carlson NG, Rogers SW . Interleukin-1 alpha in the brain is induced by audiogenic seizure Neurobiol Dis 1997; 3: 263–269

    CAS  PubMed  Google Scholar 

  29. Vezzani A, Conti M, De Luigi A et al. Interleukin-1beta 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

    CAS  PubMed  Google Scholar 

  30. de Bock F, Dornand J, Rondouin G . Release of TNF alpha in the rat hippocampus following epileptic seizures and excitotoxic neuronal damage Neuroreport 1996; 7: 1125–1129

    CAS  PubMed  Google Scholar 

  31. Ben-Ari Y . Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy Neuroscience 1985; 14: 375–403

    CAS  PubMed  Google Scholar 

  32. Goto Y, Araki T, Kato M, Fukui M . Propagation of hippocampal seizure activity arising from the hippocampus: a local cerebral blood flow study Brain Res 1994; 634: 203–213

    CAS  PubMed  Google Scholar 

  33. Gass P, Bruehl C, Herdegen T, Kiessling M, Lutzenburg M, Witte OW . Induction of FOS and JUN proteins during focal epilepsy: congruences with and differences to [14C]deoxyglucose metabolism Brain Res Mol Brain Res 1997; 46: 177–184

    CAS  PubMed  Google Scholar 

  34. MacNamara JO . Cellular and molecular basis of epilepsy J Neurosci 1994; 14: 3413–3425

    Google Scholar 

  35. Tchélingérian J, Quinonero J, Booss J, Jacque C . Localization of TNF alpha and IL-1 alpha immunoreactivities in striatal neurons after surgical injury to the hippocampus Neuron 1993; 10: 213–224

    PubMed  Google Scholar 

  36. Gabellec M, Crumeyrolle-Arias M, Le Saux F, Auriou N, Jacque C, Haour F . Expression of IL-1 genes and IL-1 receptors in the mouse brain after hippocampal injury Neurosci Res 1999; 33: 251–256

    CAS  PubMed  Google Scholar 

  37. Tchélingérian J, Vignais L, Jacque C . TNF alpha gene expression is induced in neurons after hippocampal lesion Neuroreport 1994; 5: 585–588

    PubMed  Google Scholar 

  38. Lowenstein DH, Simon RP, Sharp FR . The pattern of 72-kDa heat shock protein-like immunoreactivity in the rat brain following flurothyl-induced status epilepticus Brain Res 1990; 531: 173–182

    CAS  PubMed  Google Scholar 

  39. White LE, Price JL . The functional anatomy of limbic status epilepticus in the rat. I. Patterns of 14C-2-deoxyglucose uptake and Fos immunocytochemistry J Neurosci 1993; 13: 4787–4809

    CAS  PubMed  Google Scholar 

  40. Tchélingérian J, Le Saux F, Pouzet B, Jacque C . Widespread neuronal expression of c-Fos throughout the brain and local expression in glia following a hippocampal injury Neurosci Lett 1997; 226: 175–178

    PubMed  Google Scholar 

  41. Sigurdsson EM, Lee JM, Dong XW, Hejna MJ, Lorens SA . Bilateral injections of amyloid-beta 25–35 into the amygdala of young Fischer rats: behavioral, neurochemical, and time dependent histopathological effects Neurobiol Aging 1997; 18: 591–608

    CAS  PubMed  Google Scholar 

  42. Grilli M, Memo M . Nuclear factor-kappaB/Rel proteins: a point of convergence of signalling pathways relevant in neuronal function and dysfunction Biochem Pharmacol 1999; 57: 1–7

    CAS  PubMed  Google Scholar 

  43. O'Neill LA, Kaltschmidt C . NF-kappa B: a crucial transcription factor for glial and neuronal cell function Trends Neurosci 1997; 20: 252–258

    CAS  PubMed  Google Scholar 

  44. Stojkovic T, Colin C, Le Saux F, Jacque C . Specific pattern of nitric oxide synthetase expression in glial cells after hippocampal injury Glia 1998; 22: 329–337

    CAS  PubMed  Google Scholar 

  45. Rothwell NJ, Hopkins SJ . Cytokines and the nervous system II: actions and mechanisms of action Trends Neurosci 1995; 18: 130–136

    CAS  PubMed  Google Scholar 

  46. Herkenham M, Lee HY, Baker RA . Temporal and spatial patterns of c-fos mRNA induced by intravenous interleukin-1: a cascade of non-neuronal cellular activation at the blood—brain barrier J Comp Neurol 1998; 400: 175–196

    CAS  PubMed  Google Scholar 

  47. Laflamme N, Rivest S . Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor kappaB alpha within specific cellular populations of the rat brain J Neurochem 1999; 73: 309–321

    CAS  PubMed  Google Scholar 

  48. Wong M, Licinio J . Localization of interleukin-1 type I receptor mRNA in rat brain Neuroimmunomodulation 1994; 1: 110–115

    CAS  PubMed  Google Scholar 

  49. Yabuuchi K, Minami M, Katsumata S, Satoh M . Localization of type I interleukin-1 receptor mRNA in the rat brain Mol Brain Res 1994; 27: 27–36

    CAS  PubMed  Google Scholar 

  50. Ericsson A, Liu C, Hart R, Sawchenko P . Type I interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1-induced cellular activation J Comp Neurol 1995; 361: 681–698

    CAS  PubMed  Google Scholar 

  51. Cao C, Matsumura K, Yamagata K, Watanabe Y . Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever Brain Res 1996; 733: 263–272

    CAS  PubMed  Google Scholar 

  52. Wong ML, Bongiorno PB, al-Shekhlee A, Esposito A, Khatri P, Licinio J . IL-1 beta, IL-1 receptor type I and iNOS gene expression in rat brain vasculature and perivascular areas Neuroreport 1996; 7: 2445–2448

    CAS  PubMed  Google Scholar 

  53. Quan N, Whiteside M, Herkenham M . Cyclooxygenase 2 mRNA expression in rat brain after peripheral injection of lipopolysaccharide Brain Res 1998; 802: 189–197

    CAS  PubMed  Google Scholar 

  54. Brady LS, Lynn AB, Herkenham M, Gottesfeld Z . Systemic interleukin-1 induces early and late patterns of c-fos mRNA expression in brain J Neurosci 1994; 14: 4951–4964

    CAS  PubMed  Google Scholar 

  55. Konsman J, Kelley K, Dantzer R . Temporal and spatial relationship between LPS-induced expression of Fos, interleukin-1 beta and inducible NO synthase in rat brain Neuroscience 1999; 89: 535–548

    CAS  PubMed  Google Scholar 

  56. Hashimoto M, Ishikawa Y, Yokota S et al. Action site of circulating interleukin-1 on the rabbit brain Brain Res 1991; 540: 217–223

    CAS  PubMed  Google Scholar 

  57. Broadwell RD, Sofroniew MV . Serum proteins bypass the blood–brain fluid barriers for extracellular entry to the central nervous system Exp Neurol 1993; 120: 245–263

    CAS  PubMed  Google Scholar 

  58. Quan N, Stern EL, Whiteside MB, Herkenham M . Induction of pro-inflammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat J Neuroimmunol 1999; 93: 72–80

    CAS  PubMed  Google Scholar 

  59. Blatteis CM, Bealer SL, Hunter WS, Llanos-Q J, Ahokas RA, Mashburn TA Jr . Suppression of fever after lesions of the anteroventral third ventricle in guinea pigs Brain Res Bull 1983; 11: 519–526

    CAS  PubMed  Google Scholar 

  60. Caldwell FT, Graves DB, Wallace BH . Studies on the mechanism of fever after intravenous administration of endotoxin J Trauma 1998; 44: 304–312

    CAS  PubMed  Google Scholar 

  61. Lin JH, Lin MT . Inhibition of nitric oxide synthase or cyclo-oxygenase pathways in organum vasculosum laminae terminalis attenuates interleukin-1 beta fever in rabbits Neurosci Lett 1996; 208: 155–158

    CAS  PubMed  Google Scholar 

  62. Lee HY, Whiteside MB, Herkenham M . Area postrema removal abolishes stimulatory effects of intravenous interleukin-1beta on hypothalamic-pituitary-adrenal axis activity and c-fos mRNA in the hypothalamic paraventricular nucleus Brain Res Bull 1998; 46: 495–503

    CAS  PubMed  Google Scholar 

  63. Gotow T, Hashimoto PH . Fine structure of the ependyma and intercellular junctions in the area postrema of the rat Cell Tissue Res 1979; 201: 207–225

    CAS  PubMed  Google Scholar 

  64. Gotow T, Hashimoto PH . Graded differences in tightness of ependymal intercellular junctions within and in the vicinity of the rat median eminence J Ultrastruct Res 1981; 76: 293–311

    CAS  PubMed  Google Scholar 

  65. Broadwell RD, Balin BJ, Salcman M, Kaplan RS . Brain–blood barrier? Yes and no Proc Natl Acad Sci USA 1983; 80: 7352–7356

    CAS  PubMed  Google Scholar 

  66. Banks WA, Kastin AJ . Blood to brain transport of interleukin links the immune and central nervous systems Life Sci 1991; 48: PL117–PL121

    CAS  PubMed  Google Scholar 

  67. Quan N, Sundar SK, Weiss JM . Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide J Neuroimmunol 1994; 49: 125–134

    CAS  PubMed  Google Scholar 

  68. Komatsu T, Ireland DD, Cheung N, Dore A, Yoder M, Shoshkess Reiss C . Regulation of the BBB during viral encephalitis: roles of IL-12 and NOS Nitric Oxide 1999; 3: 327–339

    CAS  PubMed  Google Scholar 

  69. Niimi M, Sato M, Wada Y, Takahara J, Kawanishi K . Effect of central and continuous intravenous injection of interleukin-1 beta on brain c-fos expression in the rat: involvement of prostaglandins Neuroimmunomodulation 1996; 3: 87–92

    CAS  PubMed  Google Scholar 

  70. Laye S, Ghensi G, Cremona S et al. Endogenous brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine expression Am J Physiol Regul Integr Comp Physiol 2000; 279: R93–R98

    CAS  PubMed  Google Scholar 

  71. Gallo P, Frei K, Rordorf C, Lazdins J, Tavolato B, Fontana A . Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system: an evaluation of cytokines in cerebrospinal fluid J Neuroimmunol 1989; 23: 109–116

    CAS  PubMed  Google Scholar 

  72. Laverda AM, Gallo P, De Rossi A et al. Cerebrospinal fluid analysis in HIV-1-infected children: immunological and virological findings before and after AZT therapy Acta Paediatrica 1994; 83: 1038–1042

    CAS  PubMed  Google Scholar 

  73. Blum-Degen D, Müller T, Kuhn W, Gerlach M, Przuntek H, Riederer P . Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients Neurosci Lett 1995; 202: 17–20

    CAS  PubMed  Google Scholar 

  74. Tsukada N, Miyagi K, Matsuda M, Yanagisawa N, Yone K . Tumor necrosis factor and interleukin-1 in the CSF and sera of patients with multiple sclerosis J Neurol Sci 1991; 104: 230–234

    CAS  PubMed  Google Scholar 

  75. Mustafa MM, Ramilo O, Sáez-Llorens X, Olsen KD, Magness RR, McCracken GHJ . Cerebrospinal fluid prostaglandins, interleukin 1 beta, and tumor necrosis factor in bacterial meningitis. Clinical and laboratory correlations in placebo-treated and dexamethasone-treated patients Am J Dis Child 1990; 144: 883–887

    CAS  PubMed  Google Scholar 

  76. McClain CJ, Cohen D, Ott L, Dinarello CA, Young B . Ventricular fluid interleukin-1 activity in patients with head injury J Lab Clin Med 1987; 110: 48–54

    CAS  PubMed  Google Scholar 

  77. Agnati L, Zoli M, Strömberg I, Fuxe K . Intercellular communication in the brain wiring versus volume transmission Neuroscience 1995; 69: 711–726

    CAS  PubMed  Google Scholar 

  78. Blatteis CM . Neuromodulative actions of cytokines Yale J Biol Med 1990; 63: 133–146

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Ericsson A, Arias C, Sawchenko PE . Evidence for an intramedullary prostaglandin-dependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1 J Neurosci 1997; 17: 7166–7179

    CAS  PubMed  Google Scholar 

  80. Davson H, Welch K, Segal MB . The Physiology and Pathophysiology of the Cerebrospinal Fluid Churchill Livingstone: Edinburgh 1987

    Google Scholar 

  81. Chen G, Castro WL, Chow HH, Reichlin S . Clearance of 1251-labeled interleukin-6 from brain into blood following intracerebroventricular injection in rats Endocrinology 1997; 138: 4830–4836

    CAS  PubMed  Google Scholar 

  82. Chen G, Reichlin S . Clearance of 125I-tumor necrosis factor-alpha from the brain into the blood after intracerebroventricular injection in rats Neuroimmunomodulation 1998; 5: 261–269

    CAS  PubMed  Google Scholar 

  83. Brightman MW . The intracerebral movement of proteins injected into blood and cerebrospinal fluid of mice Prog Brain Res 1968; 29: 19–40

    CAS  PubMed  Google Scholar 

  84. Bjelke B, England R, Nicholson C et al. Long distance pathways of diffusion for dextran along fibre bundles in brain. Relevance for volume transmission Neuroreport 1995; 6: 1005–1009

    CAS  PubMed  Google Scholar 

  85. Lawrence C, Allan S, Rothwell N . Interleukin-1β and the interleukin-1 receptor antagonist act in the striatum to modify excitotoxic brain damage in the rat Eur J Neurosci 1998; 10: 1188–1195

    CAS  PubMed  Google Scholar 

  86. Stroemer R, Rothwell N . Exacerbation of ischemic brain damage by localized striatal injection of interleukin-1 beta in the rat J Cereb Blood Flow Metab 1998; 18: 833–839

    CAS  PubMed  Google Scholar 

  87. Cserr HF, Cooper DN, Milhorat TH . Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus Exp Eye Res 1977; 25 Suppl: 461–473

    CAS  PubMed  Google Scholar 

  88. Ichimura T, Fraser PA, Cserr HF . Distribution of extracellular tracers in perivascular spaces of the rat brain Brain Res 1991; 545: 103–113

    CAS  PubMed  Google Scholar 

  89. Weller RO . Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis J Neuropathol Exp Neurol 1998; 57: 885–894

    CAS  PubMed  Google Scholar 

  90. Schneider H, Pitossi F, Balschun D, Wagner A, del Rey A, Besedovsky HO . A neuromodulatory role of interleukin-1 beta in the hippocampus Proc Natl Acad Sci USA 1998; 95: 7778–7783

    CAS  PubMed  Google Scholar 

  91. Meberg PJ, Kinney WR, Valcourt EG, Routtenberg A . Gene expression of the transcription factor NF-kappa B in hippocampus: regulation by synaptic activity Brain Res Mol Brain Res 1996; 38: 179–190

    CAS  PubMed  Google Scholar 

  92. Giaume C, Venance L . Intercellular calcium signaling and gap junctional communication in astrocytes Glia 1998; 24: 50–64

    CAS  PubMed  Google Scholar 

  93. Dani JW, Chernjavsky A, Smith SJ . Neuronal activity triggers calcium waves in hippocampal astrocyte networks Neuron 1992; 8: 429–440

    CAS  PubMed  Google Scholar 

  94. Lee SH, Magge S, Spencer DD, Sontheimer H, Cornell-Bell AH . Human epileptic astrocytes exhibit increased gap junction coupling Glia 1995; 15: 195–202

    CAS  PubMed  Google Scholar 

  95. Jung P, Cornell-Bell A, Madden KS, Moss F . Noise-induced spiral waves in astrocyte syncytia show evidence of self-organized criticality J Neurophysiol 1998; 79: 1098–1101

    CAS  PubMed  Google Scholar 

  96. Lee SH, Kim WT, Cornell-Bell AH, Sontheimer H . Astrocytes exhibit regional specificity in gap-junction coupling Glia 1994; 11: 315–325

    CAS  PubMed  Google Scholar 

  97. Zahs KR . Heterotypic coupling between glial cells of the mammalian central nervous system Glia 1998; 24: 85–96

    CAS  PubMed  Google Scholar 

  98. McCall MA, Gregg RG, Behringer RR et al. Targeted deletion in astrocyte intermediate filament (GFAP) alters neuronal physiology Proc Natl Acad Sci USA 1996; 93: 6361–6366

    CAS  PubMed  Google Scholar 

  99. Yuan LL, Ganetzky B . A Glial-neuronal signaling pathway revealed by mutations in a neurexin-related protein Science 1999; 283: 1343–1345

    CAS  PubMed  Google Scholar 

  100. Baumann H, Gauldie J . The acute phase response Immunol Today 1994; 15: 74–80

    CAS  PubMed  Google Scholar 

  101. Arzt E, Stalla GK . Cytokines: autocrine and paracrine roles in the anterior pituitary Neuroimmunomodulation 1996; 3: 28–34

    CAS  PubMed  Google Scholar 

  102. Vitkovic L, Chatham JJ, da Cunha A . Distinct expressions of three cytokines by IL-1-stimulated astrocytes in vitro and in AIDS brain Brain Behav Immun 1995; 9: 378–388

    CAS  PubMed  Google Scholar 

  103. Plata-Salaman CR, Ilyin SE . Interleukin-1beta (IL-1beta)-induced modulation of the hypothalamic IL-1beta system, tumor necrosis factor-alpha, and transforming growth factor-betal mRNAs in obese (fa/fa) and lean (Fa/Fa) Zucker rats: implications to IL-1beta feedback systems and cytokine-cytokine interactions J Neurosci Res 1997; 49: 541–550

    CAS  PubMed  Google Scholar 

  104. Chai Z, Gatti S, Toniatti C, Poli V, Bartfai T . Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1 beta: a study on IL-6-deficient mice J Exp Med 1996; 183: 311–316

    CAS  PubMed  Google Scholar 

  105. Kluger MJ, Kozak W, Leon LR, Soszynski D, Conn CA . Fever and antipyresis Prog Brain Res 1998; 115: 465–475

    CAS  PubMed  Google Scholar 

  106. Murakami N, Sakata Y, Watanabe T . Central action sites of interleukin-1 beta for inducing fever in rabbits J Physiol (Lond) 1990; 428: 299–312

    CAS  Google Scholar 

  107. Dinarello CA, Cannon JG, Mancilla J, Bishai I, Lees J, Coceani F . Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells Brain Res 1991; 562: 199–206

    CAS  PubMed  Google Scholar 

  108. Rothwell NJ, Busbridge NJ, Lefeuvre RA, Hardwick AJ, Gauldie J, Hopkins SJ . Interleukin-6 is a centrally acting endogenous pyrogen in the rat Can J Physiol Pharmacol 1991; 69: 1465–1469

    CAS  PubMed  Google Scholar 

  109. Cao C, Matsumura K, Yamagata K, Watanabe Y . Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in the febrile response Brain Res 1995; 697: 187–196

    CAS  PubMed  Google Scholar 

  110. Breder CD, Saper CB . Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide Brain Res 1996; 713: 64–69

    CAS  PubMed  Google Scholar 

  111. Elmquist JK, Breder CD, Sherin JE et al. Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages J Comp Neurol 1997; 381: 119–129

    CAS  PubMed  Google Scholar 

  112. Quan N, Whiteside M, Herkenham M . Time course and localization patterns of interleukin-1beta messenger RNA expression in brain and pituitary after peripheral administration of lipopolysaccharide Neuroscience 1998; 83: 281–293

    CAS  PubMed  Google Scholar 

  113. Hashimoto M, Bando T, Iriki M, Hashimoto K . Effect of indomethacin on febrile response to recombinant human interleukin 1-alpha in rabbits Am J Physiol 1988; 255: R527–R533

    CAS  PubMed  Google Scholar 

  114. Scammell TE, Elmquist JK, Saper CB . Inhibition of nitric oxide synthase produces hypothermia and depresses lipopolysacharide fever Am J Physiol 1996; 271: R333–R338

    CAS  PubMed  Google Scholar 

  115. Cao C, Matsumura K, Yamagata K, Watanabe Y . Involvement of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA by LPS in the rat brain Am J Physiol 1997; 272: R1712–R1725

    CAS  PubMed  Google Scholar 

  116. Lacroix S, Rivest S . Functional circuitry in the brain of immune-challenged rats: partial involvement of prostaglandins J Comp Neurol 1997; 387: 307–324

    CAS  PubMed  Google Scholar 

  117. Scammell T, Gerashchenko D, Urade Y, Onoe H, Saper C, Hayaishi O . Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2 Proc Natl Acad Sci USA 1998; 95: 7754–7759

    CAS  PubMed  Google Scholar 

  118. Krueger JM, Fang J, Taishi P, Chen Z, Kushikata T, Gardi J . Sleep. A physiologic role for IL-1 beta and TNF-alpha Ann NY Acad Sci 1998; 856: 148–159

    CAS  PubMed  Google Scholar 

  119. Sheng JG, Ito K, Skinner RD et al. In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis Neurobiol Aging 1996; 17: 761–766

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Mogi M, Harada M, Kondo T et al. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients Neurosci Lett 1994; 180: 147–150

    CAS  PubMed  Google Scholar 

  121. Merrill JE, Benveniste EN . Cytokines in inflammatory brain lesions: helpful and harmful Trends Neurosci 1996; 19: 331–338

    CAS  PubMed  Google Scholar 

  122. Barone F, Arvin B, White B et al. Tumor necrosis factor alpha. A mediator of focal ischemic brain injury Stroke 1997; 28: 1233–1244

    CAS  PubMed  Google Scholar 

  123. Feueurstein G, Liu T, Barone F . Cytokines, inflammation and brain injury: role of TNF alpha Cerebrovasc Brain Metab Rev 1994; 6: 341–360

    Google Scholar 

Download references

Acknowledgements

We thank E Kandel for commenting on an earlier version of this manuscript, JL Tchélingérian and F Le Saux for contributions to Figure 1 and M Passama for producing the figures. LV was a Professor of the French Academy of Sciences, Chair ELF Aquitaine while this work was done. He thanks ELF Aquitaine for support. This work was also supported by the French Foundation for Medical Research (EP001195/01 to LV), European community (BIOMED 2, CT97–2492 and TMR, CT-97-0142 to RD), French Association Against Cancer (9781 to JB), INSERM and ARSEP (to CJ).

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Vitkovic, L., Konsman, J., Bockaert, J. et al. Cytokine signals propagate through the brain. Mol Psychiatry 5, 604–615 (2000). https://doi.org/10.1038/sj.mp.4000813

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  • DOI: https://doi.org/10.1038/sj.mp.4000813

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