Effects of Interleukin Families Polymorphisms on Systemic Lupus Erythematosus: Focus on Interleukin-1

authors:

avatar Maryam Moossavi 1 , 2 , avatar Maryam Shojaee 3 , avatar Arezoo Mollashahi 4 , avatar Jafar Poodineh 5 , avatar Seyedeh Zahra Moossavi 6 , avatar Maryam Alaei 7 , avatar Mostafa Ibrahimi 7 , * , avatar Milad Mohammadoo Khorasani 7 , **

Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran
Department of Biology, Payame Noor University of Mashhad, IR Iran
Department of Biology, Payame Noor University of Esfehan, IR Iran
Department of Clinical Biochemistry, School of Medicine, Zabol University of Medical Sciences, Zabol, IR Iran
Shiraz University of Medical Sciences, Shiraz, IR Iran
Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, IR Iran
Corresponding Authors:
Gene, Cell and Tissue: Vol.5, issue 1; e69365
published online: January 31, 2018
article type: Review Article
received: December 15, 2017
revised: January 5, 2018
accepted: January 15, 2018
DOI: https://doi.org/10.5812/gct.69365

how to cite: Moossavi M, Shojaee M, Mollashahi A, Poodineh J, Moossavi S Z, et al. Effects of Interleukin Families Polymorphisms on Systemic Lupus Erythematosus: Focus on Interleukin-1. Gene Cell Tissue. 2018;5(1):e69365. https://doi.org/10.5812/gct.69365.

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic human autoimmune disease, which is characterized by increased activity of B cells and production of antibodies against tissue antigens. It engages many tissues and organs, including joints, kidneys, heart, and the nervous system. Although the exact pathogenesis of SLE remains to be elucidated, it is suggested that genetic background plays a paramount role in SLE etiology. Increasing evidence is indicating an important role for interleukins in progression of SLE. Interleukins are a group of cytokines secreted by T helper cells, monocytes, macrophages, and B cells, which are involved in growth and differentiation of T and B cells. The expression level of interleukins is influenced greatly by genetic composition. Therefore, some polymorphisms can control the expression of interleukins. Consequently, genetic studies can shed light on our understanding of SLE nature. Therefore, in the present study, the researchers reviewed the roles of eight key interleukin polymorphisms and their effects on SLE pathogenic.

1. Background

Systemic lupus erythematosus (SLE) is a chronic human autoimmune disease, which engages various human organs. It is characterized by increased activity of B cells and over production of antibodies against endogenous antigens. Accumulation of antibodies in tissues and organs plays a key role in clinical signs of SLE (1, 2). Lupus mostly effects the kidneys, heart, and the nervous system. The joints are affected more in some specific SLE types and the skin is affected in all types of lupus (3, 4).

The prevalence of lupus in different populations ranges from 20 to 150 cases per 100,000 individuals around the world (2). Moreover, in females of the reproductive age, SLE is about nine times more frequent than males, and its incidence is variable in different races, ethnicities, geographic regions, and social and economic status. This disease is not common in children younger than 15 years old, and consists of about 20% of the patients (5).

The exact pathogenesis of SLE remains to be elucidated, yet genetic and environmental factors play an important role in SLE pathogenesis (6-8). Understanding complicated genetic background of lupus and determining the number of genes involved, is a heavy burden (9). Seemingly, lupus stemmed from loss of tolerance to insider's antigens and then production of antibodies against the cell’s nucleus (10, 11). Generally, lupus is categorized to four groups, including discoid lupus, drug-induced lupus, neonatal lupus, and systemic lupus erythematosus (12).

Interleukins (IL) are a group of cytokines, secreted mostly by T helper cells, monocytes, macrophages, dendritic cells, natural killer cells, and B cell. The interleukins are mainly involved in growth and differentiation of T and B cells and activate natural killer cells. It has been shown by several studies that the role of inflammatory interleukin gene’s polymorphisms in creation of SLE is of paramount importance. Interleukins involved in SLE include interleukin 1 (13), interleukin 1 beta (14), interleukin 4 (14), interleukin 6 (15), interleukin 7 (16), interleukin 10 (15), interleukin 21 (17), interleukin 19 (18), interleukin 27 (19), interleukin 31 (20), and interleukin 32 (21).

Knowledge on interleukins can cast light on our knowledge of SLE and leads to early diagnosis and development of novel treatment methods. In the present article, the role of inflammatory interleukin genes, especially the Interleukin 1 gene family, in creating the SLE was reviewed.

2. Interleukins Involved in Systemic Lupus Erythematous

Cytokines are secreted by cells involved in the immune system, including T cells and other immune response cells. According to T cell types, some cytokines play inhibitory roles while, some others play excitatory roles. Maintaining Th1/Th2 balance is a key factor for immune homeostasis, the distortion of which is supposed to be the cause of SLE. However, there is no comprehensive information on the relationship between Th1 and Th2 levels; however, it is clear that increasing levels of Th2 is a crucial step in progression of SLE. On the other hand, reducing levels of Th1 are involved in progression of SLE. There are many important Th1 and Th2 cytokines, involved in the pathogenesis of SLE, such as IL-12, IL-4, IL-10, and IL-6 (4, 22, 23).

Genetic composition is a determinative factor in controlling production of interleukins and, it has been elucidated that presence of some polymorphisms can increase or decrease the expression of interleukin genes, and in turn, increase the susceptibility to certain diseases (24). Studies concerning the association between interleukins and SLE are reviewed below.

2.1. Interleukin 23 (IL-23)

Interleukin-23 is believed to be an important factor in pathogenesis of autoimmune diseases. It was recently reported that IL-23 abnormalities contributed to the development of SLE. Interleukin-23 is able to stimulate TCD4 production of pro-inflammatory cytokines, such as IL-17 and IFNγ. This cytokine plays an important role in progression of SLE. Also, clinical and pathological signs of SLE nephritis were decreased in defect of IL-23 receptors. Therefore, it seems that IL-23 is an essential factor in damaging the kidneys in patients with SLE (25, 26).

2.2. Interleukin 21 (IL-21)

Interleukin-21 is produced by follicular T cells. This cytokine induces differentiation and development of T helper cell, and stimulates the production of antibodies by B cells (27). It has been reported by previous studies that plasma level of IL-21 is increased in patients with SLE.

Variations in the IL-21 gene may lead to change in the IL-21 protein, which subsequently alters the susceptibility of individuals to SLE. Several polymorphisms in the IL-21 gene have been identified in association with SLE (28-30). Recently, some studies showed that IL-21 increases inflammatory diseases and autoimmune chronic diseases in humans. Also, animal studies reported that IL-21 plays an important role in the pathogenesis of SLE, and its serum level in SLE patients was higher compared with the control group. In addition, some other studies indicated the association between IL-21 and its receptor polymorphism with SLE susceptibility (31).

2.3. Interleukin 18 (IL-18)

Interleukin-18 is a member of the IL-1 family. Inactive IL-18 is cut by caspase-1 to be converted to the biological active form. Its biological function includes influencing of dendritic cells, T lymphocytes and natural killer cells, and inducing IFN-A to increase differentiation of Th1 (32). Elevated concentration of IL-18 in patients with SLE has been introduced by previous studies. Moreover, it has been reported that IL-18 level is associated with urine micro-albumin level and kidney malfunction in patients with SLE (33-35). In addition, IL-18 gene expression is increased in the glomeruli of patients with SLE nephritis (35). Also, over-expression of IL-18 is a cause of skin lesions in patients with SLE (36).

2.4. Interleukin 17 (IL-17)

Interleukin-17, a pro-inflammatory cytokine, is a key regulator of inflammation process. Six members of the IL-17 family, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F, have been recently reported to be involved in SLE, which, are primarily released by activated T lymphocytes (37, 38). Furthermore, IL-17 induces B cell proliferation and subsequently antibodies production. Also, elevated serum levels of IL-17 has been reported to be associated with development of SLE (25, 26, 39). In SLE patients, IL-17, released by T lymphocytes, induced T cells and mRNA molecules adhesion to endothelial cells (40, 41).

2.5. Interleukin 10 (IL-10)

Interleukin-10 is suggested to be directly involved in T cells suppression. Also, this interleukin plays an important role in B cells activation. Interleukin-10 is mainly released by activated macrophages and also at lower amounts, by other cell types, such as T cells and keratinocytes (42). The serum levels of IL-10 are increased in SLE patients and this is related with disease severity. This interleukin stimulates the proliferation and differentiation of B cells. Also, IL-10 effects the expression of Bcl-2 and decreases the apoptosis rate in B cells. Therefore, it can enhance antibody production.

Recently, studies have shown that IL-10 injection to mice with SLE lead to escalated kidney damage in SLE (25, 26, 43). Also, it was reported by many studies that various polymorphisms in the promoter region of the IL-10 gene is associated with SLE (44-46). However, findings are still controversial since another study reported no significant association between IL-10 polymorphisms and susceptibility to SLE (47).

2.6. Interleukin-6 (IL-6)

Interleukin-6 (IL-6) production is promoted by TNF and IL-1 and it has pleiotropic effect on many tissues in humans. Interleukin-6 is mainly secreted by macrophage cells and in lower amounts by mesangial cells, endothelial, and lymphocytes (25). Interleukin-6 increases the activation and secretion of macrophage, B lymphocyte, and immunoglobulin. Also, IL-6 can promote differentiation of Th17 cells, which plays an important role in many autoimmune diseases. Elevated levels of IL-6 in serum and urine samples of SLE patients has been observed (26). Moreover, IL-6 and renal malfunction association was also considered recently (48).

2.7. Interleukin 4 (IL-4)

Interleukin-4 is an anti-inflammatory cytokine, which is produced by Th2 CD4+ cells on the surface of Basophils and Mast cells (49). Interleukin-4 protein, as a key cytokine, promotes activation and differentiation of B cells and is also involved in development of T cells (50). This cytokine also has a flip side cytotoxic effect and triggers inhibition of nitric oxide synthase, release of dismutase anions by macrophages, and some other anti-inflammatory effects. The role of IL-4 is well-known in autoimmune diseases. It was implied by various studies, including recent findings by the current authors, that the effect of IL-4 on SLE development is closely contributed with its gene polymorphism (14, 51, 52).

3. Interleukin 1 Family

Interleukin-1 (IL-1) gene cluster is, a 430-kb region, including IL-1α (IL-1A), IL-1β (IL-1B) and Receptor Antagonist of Interleukin-1 (IL-1RN) genes. Different studies have found significant differences in expression level of IL-1 family among patients with SLE and healthy subjects (13, 24). Interleukin-1A and IL-1B proteins are pro-inflammatory cytokines and play important roles in extensive biological processes. Furthermore, IL-1A and IL-1B bound to IL-1 receptor trigger signal transduction, followed by biological effects. On the contrary, IL-1Ra protein is a competitive inhibitor, which binds to IL-1 receptors and inhibit intracellular signaling (53). It is believed that expression imbalance of these three proteins and their receptors may play an important role in creation of autoimmune diseases.

4. Interleukin 1 and SLE

Interleukin-1 protein family includes IL-1 alpha (IL-1α), IL-1 beta (IL-1β), and IL receptor antagonist (IL-RA). Interleukin-1 is located on chromosome 2 (2q13-21), in the 430-kb region, and IL-1α and IL-1β genes are very close together (54, 55). Interleukin-1α and IL-1β are pro-inflammatory cytokines, which are involved in many biological activities. Studies suggested that imbalance between IL-1α, IL-1β, and IL-RA proteins can cause autoimmune response (53). Many studies reported a significant relationship between abnormal expression of IL-1 and progression of SLE, which was firstly revealed in 1983 (56-59). However, more investigations are needed to clarify the relationship between IL-1 member’s polymorphisms and SLE. Chua et al. (2009) showed that IL-1β -511C/T polymorphism increases SLE susceptibility in the Malaysian population (60). Furthermore, Parks et al. (2004) reported that T allele increases susceptibility of SLE in the African American population (59). Also Huang et al. (2002), reported no relationship between IL-1β -511C/T polymorphism and SLE in a Taiwanese population (61). In a similar study Chua et al. (2009), a significant association was reported between IL-1β + 3954E1/E2 (heterozygote) polymorphism in exon 5 and SLE in the Malaysian population, and E1 (wild allele) allele increased the SLE risk (60). Also, this result has been reported in a Columbian population, yet not in the Chinese population (62, 63).

The activity and production of IL-1α and IL-1β are controlled by IL-receptor antagonist (IL-1RA or IL-1RN). Deregulation in expression of IL-1 by IL-1RA, and abnormal activity leads to high inflammatory response and causes damage to tissues, which is one of the SLE symptoms. Many studies have been performed to evaluate the association between IL-1RN gene polymorphisms and SLE. Interleukin-1RA variable numbers of tandem repeat -86 bp (VNTR 86-bp) polymorphism in intron 2 is reported to be relevant with SLE risk (64, 65). A previous study by the current authors in association between VNTR 86-bp polymorphism and SLE showed that IL-1RN∗2 allele had no association with SLE (13). On the other hand, Blakemore et al. found an association between the IL-1RN∗2 allele and SLE susceptibility (65). Also, Lian et al. showed that IL-1RN∗2 allele is associated with SLE in the Malaysian population (66).

5. Conclusions

In the present study, the researchers focused on some interleukins, which play important roles in SLE pathogenesis. Systemic Lupus Erythematosus is an autoimmune disorder with many heterogeneous symptoms. The main mechanism of this disorder remains to be elucidated. Besides, many studies suggested that SLE is a multi-factorial disease, which involves genetic, environmental, and immunological agents. These factors increase body sensitivity toward antigens; therefore, immunologic responses become out of control in some tissues, which cause damage. Many studies performed on SLE patients and SLE animal models have shown that over expression of some members of the interleukin family have significance contribution on SLE progression. Over expression of some inflammatory interleukins lead to B cell auto-reaction, which in turn, increases the production of autoantibodies.

References

  • 1.

    Sahebari M, Hatef MR, Rezaieyazdi Z, Abbasi M, Abbasi B, Mahmoudi M. Correlation between serum levels of soluble Fas (CD95/Apo-1) with disease activity in systemic lupus erythematosus patients in Khorasan, Iran. Arch Iran Med. 2010;13(2):135-42. [PubMed ID: 20187668].

  • 2.

    Crispin JC, Liossis SN, Kis-Toth K, Lieberman LA, Kyttaris VC, Juang YT, et al. Pathogenesis of human systemic lupus erythematosus: recent advances. Trends Mol Med. 2010;16(2):47-57. [PubMed ID: 20138006]. [PubMed Central ID: PMC2823952]. https://doi.org/10.1016/j.molmed.2009.12.005.

  • 3.

    Fu SM, Deshmukh US, Gaskin F. Pathogenesis of systemic lupus erythematosus revisited 2011: end organ resistance to damage, autoantibody initiation and diversification, and HLA-DR. J Autoimmun. 2011;37(2):104-12. [PubMed ID: 21632208]. [PubMed Central ID: PMC3173577]. https://doi.org/10.1016/j.jaut.2011.05.004.

  • 4.

    Namazi S, Ziaee V, Rezaei N. The role of cytokines in systemic lupus erythematosis. Tehran Univ Med J. 2015;73(6):397-404.

  • 5.

    Murphy G, Lisnevskaia L, Isenberg D. Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatment. Lancet. 2013;382(9894):809-18. [PubMed ID: 23972423]. https://doi.org/10.1016/S0140-6736(13)60889-2.

  • 6.

    Mohammadoo-Khorasani M, Musavi M, Mousavi M, Moossavi M, Khoddamian M, Sandoughi M, et al. Deoxyribonuclease I gene polymorphism and susceptibility to systemic lupus erythematosus. Clin Rheumatol. 2016;35(1):101-5. [PubMed ID: 26547219]. https://doi.org/10.1007/s10067-015-3111-y.

  • 7.

    Jahantigh D, Salimi S, Mousavi M, Moossavi M, Mohammadoo-Khorasani M, Narooei-nejad M, et al. Association Between Functional Polymorphisms of DNA Double-Strand Breaks in Repair Genes XRCC5, XRCC6 and XRCC7 with the Risk of Systemic Lupus Erythematosus in South East Iran. DNA Cell Biol. 2015;34(5):360-6. [PubMed ID: 25756210]. https://doi.org/10.1089/dna.2014.2465.

  • 8.

    Salimi S, Noora M, Nabizadeh S, Rezaei M, Shahraki H, Milad MK, et al. Association of the osteopontin rs1126616 polymorphism and a higher serum osteopontin level with lupus nephritis. Biomed Rep. 2016;4(3):355-60. [PubMed ID: 26998275]. [PubMed Central ID: PMC4774351]. https://doi.org/10.3892/br.2016.589.

  • 9.

    Horiuchi T, Washio M, Kiyohara C, Tsukamoto H, Tada Y, Asami T, et al. Combination of TNF-RII, CYP1A1 and GSTM1 polymorphisms and the risk of Japanese SLE: findings from the KYSS study. Rheumatology (Oxford). 2009;48(9):1045-9. [PubMed ID: 19561157]. https://doi.org/10.1093/rheumatology/kep166.

  • 10.

    Tobon GJ, Izquierdo JH, Canas CA. B lymphocytes: development, tolerance, and their role in autoimmunity—focus on systemic lupus erythematosus. Autoimmune Dis. 2013;2013.

  • 11.

    Ahearn JM, Liu CC, Kao AH, Manzi S. Biomarkers for systemic lupus erythematosus. Transl Res. 2012;159(4):326-42. [PubMed ID: 22424435]. https://doi.org/10.1016/j.trsl.2012.01.021.

  • 12.

    Tahernia L, Namazi S, Rezaei N, Ziaee V. Cytokines in systemic lupus erythematosus: their role in pathogenesis of disease and possible therapeutic opportunities. Rheumatol Res. 2017;2(1):1-9. https://doi.org/10.22631/rr.2017.69997.1010.

  • 13.

    Mohammadoo-Khorasani M, Salimi S, Tabatabai E, Sandoughi M, Zakeri Z. Association of interleukin-1 receptor antagonist gene 86bp VNTR polymorphism with systemic lupus erythematosus in south east of Iran. Zahedan J Res Med Sci. 2013;16(12).

  • 14.

    Mohammadoo-Khorasani M, Salimi S, Tabatabai E, Sandoughi M, Zakeri Z, Farajian-Mashhadi F. Interleukin-1beta (IL-1beta) & IL-4 gene polymorphisms in patients with systemic lupus erythematosus (SLE) & their association with susceptibility to SLE. Indian J Med Res. 2016;143(5):591-6. [PubMed ID: 27488002]. [PubMed Central ID: PMC4989832]. https://doi.org/10.4103/0971-5916.187107.

  • 15.

    Talaat RM, Alrefaey SA, Bassyouni IH, Ashour ME, Raouf AA. Genetic polymorphisms of interleukin 6 and interleukin 10 in Egyptian patients with systemic lupus eythematosus. Lupus. 2016;25(3):255-64. [PubMed ID: 26568585]. https://doi.org/10.1177/0961203315615219.

  • 16.

    Jagodzinski PP, Piotrowski P, Olesinska M. Interleukin-7 receptor Thr244Ile gene polymorphism and the risk of systemic lupus erythematosus. J Med Sci. 2016;85(3):192. https://doi.org/10.20883/jms.2016.123.

  • 17.

    Ahmed YM, Erfan DM, Hafez SF, Shehata IH, Morshedy NA. The association of single nucleotide polymorphism of interleukin-21 gene and serum interleukin-21 levels with systemic lupus erythematosus. Egypt J Med Human Gene. 2017;18(2):129-36. https://doi.org/10.1016/j.ejmhg.2016.04.006.

  • 18.

    Lin J, Qin H, Wang Y, Liang J, Xu J. Analysis of interleukin 19 serum levels and single nucleotide polymorphisms in systemic lupus erythematosus. Gene Mol Res. 2016;15(2).

  • 19.

    Paradowska-Gorycka A, Sowinska A, Stypinska B, Grobelna MK, Walczyk M, Olesinska M, et al. Genetic Variants in IL-12B and IL-27 in the Polish Patients with Systemic Lupus Erythematosus. Scand J Immunol. 2016;84(1):49-60. [PubMed ID: 27059274]. https://doi.org/10.1111/sji.12439.

  • 20.

    Huang HT, Chen JM, Guo J, Lan Y, Wei YS. The association of interleukin-31 polymorphisms with interleukin-31 serum levels and risk of systemic lupus erythematosus. Rheumatol Int. 2016;36(6):799-805. [PubMed ID: 26769434]. https://doi.org/10.1007/s00296-016-3422-6.

  • 21.

    Wang Y, Zhou B, Zhao Y, Yu X, Liu Y, Zhang L. Association of Plasma IL-32 Levels and Gene Polymorphisms with Systemic Lupus Erythematosus in Chinese Han Population. Dis Markers. 2016;2016:2460206. [PubMed ID: 27069296]. [PubMed Central ID: PMC4789414]. https://doi.org/10.1155/2016/2460206.

  • 22.

    Su DL, Lu ZM, Shen MN, Li X, Sun LY. Roles of pro- and anti-inflammatory cytokines in the pathogenesis of SLE. J Biomed Biotechnol. 2012;2012:347141. [PubMed ID: 22500087]. [PubMed Central ID: PMC3303597]. https://doi.org/10.1155/2012/347141.

  • 23.

    Perl A. Systems biology of lupus: mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targets for treatment. Autoimmunity. 2010;43(1):32-47. [PubMed ID: 20001421]. [PubMed Central ID: PMC4020422]. https://doi.org/10.3109/08916930903374774.

  • 24.

    Tahmasebi Z, Akbarian M, Mirkazemi S, Shahlaee A, Alizadeh Z, Amirzargar AA, et al. Interleukin-1 gene cluster and IL-1 receptor polymorphisms in Iranian patients with systemic lupus erythematosus. Rheumatol Int. 2013;33(10):2591-6. [PubMed ID: 23722873]. https://doi.org/10.1007/s00296-013-2784-2.

  • 25.

    Nishimoto N, Kishimoto T. Interleukin 6: from bench to bedside. Nat Clin Pract Rheumatol. 2006;2(11):619-26. [PubMed ID: 17075601]. https://doi.org/10.1038/ncprheum0338.

  • 26.

    Cash H, Relle M, Menke J, Brochhausen C, Jones SA, Topley N, et al. Interleukin 6 (IL-6) deficiency delays lupus nephritis in MRL-Faslpr mice: the IL-6 pathway as a new therapeutic target in treatment of autoimmune kidney disease in systemic lupus erythematosus. J Rheumatol. 2010;37(1):60-70. [PubMed ID: 19955044]. https://doi.org/10.3899/jrheum.090194.

  • 27.

    Sarra M, Monteleone G. Interleukin-21: a new mediator of inflammation in systemic lupus erythematosus. J Biomed Biotechnol. 2010;2010:294582. [PubMed ID: 20652041]. [PubMed Central ID: PMC2905909]. https://doi.org/10.1155/2010/294582.

  • 28.

    Ding L, Wang S, Chen GM, Leng RX, Pan HF, Ye DQ. A single nucleotide polymorphism of IL-21 gene is associated with systemic lupus erythematosus in a Chinese population. Inflammation. 2012;35(6):1781-5. [PubMed ID: 22752563]. https://doi.org/10.1007/s10753-012-9497-7.

  • 29.

    Leng RX, Wang W, Cen H, Zhou M, Feng CC, Zhu Y, et al. Gene-gene and gene-sex epistatic interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in systemic lupus erythematosus. PLoS One. 2012;7(12). e51090. [PubMed ID: 23236436]. [PubMed Central ID: PMC3517573]. https://doi.org/10.1371/journal.pone.0051090.

  • 30.

    Lan Y, Luo B, Wang JL, Jiang YW, Wei YS. The association of interleukin-21 polymorphisms with interleukin-21 serum levels and risk of systemic lupus erythematosus. Gene. 2014;538(1):94-8. [PubMed ID: 24434811]. https://doi.org/10.1016/j.gene.2014.01.012.

  • 31.

    Webb R, Merrill JT, Kelly JA, Sestak A, Kaufman KM, Langefeld CD, et al. A polymorphism within IL21R confers risk for systemic lupus erythematosus. Arthritis Rheum. 2009;60(8):2402-7. [PubMed ID: 19644854]. [PubMed Central ID: PMC2782592]. https://doi.org/10.1002/art.24658.

  • 32.

    Yap DY, Lai KN. The role of cytokines in the pathogenesis of systemic lupus erythematosus - from bench to bedside. Nephrology (Carlton). 2013;18(4):243-55. [PubMed ID: 23452295]. https://doi.org/10.1111/nep.12047.

  • 33.

    Wong CK, Ho CY, Li EK, Tam LS, Lam CW. Elevated production of interleukin-18 is associated with renal disease in patients with systemic lupus erythematosus. Clin Exp Immunol. 2002;130(2):345-51. [PubMed ID: 12390326]. [PubMed Central ID: PMC1906516].

  • 34.

    Amerio P, Frezzolini A, Abeni D, Teofoli P, Girardelli CR, De Pita O, et al. Increased IL-18 in patients with systemic lupus erythematosus: relations with Th-1, Th-2, pro-inflammatory cytokines and disease activity. IL-18 is a marker of disease activity but does not correlate with pro-inflammatory cytokines. Clin Exp Rheumatol. 2002;20(4):535-8. [PubMed ID: 12175109].

  • 35.

    Calvani N, Richards HB, Tucci M, Pannarale G, Silvestris F. Up-regulation of IL-18 and predominance of a Th1 immune response is a hallmark of lupus nephritis. Clin Exp Immunol. 2004;138(1):171-8. [PubMed ID: 15373921]. [PubMed Central ID: PMC1809179]. https://doi.org/10.1111/j.1365-2249.2004.02588.x.

  • 36.

    Wang D, Drenker M, Eiz-Vesper B, Werfel T, Wittmann M. Evidence for a pathogenetic role of interleukin-18 in cutaneous lupus erythematosus. Arthritis Rheum. 2008;58(10):3205-15. [PubMed ID: 18821674]. https://doi.org/10.1002/art.23868.

  • 37.

    Sutton CE, Mielke LA, Mills KH. IL-17-producing gammadelta T cells and innate lymphoid cells. Eur J Immunol. 2012;42(9):2221-31. [PubMed ID: 22949320]. https://doi.org/10.1002/eji.201242569.

  • 38.

    Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol. 2011;187(1):490-500. [PubMed ID: 21606249]. [PubMed Central ID: PMC3119764]. https://doi.org/10.4049/jimmunol.1100123.

  • 39.

    Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371(9617):987-97. [PubMed ID: 18358926]. https://doi.org/10.1016/S0140-6736(08)60453-5.

  • 40.

    Crispin JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol. 2008;181(12):8761-6. [PubMed ID: 19050297]. [PubMed Central ID: PMC2596652].

  • 41.

    Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009;60(5):1472-83. [PubMed ID: 19404966]. https://doi.org/10.1002/art.24499.

  • 42.

    Sabat R. IL-10 family of cytokines. Cytokine Growth Factor Rev. 2010;21(5):315-24. [PubMed ID: 21112807]. https://doi.org/10.1016/j.cytogfr.2010.11.001.

  • 43.

    Okamoto A, Fujio K, Okamura T, Yamamoto K. Regulatory T-cell-associated cytokines in systemic lupus erythematosus. J Biomed Biotechnol. 2011;2011:463412. [PubMed ID: 22219657]. [PubMed Central ID: PMC3247013]. https://doi.org/10.1155/2011/463412.

  • 44.

    Lin PW, Huang CM, Huang CC, Tsai CH, Tsai JJ, Chang CP, et al. The association of -627 interleukin-10 promoter polymorphism in Chinese patients with systemic lupus erythematosus. Clin Rheumatol. 2007;26(3):298-301. [PubMed ID: 16826368]. https://doi.org/10.1007/s10067-006-0329-8.

  • 45.

    Sobkowiak A, Lianeri M, Wudarski M, Lacki JK, Jagodzinski PP. Genetic variation in the interleukin-10 gene promoter in Polish patients with systemic lupus erythematosus. Rheumatol Int. 2009;29(8):921-5. [PubMed ID: 19082598]. https://doi.org/10.1007/s00296-008-0776-4.

  • 46.

    Lin YJ, Wan L, Huang CM, Sheu JJ, Chen SY, Lin TH, et al. IL-10 and TNF-alpha promoter polymorphisms in susceptibility to systemic lupus erythematosus in Taiwan. Clin Exp Rheumatol. 2010;28(3):318-24. [PubMed ID: 20576226].

  • 47.

    Rezaei A, Ziaee V, Sharabian FT, Harsini S, Mahmoudi M, Soltani S, et al. Lack of association between interleukin-10, transforming growth factor-beta gene polymorphisms and juvenile-onset systemic lupus erythematosus. Clin Rheumatol. 2015;34(6):1059-64. [PubMed ID: 25633651]. https://doi.org/10.1007/s10067-015-2877-2.

  • 48.

    Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010;62(2):542-52. [PubMed ID: 20112381]. [PubMed Central ID: PMC3057537]. https://doi.org/10.1002/art.27221.

  • 49.

    Pereira VA, Sanchez-Arcila JC, Teva A, Perce-da-Silva DS, Vasconcelos MP, Lima CA, et al. IL10A genotypic association with decreased IL-10 circulating levels in malaria infected individuals from endemic area of the Brazilian Amazon. Malar J. 2015;14:30. [PubMed ID: 25627396]. [PubMed Central ID: PMC4334410]. https://doi.org/10.1186/s12936-015-0548-z.

  • 50.

    Salimi S, Mohammadoo-Khorasani M, Yaghmaei M, Mokhtari M, Moossavi M. Possible association of IL-4 VNTR polymorphism with susceptibility to preeclampsia. Biomed Res Int. 2014;2014:497031. [PubMed ID: 24877103]. [PubMed Central ID: PMC4020502]. https://doi.org/10.1155/2014/497031.

  • 51.

    Mahmoudi M, Tahghighi F, Ziaee V, Harsini S, Rezaei A, Soltani S, et al. Interleukin-4 single nucleotide polymorphisms in juvenile systemic lupus erythematosus. Int J Immunogenet. 2014;41(6):512-7. [PubMed ID: 25320043]. https://doi.org/10.1111/iji.12152.

  • 52.

    Yu HH, Liu PH, Lin YC, Chen WJ, Lee JH, Wang LC, et al. Interleukin 4 and STAT6 gene polymorphisms are associated with systemic lupus erythematosus in Chinese patients. Lupus. 2010;19(10):1219-28. [PubMed ID: 20530519]. https://doi.org/10.1177/0961203310371152.

  • 53.

    Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87(6):2095-147. [PubMed ID: 8630372].

  • 54.

    Suzuki H, Takemura H, Kashiwagi H. Interleukin-1 receptor antagonist in patients with active systemic lupus erythematosus. Enhanced production by monocytes and correlation with disease activity. Arthritis Rheum. 1995;38(8):1055-9. [PubMed ID: 7639800].

  • 55.

    Salimi S, Mohammadoo-Khorasani M, Mousavi M, Yaghmaei M, Mokhtari M, Farajian-Mashhadi F. Association of interleukin-1 receptor antagonist VNTR polymorphism and risk of pre-eclampsia in southeast Iranian population. J Obstet Gynaecol Res. 2016;42(2):142-7. [PubMed ID: 26555681]. https://doi.org/10.1111/jog.12865.

  • 56.

    Rus V, Atamas SP, Shustova V, Luzina IG, Selaru F, Magder LS, et al. Expression of cytokine- and chemokine-related genes in peripheral blood mononuclear cells from lupus patients by cDNA array. Clin Immunol. 2002;102(3):283-90. [PubMed ID: 11890715]. https://doi.org/10.1006/clim.2001.5182.

  • 57.

    Tayal V, Kalra BS. Cytokines and anti-cytokines as therapeutics--an update. Eur J Pharmacol. 2008;579(1-3):1-12. [PubMed ID: 18021769]. https://doi.org/10.1016/j.ejphar.2007.10.049.

  • 58.

    Scuderi F, Convertino R, Molino N, Provenzano C, Marino M, Zoli A, et al. Effect of pro-inflammatory/anti-inflammatory agents on cytokine secretion by peripheral blood mononuclear cells in rheumatoid arthritis and systemic lupus erythematosus. Autoimmunity. 2003;36(2):71-7. [PubMed ID: 12820688].

  • 59.

    Parks CG, Pandey JP, Dooley MA, Treadwell EL, St Clair EW, Gilkeson GS, et al. Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism. Hum Immunol. 2004;65(6):622-31. [PubMed ID: 15219382]. https://doi.org/10.1016/j.humimm.2004.03.001.

  • 60.

    Chua KH, Lau TP, Tee ZY, Tan SY, Lian LH. Genetic Polymorphisms of the Interleukin-1 beta (IL-1β) -511 and +3954 Single Nucleotide Polymorphisms (SNPs) in Malaysian Systemic Lupus Erythematosus (SLE) Patients. J Health Sci. 2009;55(4):657-62. https://doi.org/10.1248/jhs.55.657.

  • 61.

    Yu MC, Huang CM, Wu MC, Wu JY, Tsai FJ. Association of TAP2 gene polymorphisms in Chinese patients with rheumatoid arthritis. Clin Rheumatol. 2004;23(1):35-9. [PubMed ID: 14749980]. https://doi.org/10.1007/s10067-003-0769-3.

  • 62.

    Huang CM, Wu MC, Wu JY, Tsai FJ. Lack of association of interleukin-1ß gene polymorphisms in Chinese patients with systemic lupus erythematosus. Rheumatol Int. 2002;21(5):173-5. https://doi.org/10.1007/s00296-001-0164-9.

  • 63.

    Camargo JF, Correa PA, Castiblanco J, Anaya JM. Interleukin-1beta polymorphisms in Colombian patients with autoimmune rheumatic diseases. Genes Immun. 2004;5(8):609-14. [PubMed ID: 15470475]. https://doi.org/10.1038/sj.gene.6364133.

  • 64.

    Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Steinkasserer A, et al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet. 1993;91(4):403-4. [PubMed ID: 8500797].

  • 65.

    Blakemore AI, Tarlow JK, Cork MJ, Gordon C, Emery P, Duff GW. Interleukin-1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus. Arthritis Rheum. 1994;37(9):1380-5. [PubMed ID: 7945503].

  • 66.

    Chai HC, Phipps ME, Chua KH. Genetic risk factors of systemic lupus erythematosus in the Malaysian population: a minireview. Clin Dev Immunol. 2012;2012:963730. [PubMed ID: 21941582]. [PubMed Central ID: PMC3176625]. https://doi.org/10.1155/2012/963730.