Pro-inflammatory Cytokines in Psychiatric Disorders in Children and Adolescents: A Review

  • Paulina MiłkowskaEmail author
  • Katarzyna Popko
  • Urszula Demkow
  • Tomasz Wolańczyk
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1021)


Cytokines are a large group of small proteins which play a significant role in cell signaling and regulate a variety of processes in organisms, including proliferation and differentiation of many cells, mediation in defense reactions and regulation of hematopoiesis. Cytokines can be divided into those with pro- and those with anti-inflammatory properties. In the group of pro-inflammatory cytokines the most important are: IL-1 beta, IL-6, TNF-alpha, and IFN-gamma. Pro-inflammatory cytokines might be involved in the pathophysiology of many psychiatric conditions in adults, but their role in children and adolescents is less clear. The aim of this article is to demonstrate the patterns of pro-inflammatory cytokines in children and adolescents.


Adolescents Anorexia nervosa Bipolar disorder Children Cytokines Depression Inflammation Posttraumatic stress disorder Psychosis 


Conflicts of Interest

The authors declare no conflicts of interest in relation to this article.


  1. Amitai M, Taler M, Carmel M, Michaelovsky E, Eilat T, Yablonski M, Orpaz N, Chen A, Apter A, Weizman A, Fennig S (2016) The relationship between plasma cytokine levels and response to selective serotonin reuptake inhibitor treatment in children and adolescents with depression and/or anxiety disorders. J Child Adolesc Psychopharmacol 26:727–732CrossRefPubMedGoogle Scholar
  2. Amminger GP, Schäfer R, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE (2010) Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 6:146–154CrossRefGoogle Scholar
  3. Baker DG, Ekhator NN, Kasckow JW, Hill KK, Zoumakis E, Dashevsky BA, Chrousos GP, Geracioti TD Jr (2001) Plasma and cerebrospinal fluid interleukin-6 concentrations in posttraumatic stress disorder. Neuroimmunomodulation 9:209–217CrossRefPubMedGoogle Scholar
  4. Brambilla F, Monteleone P, Maj M (2004) Interleukin-1beta and tumor necrosis factor-alpha in children with major depressive disorder or dysthymia. J Affect Disord 78:273–277CrossRefPubMedGoogle Scholar
  5. Chaudhry IB, Husain N, Husain MO, Hallak J, Drake R, Kazmi A, Rahman R, Hamirani MM, Kiran T, Mehmood N, Stirling J, Dunn G, Deakin B (2013) Ondansetron and simvastatin added to treatment as usual in patients with schizophrenia: study protocolfor a randomized controlled trial. Trials 14:101CrossRefPubMedPubMedCentralGoogle Scholar
  6. Falcone T, Carlton E, Lee C, Janigro M, Fazio V, Espi Forcen F, Franco K, Janigro D (2015) Does systemic inflammation play a role in pediatric psychosis? Clin Schizophr Relat Psychoses 9:65–78BCrossRefPubMedGoogle Scholar
  7. Gabbay V, Klein RG, Alonso CM, Babb JS, Nishawala M, de Jesus G, Gonzalez CJ (2009a) Immune system dysregulation in adolescent major depressive disorder. J Affect Disord 115:177–182CrossRefPubMedGoogle Scholar
  8. Gabbay V, Klein RG, Guttman LE, Babb JS, Alonso CM, Nishawala M, Katz Y, Gaite MR, Gonzalez CJ (2009b) A preliminary study of cytokines in suicidal and nonsuicidal adolescents with major depression. J Child Adolesc Psychopharmacol 19:423–430CrossRefPubMedPubMedCentralGoogle Scholar
  9. Gaffena S, Liu KD (2004) Overview of interleukin-2 function, production and clinical applications. Cytokine 28:103–129Google Scholar
  10. Gałecki P, Szemraj J, Bieńkiewicz M, Zboralski K, Gałecka E (2009) Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients. Hum Psychopharmacol 24:277–286CrossRefPubMedGoogle Scholar
  11. Goldstein BI, Lotrich F, Axelson DA, Gill MK, Hower H, Goldstein TR, Fan J, Yen S, Diler R, Dickstein D, Strober MA, Iyengar S, Ryan ND, Keller MB, Birmaher B (2015) Inflammatory markers among adolescents and young adults with bipolar spectrum disorders. J Clin Psychiatry 76(11):1556–1563CrossRefPubMedPubMedCentralGoogle Scholar
  12. Henje-Blom E, Lekander M, Ingvar M, Åsberg M, Mobarrez F, Serlachius E (2012) Pro-inflammatory cytokines are elevated in adolescent females with emotional disorders not treated with SSRIs. J Affect Disord 136:716–723CrossRefPubMedGoogle Scholar
  13. Hood KK, Lawrence JM, Anderson A, Bell R, Dabalea D, Daniels S, Dolan LM (2012) Metabolic and inflammatory links to depression in youth with diabetes. Diabetes Care 35:2443–2446CrossRefPubMedPubMedCentralGoogle Scholar
  14. Husain MI, Chaudhry IB, Rahman RR, Hamirani MM, Qurashi I, Khoso AB, Deakin JF, Husain N, Young AH (2015) Minocycline as an adjunct for treatment-resistant depressive symptoms: study protocol for a pilot randomised controlled trial. Trials 16:410CrossRefPubMedPubMedCentralGoogle Scholar
  15. Inui A (2001) Eating behavior in anorexia nervosa - an excess of both orexigenic and anorexigenic signalling? Mol Psychiatry 6:620–624CrossRefPubMedGoogle Scholar
  16. Kaneko M, Stellwagen D, Malenka RC, Stryker M (2008) Tumor necrosis factor-α mediates one component of competitive, experience-dependent plasticity in developing visual cortex. Neuron 58:673–680CrossRefPubMedPubMedCentralGoogle Scholar
  17. Khandaker GM, Dantzer R (2016) Is there a role for immune-to-brain communication in schizophrenia? Psychopharmacology (Berl) 233(9):1559–1573CrossRefGoogle Scholar
  18. Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB (2014) Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiat 71:1121–1128CrossRefGoogle Scholar
  19. Krueger JM (2008) The role of cytokines in sleep regulation. Curr Pharm Des 14(32):3408–3416CrossRefPubMedPubMedCentralGoogle Scholar
  20. Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H (2010) Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 71:520–527CrossRefPubMedGoogle Scholar
  21. Maes M, Lin AH, Delmeire L, Van Gastel A, Kenis G, De Jongh R, Bosmans E (1999) Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biol Psychiatry 45(7):833–839CrossRefPubMedGoogle Scholar
  22. Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N (2006) Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol 21:227–231CrossRefPubMedGoogle Scholar
  23. Miklowitz DJ, Portnoff LC, Armstrong CC, Keenan-Miller D, Breen EC, Muscatell KA, Eisenberger NI, Irwin MR (2016) Inflammatory cytokines and nuclear factor-kappa B activation in adolescents with bipolar and major depressive disorders. Psychiatry Res 241:315–322CrossRefPubMedPubMedCentralGoogle Scholar
  24. Miller GE, Cole SW (2012) Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. Biol Psychiatry 72:34–40CrossRefPubMedPubMedCentralGoogle Scholar
  25. Mills NT, Scott JG, Wray NR, Cohen-Woods S, Baune BT (2013) Research review: the role of cytokines in depression in adolescents: a systematic review. J Child Psychol Psychiatry 54:816–835CrossRefPubMedGoogle Scholar
  26. Misra M, Miller KK, Tsai P, Stewart V, End A, Freed N, Herzog DB, Goldstein M, Riggs S, Klibanski A (2006) Uncoupling of cardiovascular risk markers in adolescent girls with anorexia nervosa. J Pediatr 149:763–769CrossRefPubMedGoogle Scholar
  27. Mitchell RH, Goldstein BI (2014) Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review. J Am Acad Child Adolesc Psychiatry 53(3):274–296CrossRefPubMedGoogle Scholar
  28. Müller N, Riedel M, Scheppach C, Brandstätter B, Sokullu S, Krampe K, Ulmschneider M, Engel RR, Möller HJ, Schwarz MJ (2002) Beneficial antipsychotic effects of celecoxib add-in therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 159:1029–1034CrossRefPubMedGoogle Scholar
  29. Nájera-Medina O, Palacios-Martínez M, Rodríguez-Cruz L, Cortés-Bejar Cdel C, Valencia-Chavarría F, Martínez-Gómez D, González-Torres MC (2014) Cytokine patterns in paediatric patients presenting serious gastrointestinal and respiratory bacterial infections. Cent Eur J Immunol 39:223–227CrossRefPubMedPubMedCentralGoogle Scholar
  30. Nova E, Gómez-Martínez S, Morandé G, Marcos A (2002) Cytokine production by blood mononuclear cells from in-patients with anorexia nervosa. Br J Nutr 88:183–188CrossRefPubMedGoogle Scholar
  31. Ostrowska Z, Ziora K, Oświęcimska J, Marek B, Świętochowska E, Kajdaniuk D, Strzelczyk J, Cieślicka A, Wołkowska-Pokrywa K, Kos-Kudła B (2015) Selected pro-inflammatory cytokines, bone metabolism, osteoprotegerin, and receptor activator of nuclear factor kB ligand in girls with anorexia nervosa. Endokrynol Pol 66:313–321CrossRefPubMedGoogle Scholar
  32. Pallavi P, Sagar R, Mehta M, Sharma S, Subramanium A, Shamshi F, Sengupta U, Pandey RM, Mukhopadhyay AK (2015) Serum cytokines and anxiety in adolescent depression patients: gender effect. Psychiatry Res 229:374–380CrossRefPubMedGoogle Scholar
  33. Pandey GN, Rizavi HS, Ren X, Fareed J, Hoppensteadt DA, Roberts RC, Dwivedi Y (2012) Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. J Psychiatr Res 46(1):57–63CrossRefPubMedGoogle Scholar
  34. Pervanidou P, Kolaitis G, Charitaki S, Margeli A, Ferentinos S, Bakoula C, Lazaropoulou C, Papassotiriou I, Tsiantis J, Chrousos GP (2007) Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident. Psychoneuroendocrinology 32:991–999CrossRefPubMedGoogle Scholar
  35. Plata-Salamán CR (2001) Cytokines and feeding. Int J Obes (Lond) 25:48–52CrossRefGoogle Scholar
  36. Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813:878–888CrossRefPubMedGoogle Scholar
  37. Schoenborn JR, Wilson CB (2007) Regulation of Interferon-γ During Innate and Adaptive Immune Responses. Adv Immunol 96:41–101CrossRefPubMedGoogle Scholar
  38. Señarís RM, Trujillo ML, Navia B, Comes G, Ferrer B, Giralt M, Hidalgo J (2011) Interleukin-6 regulates the expression of hypothalamic neuropeptides involved in body weight in a gender-dependent way. J Neuroendocrinol 23(8):675–686CrossRefPubMedGoogle Scholar
  39. Shimizu T, Satoh Y, Kaneko N, Suzuki M, Lee T, Tanaka K, Iijima M, Yamashiro Y (2005) Factors involved in the regulation of plasma leptin levels in children and adolescents with anorexia nervosa. Pediatr Int 47:154–158CrossRefPubMedGoogle Scholar
  40. Sims JE, Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10:89–102CrossRefPubMedGoogle Scholar
  41. Smith RS (1991) The macrophage theory of depression. Med Hypotheses 35:298–306CrossRefPubMedGoogle Scholar
  42. Smith RS (1992) A comprehensive macrophage-T-lymphocyte theory of schizophrenia. Med Hypotheses 39:248–257CrossRefPubMedGoogle Scholar
  43. Solmi M, Veronese N, Favaro A, Santonastaso P, Manzato E, Sergi G, Correll CU (2015) Inflammatory cytokines and anorexia nervosa: A meta-analysis of cross-sectional and longitudinal studies. Psychoneuroendocrinology 51:237–252CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Paulina Miłkowska
    • 1
    Email author
  • Katarzyna Popko
    • 2
  • Urszula Demkow
    • 2
  • Tomasz Wolańczyk
    • 1
  1. 1.Department of Child PsychiatryWarsaw Medical UniversityWarsawPoland
  2. 2.Department of Laboratory Diagnostics and Clinical Immunology of Developmental AgeWarsaw Medical UniversityWarsawPoland

Personalised recommendations