Imbalance between Pro- and Anti-inflammatory Cytokines, and between Th1 and Th2 Cytokines in Depressed Patients: The Effect of Electroacupuncture or Fluoxetine Treatment

Abstract

Background: An increase in inflammatory response and an imbalance between T-helper (Th) 1 and 2 functions have been implicated in major depression. The aims of the present study were to 1) study the relationship between pro- and anti-inflammatory cytokines and between Th1 and Th2 produced cytokines in depressed patients and 2) evaluate and compare the effect of treatments with electroacupuncture (EA) and fluoxetine on these cytokines.

Methods: 95 outpatients with major depressive disorder were treated for 6 weeks with EA, fluoxetine or placebo. Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression (CGI) were used to assess severity and therapeutic effects. 30 volunteers served as controls. Serum cytokine concentrations were measured by ELISA.

Results: Increased proinflammatory cytokine interleukin (IL)-1β and decreased anti-inflammatory cytokine IL-10 were found in the depressed patients. By contract, Th1 produced proinflammatory cytokines, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were decreased, and Th2 produced cytokine IL-4 was significantly increased in depressed patients. The ratio of IFN/IL-4 was also increased. Both acupuncture and fluoxetine treatments, but not the placebo, reduced IL-1β concentrations in responders. However, only acupuncture attenuated TNF-α concentration and INF-γ/IL-4 ratio towards the control level.

Discussion: These results suggest that an imbalance between the pro- and anti-inflammatory cytokines (IL-1 and IL-10), and between Th1 and Th2 cytokines (INF-γ or TNF-α and IL-4) occurred in untreated depressed patients. Both EA and fluoxetine had an anti-inflammatory effect by reducing IL-1β. EA treatment also restored the balance between Th1 and Th2 systems by increasing TNF-α and decreasing IL-4.

References

• 1 Licinio J, Wong ML. 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. 1999;  4 317-427
• 2 Maes M, Smith R, Scharpe S. The monocyte-T-lymphocyte hypothesis of major depression.  Psychoneuroendocrinology. 1995;  20 111-116
• 3 Bry K, Teramo K, Lappalainen U. et al . Interleukin-1 receptor antagonist in the fetomaternal compartment.  Acta Paediatr. 1995;  84 233-236
• 4 Song C, Lin A, Bonaccorso S. et al . The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression.  J Affect Disord. 1998;  49 211-219
• 5 Cassidy EM, Manning D, Byrne S. et al . Acute effects of low-dose interferon-alpha on serum cortisol and plasma interleukin-6.  Psychopharmacol. 2002;  16 230-234
• 6 Hirschfeld RMA, Goodwin FK. Mood disorders.  In Textbook of Psychiatry (eds: Talbott JA, Hales RE, Yudofsky SC). Washington: American Psychiatric Press 1988
• 7 Capuron L, Ravaud A, Dantzer R. Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy.  J Clin Oncol. 2000;  18 2143-2151
• 8 Meyers CA. Mood and cognitive disorders in cancer patients receiving cytokine therapy.  Adv Exp Med Biol. 1999;  461 75-81
• 9 Maes M, Bosmans E, Suy E. et al . Depression-related disturbances in mitogen-induced lymphocyte responses and interleukin-1 beta and soluble interleukin-2 receptor production.  Acta Psychiatr Scand. 1991;  84 379-386
• 10 Fearon DT, Locksley RM. The instructive role of innate immunity in the acquired immune response.  Science. 1996;  272 50-53
• 11 Maes M, Bosmans E, Jongh R De. et al . Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression.  Cytokine. 1997;  9 853-858
• 12 Nassberger L, Traskman-Bendz L. Increased soluble interleukin-2 receptor concentrations in suicide attempters.  Acta Psychiatr Scand. 1993;  88 48-52
• 13 Connor TJ, Song C, Leonard BE. et al . An assessment of the effects of central interleukin-1beta, -2, -6, and tumor necrosis factor-alpha administration on some behavioural, neurochemical, endocrine and immune parameters in the rat.  Neuroscience. 1998;  84 923-933
• 14 Song C, Leonard BE, Horrobin DF. Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats.  Stress. 2004;  7 43-54
• 15 Hamilton A. A rating scale for depression.  J Neural Neurosurge Psychiatry. 1960;  23 56-62
• 16 Li QQ, Bever CT. Th1 cytokines stimulate RANTES chemokine secretion by human astroglial cells depending on de novo transcription.  Neurochem Res. 2001;  26 125-133
• 17 National Institute of Mental Health .CGI: Clinical Global Impression.  In: Manual 40 ECDEU Assessment Battery, Volume 2 revised edition. Guy, W.: Bonatorr (Editors), NIMH, Chevy Chase MD 1970: 21-26
• 18 Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production.  Curr Drug Targets Inflamm Allergy. 2004;  3 97-104
• 19 Schwarz MJ, Chiang S, Muller N. et al . T-helper-1 and T-helper-2 responses in psychiatric disorders.  Brain Behav Immun. 2001;  15 340-370
• 20 Pavon L, Sandoval-Lopez G, Eugenia Hernandez M. et al . Th2 cytokine response in Major Depressive Disorder patients before treatment.  J Neuroimmunol. 2006;  172 156-165
• 21 Myint AM, Leonard BE, Steinbusch HW. et al . Th1, Th2, and Th3 cytokine alterations in major depression.  J Affect Disord. 2005;  88 167-173
• 22 Ravindran AV, Griffiths J, Merali Z. et al . Lymphocyte subsets associated with major depression and dysthymia: modification by antidepressant treatment.  Psychosom Med. 1995;  57 555-563
• 23 Sluzewska A, Rybakowski JK, Laciak M. et al . Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine.  Ann N Y Acad Sci. 1995;  762 474-476
• 24 Maes M, Song C, Lin AH. et al . Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion.  Neuropsychopharmacology. 1999;  20 370-379
• 25 Xia Z, DePierre JW, Nassberger L. 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. 1996;  34 27-37
• 26 Chang FC, Tsai HY, Yu MC. et al . The central serotonergic system mediates the analgesic effect of electroacupuncture on ZUSANLI (ST36) acupoints.  J Biomed Sci. 2004;  11 179-185
• 27 Ma QP, Zhou Y, Yu YX. et al . Electroacupuncture accelerated the expression of c-fos protooncogene in serotonergic neurons of nucleus raphe dorsalis.  Int J Neurosci. 1992;  67 111-117
• 28 Song C, Chen RY. The effect of acupuncture on the uptake of [3H]-5-HT in the raphe nuclei of midbrain of adult and aging rats.  J Tsinghua University (China). 1992;  31 78-83
• 29 Yano T, Kato B, Fukuda F. et al . Alterations in the function of cerebral dopaminergic and serotonergic systems following electroacupuncture and moxibustion applications: possible correlates with their antistress and psychosomatic actions.  Neurochem Res. 2004;  29 283-293
• 30 Mendlovic S, Mozes E, Eilat E. et al . Immune activation in non-treated suicidal major depression.  Immunol Lett. 1999;  67 105-108
• 31 Brambilla F, Maggioni M. Blood levels of cytokines in elderly patients with major depressive disorder.  Acta Psychiatr Scand. 1998;  97 309-313
• 32 Natelson BH, Denny T, Zhou XD. et al . Is depression associated with immune activation?.  J Affect Disord. 1999;  53 179-184
• 33 Owen BM, Eccleston D, Ferrier IN. et al . Raised levels of plasma interleukin-1beta in major and postviral depression.  Acta Psychiatr Scand. 2001;  103 226-228
• 34 Schlatter J, Ortuno F, Cervera-Enguix S. Monocytic parameters in patients with dysthymia versus major depression.  J Affect Disord. 2004;  78 243-247
• 35 Hestad KA, Tonseth S, Stoen CD. et al . Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy.  J ECT. 2003;  19 183-188
• 36 Tuglu C, Kara SH, Caliyurt O. et al . Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder.  Psychopharmacology (Berl). 2003;  170 429-433
• 37 Haack M, Hinze-Selch D, Fenzel T. et al . Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis.  J Psychiatr Res. 1999;  33 407-418
• 38 Kraus T, Haack M, Schuld A. et al . Body weight, the tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine.  Pharmacopsychiatry. 2002;  35 220-225
• 39 Song C, Horrobin DF, Leonard BE. The comparison of changes in behavior, neurochemistry, endocrine, and immune functions after different routes, doses and durations of administrations of IL-1beta in rats.  Pharmacopsychiatry.. 2006;  39 88-99
• 40 Asai K, Hiki N, Mimura Y. et al . Gender differences in cytokine secretion by human peripheral blood mononuclear cells: role of estrogen in modulating LPS-induced cytokine secretion in an ex vivo septic model.  Shock. 2001;  16 340-343
• 41 Rook GA, Zumla A. Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile?.  Lancet. 1997;  349 1831-1833
• 42 Rothermundt M, Arolt V, Fenker J. et al . Different immune patterns in melancholic and non-melancholic major depression.  Eur Arch Psychiatry Clin Neurosci. 2001;  251 90-97
• 43 Kubera M, Lin AH, Kenis G. et al . Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio.  J Clin Psychopharmacol. 2001;  21 199-206
• 44 Merali Z, Brennan K, Brau P. et al . Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for “free chow” and “earned” sucrose intake.  Psychopharmacology (Berl). 2003;  165 413-418
• 45 Yaron I, Shirazi I, Judovich R. et al . Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures.  Arthritis Rheum. 1999;  4 2561-2568
• 46 Yirmiya R, Pollak Y, Barak O. et al . Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents.  Neuropsychopharmacology. 2001;  24 531-544
• 47 Fang JQ, Aoki E, Yu Y. et al . Inhibitory effect of electroacupuncture on murine collagen arthritis and its possible mechanisms.  In Vivo. 1999;  13 311-318
• 48 Jeong HJ, Hong SH, Nam YC. et al . The effect of acupuncture on proinflammatory cytokine production in patients with chronic headache: a preliminary report.  Am J Chin Med. 2003;  31 945-954
• 49 Park MB, Ko E, Ahn C. et al . Suppression of IgE production and modulation of Th1/Th2 cell response by electroacupuncture in DNP-KLH immunized mice.  J Neuroimmunol. 2004;  151 40-44
• 50 Tian L, Huang YX, Tian M. et al . Downregulation of electroacupuncture at ST36 on TNF-alpha in rats with ulcerative colitis.  World J Gastroenterol. 2003;  9 1028-1033
• 51 Xu ZF, Wu GC, Cao XD. Effect of electroacupuncture on the expression of interlukin-1beta mRNA after transient focal cerebral ischemia.  Acupunct Electrother Res. 2002;  27 29-35
• 52 Schuld A, Schmid DA, Haack M. et al . Hypothalamo-pituitary-adrenal function in patients with depressive disorders is correlated with baseline cytokine levels, but not with cytokine responses to hydrocortisone.  J Psychiatr Res. 2003;  37 463-470
• 53 Smith RS. The macrophage theory of depression.  Med Hypoth. 1991;  35 298-306
• 54 Han JS, Chen XH, Sun SL. et al . Effect of low- and high-frequency TENS on Met-enkephalin-Arg-Phe and dynorphin A immunoreactivity in human lumbar CSF.  Pain. 1991;  47 295-298
• 55 Le Bars D, Dickerson AH, Besson JM. Diffuse noxious inhibitory controls: effects on dorsal horn convergent neurons in the rat.  Pain. 1979;  6 305-327
• 56 Nickel T, Sonntag A, Backmund M. et al . Depression during therapy with interferon alpha–how long should an antidepressant treatment last?.  Pharmacopsychiatry. 2005;  38 102-104
• 57 Song Y, Zhou D, Fan J. et al . Effects of electroacupuncture and fluoxetine on the density of GTP-binding-proteins in platelet membrane in patients with major depressive disorder.  J Affect Disord. 2007;  98 253-257

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