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Cytokine Polymorphisms in the Pathophysiology of Mood Disorders

Published online by Cambridge University Press:  07 November 2014

Mario Clerici ,
Beatrice Arosio ,
Emanuela Mundo ,
Elisabetta Cattaneo ,
Sara Pozzoli ,
Bernardo Dell'Osso ,
Carlo Vergani ,
Daria Trabattoni  and
A. Carlo Altamura
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Abstract

Introduction: An increasing amount of data suggests that dysregulation of the immune system, including the cytokine network, is associated with the etiology and pathophysiology of mood disorders. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. The aim of this study was to define the genetic immunologic scenario associated with major depressive disorder (MDD) and bipolar disorder.

Methods: Eighty-four Italian outpatients affected by bipolar disorder type I, bipolar disorder type II, or MDD, and 363 healthy controls were enrolled into the study. We analyzed allele and genotype distribution of −308 (G/A) tumor necrosis factor-α (TNF-α), +874 (T/A) interferon-γ (IFN-γ), -174 (G/C) interleukin (IL)-6, and −1082 (G/A) IL-10 promoter polymorphisms by Polymerase Chain Reaction Sequence Specific Primers technique.

Results: We observed different genotype and allele distributions of TNF-α, IFN-γ, and IL-10 polymorphisms in the three groups of patients analyzed. In particular, bipolar II patients were characterized by an absence of adenine (A) high producer allele of TNF-α (P<.001) and a lower percentage of TT high producer genotype of IFN-γ (P <.001); bipolar I individuals showed reduced percentage of AA low producer genotype of IL-10 (P<.001). Both bipolar I and bipolar II patients not carrying guanine (G) high producer IL-6 allele showed a lower mean age at onset (P=.048).

Conclusion: These data support the existence of a genetic profile related to pro-inflammatory cytokines in patients affected by mood disorders. The differences observed across the three clinical phenotypes suggest the presence of different pathogenetic mechanisms involved in the susceptibility of phenotypically different mood disorders.

Type
Original Research
Information
CNS Spectrums , Volume 14 , Issue 8 , August 2009 , pp. 419 - 425
Copyright
Copyright © Cambridge University Press 2009

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References

REFERENCES

1.Kronfol, Z, Remick, DG. Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry. 2000;157:683–694.Google Scholar
2.Kim, YK, Na, KS, Shin, KH, Jung, HY, Choi, SH, Kim, JB. Cytokine imbalance in the pathophysiology of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1044–1053.CrossRefGoogle ScholarPubMed
3.Altamura, AC, Boin, F, Maes, M. HPA axis and cytokines dysregulation in schizophrenia: Potential implications for the antipsychotics treatment. Eur Neuropsychopharmacol. 1999;10:1–4.Google Scholar
4.Müller, N, Riedel, M, Ackenheil, M, Schwarz, MJ. The role of immune function in schizophrenia: An overview. Eur Arch of Psychiatry Clin Neurosci. 1999;249(Suppl 4):62–68.Google Scholar
5.Kim, YK, Paik, JW, Lee, SW, Yoon, D, Han, C, Lee, BH. Increased plasma nitric oxide level associated with suicide attempt in depressive patients. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1091–1096.Google Scholar
6.Pace, TW, Mletzko, TC, Alagbe, O, et al.Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630–1633.Google Scholar
7.Watkins, LR, Maier, SF, Goehler, LE. Cytokine-to-brain communication: a review and analysis of alternative mechanisms. Life Sci. 1995;57:1011–1026.CrossRefGoogle ScholarPubMed
8.Banks, WA. Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des. 2005;11:973–984.CrossRefGoogle ScholarPubMed
9.Brebner, K, Hayley, S, Zacharko, R, Merali, Z, Anisman, H. Synergistic effects of interleukin-1beta, interleukin-6, and tumour necrosis factor-alpha: central monoamine, corticosterone, and behavioral variations. Neuropsychopharmacology. 2000;22:566–580.Google Scholar
10.McCarthy, DO, Kluger, MJ, Vander, AJ. The role of fever in appetite suppression after endotoxin administration. Am J Clin Nutr. 1984;40:310–316.CrossRefGoogle ScholarPubMed
11.Bluthé, RM, Pawlowski, M, Suarez, S, et al.Synergy between tumour necrosis factor alpha and interleukin-1 in the induction of sickness behaviour in mice. Psychoneuroen docrinology. 1994;19:197–207.Google Scholar
12.Swiergiel, AH, Smagin, GN, Johnson, LJ, Dunn, AJ. The role of cytokines in the behavioral responses to endotoxin and influenza virus infection in mice: effects of acute and chronic administration of the interleukin-1 receptor antagonist (IL-1ra). Brain Res. 1997;776:96–104.Google Scholar
13.Layé, S, Gheusi, 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.Google Scholar
14.Dantzer, R. Cytokine-induced sickness behavior: mechanisms and implications. Ann N Y Acad Sci. 2001;933:222–234.Google Scholar
15.Dunn, AJ, Swiergiel, AH, de Beaurepaire, R. Cytokines as mediators of depression: what can we learn from animal studies? Neurosci Biobehav Rev. 2005;29:891–909.Google Scholar
16.Schiepers, OJ, Wichers, MC, Maes, M. Cytokines and major depression. Progr Neuropsychopharmacol Biol Psychiatry. 2005;29:201–217.Google Scholar
17.Song, C, Dinan, T, Leonard, BE. Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls. J Affect Disord. 1994;30:283–288.CrossRefGoogle ScholarPubMed
18.Maes, M. Major depression and activation of the inflammatory response system. Adv Exp Med Biol. 1999;461:25–46.Google Scholar
19.Levine, J, Barak, Y, Chengappa, KN, Rapoport, A, Rebey, M, Barak, V. Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology. 1999;40:171–176.Google Scholar
20.Lanquillon, S, Krieg, JC, Bening-Abu-Shach, U, Vedder, H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology. 2000;22:370–379.Google Scholar
21.Wilson, AG, Symons, JA, McDowell, TL, McDevitt, HO, Duff, GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA. 1997;94:3195–3199.Google Scholar
22.Hayden, C, Pereira, E, Rye, P, et al.Mutation screening of interferon-gamma (IFNgamma) as a candidate gene for asthma. Clin Exp Allergy. 1997;27:1412–1416.Google Scholar
23.Khani-Hanjani, A, Lacaille, D, Hoar, D, et al.Association between dinucleotide repeat in non-coding region of interferon-gamma gene and susceptibility to, and severity of, rheumatoid arthritis. Lancet. 2000;356:820–825.Google Scholar
24.Pravica, V, Perrey, C, Stevens, A, Lee, JH, Hutchinson, IV. A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol. 2000;61:863–866.Google Scholar
25.Lee, JY, Goldman, D, Piliero, LM, Petri, M, Sullivan, KE. Interferon-gamma polymorphisms in systemic lupus erythematosus. Genes Immun. 2001;2:254–257.CrossRefGoogle ScholarPubMed
26.Bream, JH, Carrington, M, O'Toole, S, et al.Polymorphisms of the human IFNG gene noncoding regions. Immunogenetics. 2000;51:50–58.CrossRefGoogle ScholarPubMed
27.Dabora, SL, Roberts, P, Nieto, A, et al.Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patients. Am J Hum Genet. 2002;71:750–758.Google Scholar
28.Daher, S, Shulzhenko, N, Morgun, A, et al.Associations between cytokine gene polymorphisms and recurrent pregnancy loss. J Reprod Immunol. 2003;58:69–77.Google Scholar
29.Yasukawa, K, Hirano, T, Watanabe, Y, et al.Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J. 1987;6:2939–2945.Google Scholar
30.Bowcock, AM, Kidd, JR, Lathrop, GM, et al.The human “interferon-beta 2/hepatocyte stimulating factor/interleukin-6” gene: DNA polymorphism studies and localization to chromosome 7p21. Genomics. 1988;3:8–16.CrossRefGoogle ScholarPubMed
31.Fishman, D, Faulds, G, Jeffery, R, et al.The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102:1369–1376.Google Scholar
32.Terry, CF, Loukaci-V, , Green, FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275:18138–18144.Google Scholar
33.Kilpinen, S, Hulkkonen, J, Wang, XY, Hurme, M. The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults. Eur Cytokine Netw. 2001;12:62–68.Google Scholar
34.Kim, JM, Brannan, CI, Copeland, NG, Jenkins, NA, Khan, TA, Moore, KW. Structure of the mouse IL-10 gene and chromosomal localization of the mouse and human genes. J Immunol. 1992;148:3618–3623.CrossRefGoogle ScholarPubMed
35.First, MB, Spitzer, RL, Gibbon, M, Williams, JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). New York State Psychiatric Institute, New York, NY, 2002.Google Scholar
36.Poli, F, Nocco, A, Berra, S, et al.Allele frequencies of polymorphisms of TNFA, IL-6, IL-10 and IFNG in an Italian Caucasian population. Eur J Immunogenet. 2002;29:237–240.Google Scholar
37.Miller, SA, Dykes, DD, Polesky, HFA. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.Google Scholar
38.Arosio, B, Trabattoni, D, Galimberti, L, et al.Interleukin-10 and interelukin-6 gene polymorphisms as risk factors for Alzheimer's disease. Neurobiol Aging. 2004;25:1009–1015.Google Scholar
39.Yu, YW, Chen, TJ, Hong, CJ, Chen, HM, Tsai, SJ. Association study of the interleukin-1 beta (C-511T) genetic polymorphism with major depressive disorder, associated symptomatology and antidepressant response. Neuropsychopharmacology. 2003;28:1182–1185.Google Scholar
40.Reichenberg, A, Yirmiya, R, Schuld, A, et al.Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445–452.Google Scholar
41.Maes, M, Bosmans, E, Calabrese, J, Smith, R, Meltzer, HY. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res. 1995;29:141–152.Google Scholar
42.Berk, M, Wadee, AA, Kuschke, RH, O'Neill-Kerr, A. Acute phase proteins in major depression. J Psychosom Res. 1997;43:529–534.Google Scholar
43.Musselman, DL, Miller, AH, Porter, MR, et al.Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am J Psychiatry. 2001;158:1252–1257.Google Scholar
44.Liu, HC, Yang, YY, Chou, YM, Chen, KP, Shen, WW, Leu, SJ. Immunologic variables in acute mania of bipolar disorder. J Neuroimmunol. 2004;150:116–122.Google Scholar
45.Konarski, JZ, McIntyre, RS, Kennedy, SH, Rafi-Tari, S, Soczynska, JK, Ketter, TA. Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disord. 2008;10:1–37.Google Scholar