Correlation of the Metabolic Syndrome with IL-27 in Schizophrenia Patients

Document Type: Research Paper


1 Department of genetics, Faculty of Sciences, University of Shahid Chamran Ahvaz, Ahvaz, Iran

2 Department of Biology, Faculty of Sciences, University of Sistan and Baluchestan, Zahedan, Iran

3 Department of Laboratory Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran

4 Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Introduction: Growing evidence suggests that antipsychotic drugs affect the level of cytokines and metabolic syndrome parameters in schizophrenic patients. The present study aimed to investigate the serum markers of metabolic syndrome, including low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), fasting blood sugar (FBS),total cholesterol, and insulin, and interleukin-27 (IL-27) in the patients with schizophrenia and compared the levels with healthy subjects. Methods: In this cross-sectional study, the serum level of IL-27 was measured in 45 patients with schizophrenia and 45 healthy subjects using the ELISA. In addition, the markers of metabolic syndrome were measured in Dr. Salehi Laboratory in Yasouj, Iran. Data analysis was performed in SPSS version 21. Results: A significant increase was observed in IL-27 in the patients with schizophrenia (P= 0.043) compared to the healthy controls. Evaluation of the risk factors of metabolic syndrome in schizophrenic patients compared to the controls indicated no significant differences in the body mass index (P=0.764), systolic blood pressure (P=0.670), diastolic blood pressure (P=0.216), total cholesterol (P=0.103), TG (P=0.097), and LDL (P=0.255). However, the serum levels of HDL (P=0.012) and insulin (P=0.001) significantly decreased and increased, respectively in schizophrenic patients compared to the controls. Moreover, a strong, positive correlation was observed between the levels of insulin and LDL andIL-27, with the correlation-coefficients of 0.312 and 0.641, respectively. A negative correlation was also denoted between IL-27 and HDL with the correlation-coefficient of -0.413 (P=0.005). The associations between IL-27 and the other markers of metabolic syndrome were not considered significant. Conclusion: According to the results, changes in IL-27 may affect the Pathophysiology of schizophrenia. Antipsychotic therapy has been reported to increase the serum levels of IL-27, which in turn exacerbate and increase the incidence of metabolic disorders.


1. Koyama A, Ito H, Nakanishi M, Sawamura K, Higuchi T. Addition of antipsychotics to medication regimens during schizophrenic inpatient care. Psychiatry Clin Neurosci. 2008; 62(1): 56–64.

2. Chien IC, Hsu JH, Bih SH, Lin CH, Chou YJ, Lee CH, et al. Prevalence, correlates, and disease patterns of antipsychotic use in Taiwan. Psychiatry Clin Neurosci. 2008; 62: 677–84.

3. Theodoropoulou S, Spanakos G, Baxevanis CN, Economou M, Gritzapis AD, Papamichail MP, et al. Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res. 2001; 47(1):13–25.

4. Ganguli R, Brar JS, Chengappa KR, DeLeo M, Yang ZW, Shurin G, et al. Mitogen-stimulated interleukin-2 production in never-medicated, first-episode schizophrenic patients. The influence of age at onset and negative symptoms. Arch Gen Psychiatry. 1995; 52(8): 668–72.

5. Kim YK, Lee MS, Suh KY. Decreased IL-2 production in Korean schizophrenic patients .  Biol Psychiatry 1998; 43(9): 701–4.

6. Cazzullo CL, Scarone S, Grassi B, Vismara C, Trabattoni D, Clerici M et al. Cytokine production in chronic schizophrenia patients with or without paranoid behavior. Prog Neuro Psycho Pharmacol Biol Psychiatry. 1998; 22: 947–57.

7. Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis:A systematic review and meta-analysis. Schizophr Res. 2014; 155(1-3): 101-8.

8. Müller N, Schwarz MJ. Immune system and schizophrenia. Curr Immunol Rev. 2010; 6(3): 213-20.

9. Becker  T, Hux  J. Risk of Acute Complications of Diabetes Among PeopleWith Schizophrenia in Ontario, Canada . Diabetes Care. 2011; 34(2): 398-402.

10. Bray GA, Bellanger T. Epidemiology, Trends, and Morbidities of Obesity and the Metabolic Syndrome. Endocrine. 2006; 29(1): 109-17.

11. Eva Kassi, Pervanidou P, Kaltsas G, Chrousos G. Metabolic syndrome: definitions and controversies, BMC Med. 2011; 9: 48.

12. Kim SH, Kim K, Kwak MH, Kim HJ, Kim HS, Han KH. The contribution of abdominal obesity and dyslipidemia to metabolic syndrome in psychiatric patients. Korean J Intern Med.2010; 25(2):168-73.

13. Delavari A, Forouzanfar MH, Alikhani S, Sharifian A, Kelishadi R. First nationwide study of the prevalence of themetabolic syndrome and optimal cutoff points of waist circumference in the Middle East: the national survey of riskfactors for noncommunicable disease of Iran. Diabetes Care. 2009; 32(6):1092-7.

14. Zirlik A, Abdullah SM, Gerdes N, MacFarlane L, Schönbeck U, Khera A, et al. Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis: results from the Dallas Heart Study. Arterioscler Thromb Vasc Biol. 2007; 27(9): 2043-9.

15. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contributeto macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009; 15(8): 914-20.

16. Troseid M, Seljeflot I, Hjerkinn EM, Arnesen H. Interleukin-18 is a strong predictor of cardiovascular events in elderly men with the metabolic syndrome: synergistic effect of  inflammation and hyperglycemia. Diabetes Care. 2009; 32(3): 486-92.

17. Van Herpen NA, Schrauwen Hinderling VB. Lipid accumulation in non- adipose tissue and lipotoxicity. Physiol Behav. 2008; 94(2): 231-41.

18. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007; 117(1): 175-84.

19. Prieur X, Mok CY, Velagapudi VR, Núñez V, Fuentes L, Montaner D, et al. Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes. 2011; 60 (3): 797-809.

20. Zamani F, Almasi S, Kazemi T, Jahanban Esfahlan R, Aliparasti M. New Approaches to the Immunotherapy of Type 1 Diabetes Mellitus Using Interleukin-27 . Adv Pharm Bull. 2015; 5(Suppl 1): 599-603.

21. Mitchell AJ, Vancampfort D, De Herdt A, Yu W, De Hert M. Is the prevalence of metabolicsyndrome and metabolic abnormalities increasedin early schizophrenia? A comparativemeta-analysis of first episode, untreatedand treated patients. Schizophr Bull. 2013; 39(2): 295–305.

22. Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity. 2002; 16(6): 779-90.

23. Jones LL, Chaturvedi V, Uyttenhove C, Van Snick J, Vignali DA. Distinct subunit pairing criteria within the heterodimeric IL-12 cytokine family. Mol Immunol. 2012; 51(2): 234-44.

24. Liu J, Guan X, Ma X. Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-gamma mediated pathways. J Exp Med. 2007; 204(1): 141-52.

25. Jin W, Zhao Y, Yan W, Cao L, Zhang W, Wang M, et al. Elevated circulating interleukin-27 in patients with coronary artery disease is associated with dendritic cells, oxidized low-density lipoprotein, and severity of coronary artery stenosis. Mediators Inflamm. 2012; 2012: 506283.

26. Nam H, Ferguson BS, Stephens JM, Morrison RF. Impact of obesity on IL-12 family gene expression in insulin responsive tissues. Biochim Biophys Acta. 2013; 1832(1): 11-9.

27. Wang R, Han G, Wang J, Chen G, Xu R, Wang L, et al. The pathogenic role of interleukin-27 in autoimmune diabetes. Cell Mol Life Sci. 2008; 65(23): 3851-60.

28. Jafarzadeh A, Nemati M, Rezayati MT. Serum levels of interleukin (IL)-27 in patients with ischemic heart disease. Cytokine. 2011; 56(2): 153-6.

29. Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis.A systematic review and meta-analysis. Schizophr Res. 2014; 155(1-3): 101-8.

30. Müller N, Schwarz MJ. Immune system and schizophrenia. Curr Immunol Rev. 2010; 6(3): 213-20.

31. Borovcanin M, Jovanovic I, Radosavljevic G, Djukic Dejanovic S, Stefanovic V, Arsenijevic N, et al. Antipsychotics can modulate the cytokine profile in schizophrenia: Attenuation of the type-2 inflammatory response. Schizophr Res. 2013; 147(1): 103-9.

32. Na KS, Jung HY, Kim YK. The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 48: 277-86.

33. Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura GJ, Pioli R, Boin F, et al. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res. 2002; 54(3): 281–91.

34. Muller N, Schwarz MJ. Role of the cytokine in major psychoses. Advances in Molecular and Cell Biology. 2003; 31: 999–1031

35. Alidadi A, Khazaei HA, Nakhjavan Shahraki B, Andarzi S, Jalili A, Mirzaei A, et al. Comparison of IL-13 and IL-27 levels between schizophrenics and healthy subjects before and after antipsychotic administration. Health Sciences. 2016; 5(9S): 654-61.

36. Teixeira PJ, Rocha FL. The prevalence of metabolic syndrome among psychiatric inpatients in Brazil. Braz J Psychiatry. 2007; 29(4): 330-6.

37. Casey DE, L’Italien GJ, Cislo P. Incidence of metabolic syndrome in olanzapine and aripiprazole patients. In: 157th Annual Meeting of the American Psychiatric Association. New York: APA, Abstract 338, 2004.

38. Mitchell AJ, Vancampfort D, De Herdt A, Yu W, De Hert M. Is the prevalence of metabolic syndrome and metabolic abnormalities increased in early schizophrenia? A comparative meta-analysis of first episode, untreated and treated patients. Schizophr Bull. 2013; 39(2): 295–305.

39. Casey DE. Dyslipidemia and atypical antipsychotic drugs. J Clin Psychiatry. 2004; 65(Suppl 18): 27-35.

40. Henderson DC, Nguyen DD, Copeland PM, Hayden DL, Borba CP, Louie PM, et al. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality, results of a 10-year naturalistic study. J Clin Psychiatry. 2005; 66(9): 1116:21.

41. Koro CE, Fedder DO, L’Italien GJ, Weiss S, Magder LS, Kreyenbuhl J, et al. An assessment of independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients. Arch Gen Psychiatry. 59(11): 1021-6.

42. Ryan MC, Collins P, Thakore JH. Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry.  2003; 160(2): 284-9.

43. Jin W,  Zhao Y, Yan W, Cao L, Zhang W, Wang M, et al. Elevated Circulating Interleukin-27 in Patients with Coronary Artery Disease Is Associated with Dendritic Cells, Oxidized Low-Density Lipoprotein, and Severity of Coronary Artery Stenosis. Mediators Inflamm. 2012; 2012: 506283.

44. Crespo-Facorro B, Carraso-Marin E, Perez-Iglesias R, Pelayo-Teran JM, Fernandez-Prieto L, Leyva-Cobian F et al. Interleukin-12 plasma levels in drug-naive patients with a first episode of psychosis. Effects of antipsychotic drugs. Psychiatry Res. 2008; 15: 206–16.

45. Nam H, Ferguson BS, Stephens JM, Morrison RF. Impact of obesity on IL-12 family gene expression in insulin responsive tissues. Biochim Biophys Acta. 2013; 1832(1): 11-9.

46. Trotter A, Mück K, Grill H-J, Schirmer U, Hannekum A, Lang D. Gender-related plasma levels of progesterone, interleukin-8 and interleukin-10 during and after cardiopulmonary bypass in infants and children. Crit Care. 2001; 5(6): 343-8.

47. Ben-Zaken Cohen S, Pare´ PD, Man SF, Sin DD. The growing burden of Chronic Obstructive Pulmonary Disease and lung Cancer in Women: examining sex differences in cigarette smoke metabolism. Am J Respir Crit Care Med. 2007; 176(2): 113-20.