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논문KCI 등재

사이토카인과 우울증

Cytokines and Depression

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대한생물정신의학회 (The Korean Society Of Biological Psychiatry)|2008.08|생물정신의학 (Journal of Korean Society of Biological Psychiatry)|제15권 제3호|pp. 175-185

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참고문헌

키워드

DepressionImmuneCytokineSerotoninPsychoneuroimmunologyIDO
주제분류정신과학

초록

Accumulating evidence has suggested the existence of reciprocal communication between immune, endocrine, and neurotransmitter system. Cytokine hypothesis of depression implies that increased pro-inflammatory cytokine such as -1, IL-6, IL-12, TNF-α, and IFN-γ in major depression, acting neuromodulators, play a key role in the mediation of behavioral, neuroendocrine, and neurochemical disturbances in depression. Concerning the relation between cytokines and serotonin metabolism, pro-inflammatory cytokines have profound effects on the metabolism of brain serotonin through the enzyme indoleamine-2,3-dioxygenase (IDO) that metabolizes the tryptophan, the precursor of 5-HT to neurodegenerative quinolinate and neuroprotective kynurenate. The neurodegeneration process is reinforced by the neurotoxic effect of the hypercortisolemia during depression. From this perspective, it is possible that efficacy of antidepressants in the treatment of depression may, at least in part, rely on downregulation of pro-inflammatory cytokine synthesis. So, the use of cytokine synthesis inhibitors or cytokine antagonists may be a new treatment approach in depression. However, at present the question whether cytokines play a causal role in the onset of depression or are mere epiphenomena sustaining depressive symptoms remains to be elucidated. Nevertheless, cytokine hypothesis has created new perspectives in the study of psychological and pathophysiological mechanism that are associated with major depression, as well as the prospect for developing a new generation antidepressants.

Abstract

Accumulating evidence has suggested the existence of reciprocal communication between immune, endocrine, and neurotransmitter system. Cytokine hypothesis of depression implies that increased pro-inflammatory cytokine such as -1, IL-6, IL-12, TNF-α, and IFN-γ in major depression, acting neuromodulators, play a key role in the mediation of behavioral, neuroendocrine, and neurochemical disturbances in depression. Concerning the relation between cytokines and serotonin metabolism, pro-inflammatory cytokines have profound effects on the metabolism of brain serotonin through the enzyme indoleamine-2,3-dioxygenase (IDO) that metabolizes the tryptophan, the precursor of 5-HT to neurodegenerative quinolinate and neuroprotective kynurenate. The neurodegeneration process is reinforced by the neurotoxic effect of the hypercortisolemia during depression. From this perspective, it is possible that efficacy of antidepressants in the treatment of depression may, at least in part, rely on downregulation of pro-inflammatory cytokine synthesis. So, the use of cytokine synthesis inhibitors or cytokine antagonists may be a new treatment approach in depression. However, at present the question whether cytokines play a causal role in the onset of depression or are mere epiphenomena sustaining depressive symptoms remains to be elucidated. Nevertheless, cytokine hypothesis has created new perspectives in the study of psychological and pathophysiological mechanism that are associated with major depression, as well as the prospect for developing a new generation antidepressants.

참고문헌 (79)

  1. Solomon GF., "Psychoneuroimmunology: interactions between central nervous system and immune system", J Neurosci Res, 18, pp.1~9 (1987)
  2. Ader R., "Psychoneuroimmunology: interactions between the nervous system and the immune system", Lancet, 345, pp.99~103 (1995)
  3. Cserr HF., "ervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view", Immunol Today, 13, pp.507~512 (1992)
  4. Irwin MR., "Human psychoneuroimmunology: 20 years of discover", Brain Behav Immun, 22, pp.129~139 (2008)
  5. Camara EG., "The brain and the immune system: a psychosomatic network", Psychosomatics, 30, pp.140~146 (1989)
  6. Szelenyi J., "Cytokines and the central nervous system", Brain Res Bull, 54, pp.329~338 (2001)
  7. Kim YK., "The role of cytokine network in psychological stress", Acta Neuropsychiatrica, 15, pp.148~155 (2003)
  8. Gutman DA, "Persistent central nervous system effects of an adverse early environment: clinical and preclinical studies", Physiol Behav, 79, pp.471~478 (2003)
  9. Watkins LR., "Dynamic regulation of proinflammatory cytokines", dv Exp Med Biol, 461, pp.153~178 (1999)
  10. Calogero AE., "Catecholamine effects upon rat hypothalamic corticotropin-releasing hormone secretion in vitro", J Clin Invest, 82, pp.839~846 (1988)
  11. Tracey KJ., "The inflammatory reflex", Nature, 420, pp.853~859 (2002)
  12. Lacroix S., "Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and COX-2) in the rat brain", J Neurochem, 70, pp.452~466 (1998)
  13. Wong ML., "Inducible nitric oxide synthase gene expression in the brain during systemic inflammation", Nat Med, 2, pp.581~584 (1996)
  14. Wong ML., "Localization of interleukin-1 beta converting enzyme mRNA in rat brain vasculature: evidence that the genes encoding the interleukin-1 system are constitutively expressed in brain blood vessels. Pathophysiological implications", Neuroimmunomodulation, 2, pp.141~148 (1995)
  15. Freidin M., "Cultured sympathetic neurons synthesize and release the cytokine interleukin 1 beta", Proc Natl Acad Sci U S A, 89, pp.10440~10443 (1992)
  16. Maier SF., "Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition", Psychol Rev, 105, pp.83~107 (1998)
  17. Breder CD., "Interleukin-1 immunoreactive innervation of the human hypothalamus", Science, 240, pp.321~324 (1988)
  18. Aloisi F., "Cytokine regulation of astrocyte function: in-vitro studies using cells from the human brain", Int J Dev Neurosci, 13, pp.265~274 (1995)
  19. Munoz-Fernandez MA., "The role of tumour necrosis factor, interleukin 6, interferon-gamma and inducible nitric oxide synthase in the development and pathology of the nervous system", Prog Neurobiol, 56, pp.307~340 (1998)
  20. Beattie EC., "Von Zastrow M, et al. Control of synaptic strength by glial TNFalpha", Science, 295, pp.2282~2285 (2002)
  21. Anisman H., "Cytokines, stress, and depressive illness", Brain Behav Immun, 16, pp.513~524 (2002)
  22. Rothwell NJ, "Cytokines and their receptors in the central nervous system: physiology, pharmacology, and pathology", Pharmacol Ther, 69, pp.85~95 (1996)
  23. Zalcman S., "Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6", Brain Res, 643, pp.40~49 (1994)
  24. Muller N., "Role of the cytokine network in the CNS and psychiatric disorders", Nervenarzt, 68, pp.11~20 (1997)
  25. Licinio J., "The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection", Mol Psychiatry, 4, pp.317~327 (1999)
  26. Maes M., "monocyte-T-lymphocyte hypothesis of major depression", Psychoneuroendocrinology, 20, pp.111~116 (1995)
  27. Connor TJ., "Depression, stress and immunological activation: the role of cytokines in depressive disorders", Life Sci, 62, pp.583~606 (1998)
  28. Kim YK., "The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs", Mol Psychiatry, 7, pp.1107~1114 (2002)
  29. Pollak Y., "Cytokine-induced changes in mood and behaviour: implications for 'depression due to a general medical condition', immunotherapy and antidepressive treatment", Int J Neuropsychopharmacol, 5, pp.389~399 (2002)
  30. Smith RS, "The macrophage theory of depression", Med Hypotheses, 35, pp.298~306 (1991)
  31. Maes M., "Major depression and activation of the inflammatory response system", Adv Exp Med Biol, 461, pp.25~46 (1999)
  32. Myint AM, "Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression", Med Hypotheses, 61, pp.519~525 (2003)
  33. Meyers CA, "Mood and cognitive disorders in cancer patients receiving cytokine therapy", Adv Exp Med Biol, 461, pp.75~81 (1999)
  34. Dantzer R., "Mechanisms of the behavioural effects of cytokines", Adv Exp Med Biol, 461, pp.83~105 (1999)
  35. Leonard BE., "Changes in the immune system in depression and dementia: causal or co-incidental effects?", Int J Dev Neurosci, 19, pp.305~312 (2001)
  36. Kim YK, "Differences in cytokines between non-suicidal patients and suicidal patients in major depression", Prog Neuropsychopharmacol Biol Psychiatry, 32, pp.356~361 (2008)
  37. Kim YK., "Cytokine imbalance in the pathophysiology of major depressive disorder", Prog Neuropsychopharmacol Biol Psychiatry, 31, pp.1044~1053 (2007)
  38. Myint AM, "Th1, Th2, and Th3 cytokine alterations in major depression", J Affect Disord, 88, pp.167~173 (2005)
  39. Lee KM, "The role of IL-12 and TGF-beta1 in the pathophysiology of major depressive disorder", Int Immunopharmacol, 6, pp.1298~1304 (2006)
  40. Leonard BE., "HPA and immune axes in stress: involvement of the serotonergic system", Neuroimmunomodulation, 13, pp.268~276 (2006)
  41. Sapolsky R., "Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor", Science, 238, pp.522~524 (1987)
  42. Berkenbosch F., "Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1", Science, 238, pp.524~526 (1987)
  43. Maes M., "Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression", Psychiatry Res, 49, pp.11~27 (1993)
  44. Guillemin GJ., "IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment", J Interferon Cytokine Res, 21, pp.1097~1101 (2001)
  45. Sakash JB., "Cytokines induce indoleamine 2,3-dioxygenase expression in human atheroma-asociated cells: implications for persistent Chlamydophila pneumoniae infection", Infect Immun, 70, pp.3959~3961 (2002)
  46. Neveu PJ., "Is there evidence for an effect of antidepressant drugs on immune function?", Adv Exp Med Biol, 461, pp.267~281 (1999)
  47. Maes M., "Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion", Neuropsychopharmacology, 20, pp.370~379 (1999)
  48. Xia Z., "Tricyclic antidepressants inhibit IL-6, IL-1 beta and TNF-alpha release in human blood monocytes and IL-2 and interferon-gamma in T cells", Immunopharmacology, 34, pp.27~37 (1996)
  49. Suzuki E., "Induction of interleukin-1 beta and interleukin-1 receptor antagonist mRNA by chronic treatment with various psychotropics in widespread area of rat brain", Neurosci Lett, 215, pp.201~204 (1996)
  50. Nabriski D., "Role of corticotropin-releasing factor in immunosuppression", Trans Assoc Am Physicians, 104, pp.238~247 (1991)
  51. Miller AH., "Effects of cytokines on glucocorticoid receptor expression and function", Adv Exp Med Biol, 461, pp.107~116 (1999)
  52. Schildkraut JJ., "The catecholamine hypothesis of affective disorders: a review of supporting evidence", Am J Psychiatry, 122, pp.509~522 (1965)
  53. Charney DS, "Receptor sensitivity and the mechanism of action of antidepressant treatment. Implications for the etiology and therapy of depression", Arch Gen Psychiatry, 38, pp.1160~1180 (1981)
  54. Anderson IM., "Decreased plasma tryptophan concentration in major depression: relationship to melancholia and weight loss", J Affect Disord, 20, pp.185~191 (1990)
  55. Young SN., "Pihl RO Ervin FR. Tryptophan depletion causes a rapid lowering of mood in normal males", Psychopharmacology (Berl), 87, pp.173~177 (1985)
  56. Shopsin B., "Enhancement of the antidepressant response to L-tryptophan by a liver pyrrolase inhibitor: a rational treatment approach", Neuropsychobiology, 4, pp.188~192 (1978)
  57. Kasper S., "The rationale for long-term antidepressant therapy", Int Clin Psychopharmacol, 8, pp.225~235 (1993)
  58. Edwards E., "Depression and Parkinson's disease: a new look at an old problem", Depress Anxiety, 16, pp.39~48 (2002)
  59. Whyte EM., "Post stroke depression: epidemiology, pathophysiology, and biological treatment", Biol Psychiatry, 52, pp.253~264 (2002)
  60. Stommel M., "Depression and functional status as predictors of death among cancer patients", Cancer, 94, pp.2719~2727 (2002)
  61. Watanabe Y., "Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons", Brain Res, 588, pp.341~345 (1992)
  62. Luine VN., "Steroid hormone influences on spatial memory", Ann N Y Acad Sci, 743, pp.201~211 (1994)
  63. Myint AM., "Kynurenine pathway in major depression: evidence of impaired neuroprotection", J Affect Disord, 98, pp.143~151 (2007)
  64. Leonard BE., "Changes in the immune system in rodent models of depression", Int J Neuropsychopharmacol, 5, pp.345~356 (2002)
  65. Sluzewska A., "Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine", Ann N Y Acad Sci, 762, pp.474~476 (1995)
  66. Maes M., "Increased serum interleukin-1-receptor-antagonist concentrations in major depression", J Affect Disord, 36, pp.29~36 (1995)
  67. Schiepers OJ., "Cytokines and major depression", Prog Neuropsychopharmacol Biol Psychiatry, 29, pp.201~217 (2005)
  68. Leonard BE, "The immune system, depression and the action of antidepressants", Prog Neuropsychopharmacol Biol Psychiatry, 25, pp.767~780 (2001)
  69. Castanon N., "Effects of antidepressants on cytokine production and actions", Brain Behav Immun, 16, pp.569~574 (2002)
  70. Capuron L., "Treatment of cytokine-induced depression", Brain Behav Immun, 16, pp.575~580 (2002)
  71. Maier SF., "Intracerebroventricular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock", Brain Res, 695, pp.279~282 (1995)
  72. Mansbach RS., "Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist", Eur J Pharmacol, 323, pp.21~26 (1997)
  73. Myint AM, "Effect of the COX-2 inhibitor celecoxib on behavioural and immune changes in an olfactory bulbectomised rat model of depression", Neuroimmunomodulation, 14, pp.65~71 (2007)
  74. Muller N., "The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine", Mol Psychiatry, 11, pp.680~684 (2006)
  75. Bauer J., "Induction of cytokine synthesis and fever suppresses REM sleep and improves mood in patients with major depression", Biol Psychiatry, 38, pp.611~621 (1995)
  76. de Beaurepaire R., "Questions raised by the cytokine hypothesis of depression", Brain Behav Immun, 16, pp.610~617 (2002)
  77. Weizman R., "Cytokine production in major depressed patients before and after clomipramine treatment", Biol Psychiatry, 35, pp.42~47 (1994)
  78. Maes M., "Evidence for an immune response in major depression: a review and hypothesis", Prog Neuropsychopharmacol Biol Psychiatry, 19, pp.11~38 (1995)
  79. Pollmacher T., "Low levels of circulating inflammatory cytokines--do they affect human brain functions?", Brain Behav Immun, 16, pp.525~532 (2002)

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