Abstract
The proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) influence neuroendocrine activity, promote central neurotransmitter alterations, and induce a constellation of symptoms collectively referred to as sickness behaviors. These cytokines may also elicit anxiety and anhedonia, and have been associated with psychological disturbances in humans. In the present investigation, systemic IL-1β and TNF-α dose-dependently and synergistically disrupted consumption of a highly palatable food source (chocolate milk), possibly reflecting anorexia or anhedonia engendered by the treatments. As well, these cytokines synergistically increased plasma corticosterone levels. Although IL-1β and TNF-α provoked variations of amine turnover in the hypothalamus, locus coeruleus, and central amygdala, synergistic effects were not evident in this respect. Nevertheless, in view of the central amine variations induced by the cytokines, it is suggested that immune activation may come to influence complex behavioral processes, as well as affective state.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Abercrombie ED, Jacobs BL . (1987): Single-unit response of noradrenergic neurons in the locus coeruleus of freely moving cats. I. Acutely presented stressful and nonstressful stimuli. J Neurosci 9: 2837–2843
Alonso R, Chaudieu I, Diorio J, Krishnamurthy A, Quirion R, Boksa P . (1993): Interleukin-2 modulates evoked release of [3H]dopamine in rat cultured mesencephalic cells. J Neurochem 61: 1284–1290
Anisman H, Merali Z . (1999): Cytokines and stress in relation to anxiety and anhedonia. In Dantzer R, Wollman EE, Yirmiya R (eds), Cytokines, Stress and Depression. New York, Plenum Press
Anisman H, Ravindran AV, Griffiths J, Merali Z . (1998): Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features. Mol Psychiatry 4: 182–188
Berenbaum MC . (1989): What is synergy? Pharmacol Rev 41: 93–141
Blalock JE . (1994): The syntax of immune-neuroendocrine communication. Immunol Today 15: 504–511
Bluthe RM, Dantzer R, Kelley KW . (1992): Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in the rat. Brain Res 575: 318–320
Bluthe RM, Pawlowski M, Suarez S, Parnet P, Pittman Q, Kelley KW, Dantzer R . (1994): Synergy between tumor necrosis factor-α and interleukin-1 in the induction of sickness behavior in mice. Psychoneuroendocrinology 19: 197–207
Borowski T, Kokkinidis L, Merali Z, Anisman H . (1998): Lipopolysaccharide, central in vivo amine alterations, and anhedonia. NeuroReport 9: 3797–3802
Brouckaert PG, Everaerdt B, Libert C, Takahashi N, Fiers W . (1989a): Species specificity and involvement of other cytokines in endotoxin shockaction of recombinant tumor necrosis factor in mice. Agents Actions 26: 196–198
Brouckaert PG, Libert C, Everaerdt B, Takahashi N, Fiers W . (1989b): A role for interleukin-1 in the in vivo actions of tumor necrosis factor. Lymphok Res 8: 269–274
Capuron L, Ravaud A, Radat F, Dantzer R, Goodall G . (1998): Affects of interleukin-2 and alpha-interferon cytokine immunotherapy on the mood and cognitive performance of cancer patients. Neuroimmunomodulation 5: 9
Caraceni A, Martini C, Belli F, Mascheroni L, Rivoltini L, Arienti F, Cascinelli N . (1992): Neuropsychological and neurophysiological assessment of the central effects of interleukin-2 administration. Eur J Cancer 29: A: 1266–1269
Chiueh CC, Zukowska-Grojec Z, Kirk KL, Kopin JJ . (1983): 6-fluorocatechaolamine as a false adrenergic neurotransmitter. J Pharmac Exp Ther 225: 529–533
Connor TJ, Song C, Leonard BE, Merali Z, Anisman H . (1998): An assessment of the effects of central interleukin-1β, -2, -6 and tumor necrosis factor-α administration on some behavioral, neurochemical, endocrine and immune parameters in the rat. Neuroscience 84: 923–933
Cunningham ET Jr, Sawchenko PE . (1988): Anatomical specificity of noradrenergic inputs to the paraventricular and supraoptic nuclei of the rat hypothalamus. J Comp Neurol 274: 60–76
Dantzer R, Bluthe RM, Auber A, Goodall G, Bret-Dibat JL, Kent S, Goujon E, Laye S, Parnet P, Kelley KW . (1996): Cytokine actions on behavior. In Rothwell NJ (ed), Cytokines and the Nervous System. London, Landes, pp 117–144
Denicoff KD, Rubinow DR, Papa MZ, Simpson L, Seipp LA, Lotze MT, Chang AE, Rosenstein D, Rosenberg SA . (1987): The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann Int Med 107: 293–300
Dinan T . (1996): Serotonin and the regulation of hypothalamic-pituitary-adrenal axis function. Life Sci 58: 1683–1694
Dunn AJ . (1988): Systemic interleukin-1 administration stimulates hypothalamic norepinephrine metabolism paralleling the increased plasma corticosterone. Life Sci 43: 429–435
Dunn AJ . (1990): Interleukin-1 as a stimulator of hormone secretion. Prog Neurol Endocrinol Immunol 3: 26–34
Dunn AJ . (1992a): The role of interleukin-1 and tumor necrosis factor alpha in the neurochemical and neuroendocrine responses to endotoxin. Brain Res Bull 6: 807–812
Dunn AJ . (1992b): Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: Comparison with interleukin-1. J Pharmac Exp Ther 261: 964–969
Ebisui O, Fukata J, Murakami N, Kobayashi H, Segawa H, Muro S, Hanaoka I, Naito Y, Masui Y, Ohmoto Y, Imura H, Nakao K . (1994): Effect of IL-1 receptor antagonist and antiserum to TNF-α on LPS-induced plasma ACTH and corticosterone rise in rats. Am J Physiol 266: E986–E992
Elenkov IJ, Kovacs K, Duda E, Stark E, Vizi ES . (1992): Presynaptic inhibitory effect of TNF-alpha on the release of noradrenaline in isolated median eminence. J Neuroimmunol 41: 117–120
Everaerdt B, Brouckaert PG, Shaw A, Fiers W . (1989): Four different interleukin-1 species sensitize to the lethal action of tumor necrosis factor. Biochem Biophys Res Commun 163: 378–385
Feldman S, Conforti N, Melamed E . (1987): Paraventricular nucleus serotonin mediates neurally stimulated adrenocortical secretion. Brain Res Bull 18: 165–168
Franklin KBJ, Paxinos G . (1997): The Mouse Brain in Stereotaxic Coordinates. San Diego, Plenum
Gann DS, Ward DG, Baertschi AJ, Carlson DE, Maran JW . (1977): Neural control of ACTH release in response to hemorrage. Ann NY Acad Sci 297: 477–497
Gayle D, Ilyin SE, Miele ME, Plata-Salaman C . (1998): Modulation of TNF-alpha mRNA production in rat C6 glioma cells by TNF-alpha, IL-1beta, IL-6, and IFN-alpha: In vitro analysis of cytokine-cytokine interactions. Brain Res Bull 47: 231–235
Hayley S, Brebner K, Lacosta S, Merali Z, Anisman H . (1999): Sensitization to the effects of tumor necrosis factor-α; Neuroendocrine, central monoamine and behavioral variations. J Neurosci 19: 5654–5665
Herman JP, Cullinan WE . (1997): Neurocircuitry of stress: Central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20: 78–84
Hopkins SJ, Rothwell NJ . (1995): Cytokines and the nervous system. I. Expression and recognition. Trends Neurosci 18: 83–88
Ignatowski TA, Spengler RN . (1994): Tumor necrosis factor-α: Presynaptic sensitivity is modified after antidepressant drug administration. Brain Res 665: 293–299
Jeohn GH, Kong LY, Wilson B, Hudson P, Hong JS . (1998): Syergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures. J Neuroimmunol 85: 1–10
Johnson RW, Propes MJ, Shavit Y . (1996): Corticosterone modulates behavioral and metabolic effects of lipopolysaccharide. Am J Physiol 270: R192–R198
Kakucksa I, Qi Y, Clark BD, Lechan RM . (1993): Endotoxin-induced corticotropin-releasing hormone gene expression in the paraventricular nucleus is mediated by interleukin-1. Endocrinology 133: 815–821
Kent S, Bret-Dibat JL, Kelley KW, Dantzer R . (1996): Mechanisms of sickness induced decreases in food-motivated behavior. Neurosci Biobehav Rev 20: 171–175
Korte SM, Van Dunn S, Bouws GA, Koolhaas JM, Bohus B . (1991): Involvement of hypothalamic serotonin in activation of the sympathoadrenomedullary system hypothalamo-pituitary-adrenocortical axis in male wistar rats. Eur J Pharmacol 197: 225–228
Kuemmerle JF . (1998): Synergistic regulation of NOS II expression by IL-1 beta and TNF-alpha in cultured rat colonic smooth muscle cells. Am J Physiol 274: G178–G185
Lacosta S, Merali Z, Anisman H . (1999): Behavioral and neurochemical consequences of lipopolysaccharide in mice: Anxiogenic-like effects. Brain Res 818: 291–303
Lacosta S, Merali Z, Anisman H . (1998): Influence of interleukin-1beta on exploratory behaviors, plasma ACTH, corticosterone, and central biogenic amines in mice. Psychopharmacology 137: 351–361
Lapchak PA . (1992): A role for IL-2 in the regulation of striatal dopaminergic function. NeuroReport 3: 165–168
Linthorst AC, Reul JM . (1998): Brain neurotransmission during peripheral inflammation. Ann NY Acad Sci 840: 139–152
Linthorst ACE, Flachskamm C, Muller-Preuss P, Holsboer F, Reul JMHM . (1995): Effect of bacterial endotoxin and interleukin-1β on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: An in vivo microdialysis study. J Neurosci 15: 2920–2934
Long NC, Otterness I, Kunkel SL, Vander AJ, Kluger MJ . (1990): Roles of inteleukin-1β and tumor necrosis factor in lipopolysaccharide fever in rats. Am J Physiol 259: R724–R728
Lu G, Beuerman RW, Zhao S, Sun G, Nguyen DH, Ma S, Kline DG . (1997): Tumor necrosis factor-alpha and interleukin-1 induce activation of MAP kinase and SAP kinase in human nueroma fibroblasts. Neurochem Intl 30: 401–410
Maes M . (1995): Evidence for an immune response in major depression: A review and hypothesis. Prog Neuro-Psychopharmacol Biol Psychiatry 19: 11–38
Maes M, Meltzer HY, Bosmans E, Bergmans R, Vandoolaeghe E, Ranjan R, Desnyder R . (1995): Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 34: 301–309
Maier SF, Watkins LR . (1998): Cytokines for psychologists: Implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 105: 83–107
Masana MI, Heyes MP, Mefford IN . (1990): Indomethacin prevents increased catecholamine turnover in rat brain following systemic endotoxin challenge. Prog Neuro-Psychopharmacol Biol Psychiatry 14: 609–621
Matta SG, Weatherbee J, Sharp BM . (1992): A central mechanism is involved in the secretion of ACTH in response to IL-6 in rats: Comparison to and interaction with IL-1β. Neuroendocrinology 56: 516–525
Mefford IN, Masters CF, Heyes MP, Eskay RL . (1991): Cytokine-induced activation of the neuroendocrine stress axis persists in endotoxin-tolerant mice. Brain Res 557: 327–330
Merali Z, Lacosta S, Anisman H . (1997): Effects of interleukin-1beta and mild stress on alterations of norepinephrine, dopamine and serotonin neurotransmission: A regional microdialysis study. Brain Res 761: 225–235
Meyers CA, Valentine AD . (1995): Neurological and psychiatric adverse effects of immunological therapy. CNS Drugs 3: 56–68
Mino T, Sugiyama E, Taki H, Kuroda A, Yamashita N, Maruyama M, Kobayashi M . (1998): Interleukin-1alpha and tumor necrosis factor alpha syergistically stimulate prostaglandin E2-dependent production of interleukin-11 in rheumatoid synovial fibroblasts. Arthritis Rheum 41: 2004–2013
Muller N, Ackenheil M . (1998): Psychoneuroimmunology and the cytokine action in the CNS: Implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 22: 1–33
O'Reilly B, Vander AJ, Kluger MJ . (1987): Effects of chronic infusion of lipopolysaccharide on food intake and body temperature of the rat. Physiol Behav 42: 287–291
Palazzolo DL, Quadri SK . (1992): Interleukin-1 inhibits serotonin release from the hypothalamus in vitro. Life Sci 51: 1797–1802
Perlstein RS, Moughey EH, Jackson WE, Neta R . (1991): Interleukin-1 and interleukin-6 act synergistically to stimulate the release of adrenocorticotropic hormone in vivo. Lymphok Cytok Res 10: 141–146
Plata-Salaman CR . (1988): Food intake suppression by imunomodulators. Neurosci Res Comm 3: 159–165
Plata-Salaman CR, Oomura Y, Kai Y . (1988): Tumor necrosis factor and interleukin-1β: Suppression of food intake by direct action in the central nervous system. Brain Res 448: 106–114
Plata-Salaman CR, Sonti G, Borkoski JP, Wilson CD, Ffrench-Mullen JMH . (1996): Anorexia induced by chronic central administration of cytokines at estimated pathophysiological concentrations. Physiol Behav 60: 867–875
Rivier C . (1993): Effect of perhiperal and central cytokines on the hypothalamic-pituitary-adrenal axis of the rat. Ann NY Acad Sci 697: 97–105
Rothwell NJ, Allan S, Toulmond S . (1997): The role of interleukin-1 in acute neurodegeneration and stroke: pathophysiological and therapeutic implications. J Clin Invest 100: 2648–2652
Seegal RF, Bosh KO, Bush B . (1986): High performance liquid chromatography of biogenic amines and metabolites in the brain, cerebrospinal fluid, urine and plasma. J Chromatogr 377: 131–144
Shintani F, Kanba S, Nakaki T, Nibuya M, Kinoshita N, Suzuki E, Yagi G, Kato R, Asai M . (1993): Interleukin-1β augments release of norepinephrine, dopamine and serotonin in the rat anterior hypothalamus. J Neurosci 13: 3574–3581
Shintani F, Nakaki T, Kanba S, Sato K, Yagi G, Shiozawa M, Asio S, Kato R, Asai M . (1995): Involvement of interleukin-1 immobilization stress-induced increase in adrenocorticotropic hormone and in the release of hypothalamic monoamines in the rat. J Neurosci 15: 1961–1970
Song C, Merali Z, Anisman H . (1999): Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment. Neuroscience 88: 823–836
Sonti G, Ilyin SE, Plata-Salaman C . (1996): Anorexia induced by cytokine interactions at pathophysiological concentrations. Am J Physiol 270: R1394–R1402
Terao A, Oikawa M, Saito M . (1993): Cytokine-induced change in hypothalamic norepinephrine turnover: Involvement of corticotropin-releasing hormone and prostaglandins. Brain Res 622: 257–261
Tilders JJH, DeRijk RH, Van Dam AM, Vincent VAM, Schotanus K, Persoons JHA . (1993): Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: Routes and intermediate signals. Psychoneuroendocrinology 19: 209–232
Van der Meer MJM, Sweep CGJF, Pesman GJ, Borm GF, Hermus RMM . (1995): Synergism between IL-1β and TNF-α on the activity of the pituitary adrenal axis and on food intake of rats. Am J Physiol 268: E551–E557
Vogel SN, Henricson BE, Neta R . (1991): Roles of interleukin and tumor necrosis factor in lipopolysaccharide-induced hypoglycemia. Brain Behav Immun 59: 2494–2498
Wang J, Dunn AJ . (1999): The role of interleukin-6 in the activation of the hypothalamo-pituitary-adrenocortical axis and brain indoleamines by endotoxin and interleukin-1 beta. Brain Res 815: 237–248
Weiss JM . (1991): Stress induced depression: Critical neurochemical and electrophysiological changes. In Madden J (ed), Neurobiology of Learning, Emotion and Affect. New York, Raven Press
Whitnall MH . (1993): Regulation of the hypothalamic corticotropin-releasing hormone neurosecretory system. Prog Neurobiol 40: 573–629
Yang Z, Koseki M, Meguid MM, Gleason JR, Debonis D . (1994): Synergistic effect of rhTNF-α and rhIL-1α in inducing anorexia in rats. Am J Physiol 267: R1056–R1064
Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, Greenberg A . (1994): Cytokine-specific central monoamine alterations induced by interleukin (IL)-1, IL-2 and IL-6. Brain Res 643: 40–49
Zanetti G, Heusmann D, Gerain J, Kohler J, Abbet P, Barras C, Lucas R, Glauser M, Baumgartner J . (1992): Cytokine production after intravenous or peritoneal gram negative bacterial challenge in mice. J Immunol 6: 1890–1897
Zhou D, Shanks N, Riechman SE, Liang R, Kusnecov AW, Rabin BS . (1996): Interleukin 6 modulates interleukin-1 and stress-induced activation of the hypothalamic-pituitary-adrenal axis in male rats. Neuroendocrinology 63: 227–236
Acknowledgements
Supported by a grant in aid of research from the Medical Research Council of Canada. H.A. is an Ontario Mental Health Senior Research Fellow. The assistance of Jerzy Kulczycki is very much appreciated.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brebner, K., Hayley, S., Zacharko, R. et al. Synergistic Effects of Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor-α: Central Monoamine, Corticosterone, and Behavioral Variations. Neuropsychopharmacol 22, 566–580 (2000). https://doi.org/10.1016/S0893-133X(99)00166-9
Received:
Revised:
Accepted:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(99)00166-9
Keywords
This article is cited by
-
Defensive responses: behaviour, the brain and the body
Nature Reviews Neuroscience (2023)
-
Leucine-rich repeat kinase-2 (LRRK2) modulates paraquat-induced inflammatory sickness and stress phenotype
Journal of Neuroinflammation (2019)
-
Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI
Scientific Reports (2016)
-
Cerebrospinal fluid levels of IL-6 are decreased and correlate with cognitive status in DLB patients
Alzheimer's Research & Therapy (2015)
-
A requirement of serotonergic p38α mitogen-activated protein kinase for peripheral immune system activation of CNS serotonin uptake and serotonin-linked behaviors
Translational Psychiatry (2015)


