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Effects of Interleukin Families Polymorphisms on Systemic Lupus Erythematous Disorder: Focus on Interleukin-1
Systemic lupus erythematous (SLE) disease increases the activity of B cells and production of antibodies against tissue antigens. This disease damages on many tissues and organs such as joints, kidneys, heart and nervous system. The exact cause of SLE is unknown, but it is suggested that genetic background plays an important role in lupus pathogenesis. Many studies suggested that interleukins play important role in progression of SLE. Interleukins are a group of cytokines, which secreted by T helper cells, monocytes, macrophages and B cells, and involved in growth and differentiation of T and B cells. The expression levels of interleukins are controlled by genetic background. Furthermore, some polymorphisms increase or decrease the expression of interleukins. Understanding these factors increase our information about the SLE. Therefore, in present study we reviewed the roles of eight important interleukins polymorphisms and their effects on SLE pathogenic.
Keyword: Interleukin-1, Cytokines, Systemic Lupus Erythematous
Systemic lupus erythematous (SLE) is a chronic human autoimmune disease which affects various body organs in the human. This disease is created with increased activity of B cells and production of antibodies against endogenous antigens in body. Accumulation of antibodies in tissues and organs plays a key role in clinical signs of SLE (1, 2). Lupus can have an impact on many organs such as kidneys, heart and nervous system. The joints affected more in SLE type and the skin affected much more in all types of lupus (3, 4).
The prevalence of lupus in different populations is 20 to 150 cases per 100,000 individuals around the world (2). Also the disease in women of reproductive age is about 9 times more frequent than men, and its prevalence is variable in race, ethnicity, geographic and social and economic status. This disease is not common in children and about 20% of the patients are children less than 15 years (5).
The exact causes of this disease are still unknown, but genetic and environmental factors play an important role in the lupus pathogenesis (6). The genetic basis of lupus is very complex and determines the number of involved genes in different stages of disease is difficult (7). It seems that this disease is created due to the loss of the body’s tolerance to insider’s antigens and then production of antibodies against the cell’s nucleus (8, 9). Generally, lupus was classified in four groups including; discoid lupus, drug-induced lupus, neonatal lupus and systemic lupus erythematous (10).
Interleukins (IL) are a group of cytokines, which secreted mostly by T helper cells, monocytes, macrophages, dendritic cells, natural killer cells and cell B. The interleukins mainly involved in the growth and differentiation of T and B cells and activate natural killer cells. Several studies showed that inflammatory interleukin genes play an important role in creation of SLE. These interleukins include; interleukin 1 (11), interleukin 1 beta (12), interleukin 4 (12), interleukin 6 (13), interleukin 7 (14), interleukin 10 (13), interleukin 21 (15), interleukin 19 (16), interleukin 27 (17), interleukin 31 (18) and interleukin 32 (19).
Recognizing of these interleukins increases our information about the SLE disorder and leads to development of novel treatment methods and early diagnosis. In the present review the roles of inflammatory interleukin genes and especially the Interleukin 1 gene family were studied in creating the SLE disease.
2. Interleukins involved in Systemic Lupus Erythematous
The cytokines are secreted by cells which involved in immune systems, such as T cells and other immune response cells. According to the types of T cell, some of the cytokines play inhibitory roles and some other play excitatory roles. One of the most important issue is the balance between Th1/Th2 cytokines, which loss of this balance lead to SLE. Yet, there is not comprehensive information about the relationship between Th1 and Th2 levels; however, it is clear that increasing levels of Th2 is important in progression of SLE. On other hands, reducing levels of Th1 involved in progression of SLE. There are many important Th1 and Th2 cytokines, which involved in pathogenesis of SLE, such as IL-12, IL-4, IL-10 and IL-6 (4, 20, 21).
Production of interleukins can be controlled by genetic factors, and it seems that some polymorphisms can lead to increase or decrease the expression of interleukin genes, thereby increase the susceptibility to certain diseases (22). Thus, different studies reported significant association between interleukins and SLE, which will be described below.
2.1. Interleukin 23 (IL-23)
It is believed that the IL-23 is an important factor in the pathogenesis of autoimmune diseases. Recently abnormalities in this cytokine have been reported in the development of SLE. The IL-23 is able to stimulate TCD4 for production of pro-inflammatory cytokines such as IL-17 and IFNγ. So, this cytokine plays an important role in progression of SLE. Clinical and pathological signs of SLE nephritis were decreased in defect of IL-23 receptors. Therefore, it appears that IL-23 is an essential factor in damaging the kidneys in SLE patients (23, 24).
2.2. Interleukin 21 (IL-21)
IL-21 is produced from follicular T cells. This cytokine induces differentiation and development of T helper cell, and stimulates the production of antibodies by B cells. Therefore, IL-21 plays an important role in progress of SLE (25). Previous studies showed that plasma levels of IL-21 have increased in patients with SLE.
Variations in the IL-21 gene may lead to change in IL-21 protein, which can alter the susceptibility of individuals to SLE. Several polymorphisms in the IL-21 gene have been identified in association with SLE (26-28). Recently, some studies showed that IL-21 increases inflammatory diseases and autoimmune chronic diseases in human. Also animal studies reported that IL-21 plays an important role in the pathogenesis of SLE, and its serum level in patients was more than healthy persons. In addition, some other studies showed that the polymorphisms of IL-21 and its receptor were associated with susceptibility to SLE (29).
2.3. Interleukin 18 (IL-18)
The IL-18 protein is belongs to IL-1 family and it is in an inactive form, which needs to be cut by caspase-1 to become biologically active form. The IL-18 has many biological function, such as influences on dendritic cells, T lymphocytes and natural killer cells, and is a potent inducer of IFN-A to increase differentiation of Th1 cell (30). Previous studies showed that concentration of IL-18 has increased in patients with SLE. Also some other studies reported that levels of IL-18 was associated with kidney problems in SLE patients (31, 32). Serum levels of IL-18 in SLE patients was more than healthy controls and it was associated with micro-albumin levels in urine (33). In addition, the gene expression of IL-18 has increased in the glomeruli of patients with SLE nephritis (33). Also over-expression of IL-18 causes skin lesions in patients with SLE (34).
2.4. Interleukin 17 (IL-17)
The IL-17 is a pro-inflammatory cytokine, which is well-known as IL-17A and plays an important role in the regulation of inflammation process. In past years, it was identified that six types of IL-17, involved in SLE, such as IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. This pro-inflammatory cytokines, primarily released by activated T lymphocytes (35, 36). IL-17 significantly leads to proliferation of cell B and production of antibodies. Therefore, elevation of serum IL-17 have been reported in development of SLE disease (23, 24, 37). Recent studies showed that IL-17 releases significantly by lymphocytes T, in patients with SLE (38). In addition, the IL-17 induced adhesion of mRNA molecules and T cells to endothelial cells, in patients with SLE (39).
2.5. Interleukin 10 (IL-10)
It is suggested that IL-10 is involved in suppressing of T cells function, directly. However it seems that, this interleukin plays an important role in increasing B cells activation. IL-10 mainly released by activated macrophages and also at lower values, released by other cell types, such as T cells and keratinocytes (40). The serum levels of IL-10 were increased in SLE patients and it was related with disease activity. This interleukin leads to stimulate the proliferation and differentiation of B cells. Also, the IL-10 affects the expression of Bcl-2 and decreases the apoptosis in B cells. Therefore, it can enhance production of antibody.
Recently, studies showed that injection of IL-10 to mice with SLE leads to increase involvement of kidney in diseases (23, 24, 41). Also, many studies reported that various polymorphisms in the promoter region of the IL-10 gene were associated with SLE (42-44). However, another study has reported no association between IL-10 polymorphisms and susceptibility to SLE in adolescents (45).
2.6. Interleukin 6 (IL-6)
Interleukin 6 (IL-6) was produced by TNF and IL-1. It has pleiotropic effect on many tissues in human. This cytokine secreted by macrophages cells and in lower amounts secreted by mesangial, endothelial and lymphocytes (23). The IL-6 leads to increase the activation and secretion of macrophage, B lymphocyte and immunoglobulin. Also, IL-6 can promote differentiation of Th17 cells, which play important role in many autoimmune diseases. Studies showed that levels of IL-6 increased in the serum and urine in patients with SLE (24). Also many studies reported that this cytokine plays an important role in renal disease in patients with SLE (46).
2.7. Interleukin 4 (IL-4)
The IL-4 gene is an anti-inflammatory cytokine, which produced by Th2 CD4+ cells on the surface of basophils and mast cells (47). The IL-4 protein is a key cytokines, which leads to activation and differentiation of B cells and also involves in development of T cells (48). This cytokine has a cytotoxic effect, which leads to 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 seems that the role of IL-4 in the development of SLE depends on genetic background. Some studies showed that the IL-4 gene may be involved in the progress of SLE (49, 50). In our recent study on SLE patients, we demonstrated that IL-4 gene is associated with SLE and may play an important role SLE progression (12).
3. Interleukin 1 family
The interleukin-1 (IL-1) gene cluster is formed from a 430kb region and include encoding genes, such as IL-1α (IL-1A), IL-1β (IL-1B) and receptor antagonist of interleukin-1 (IL-1RN). Many studies showed significant differences in the expression level of IL-1 family between patients with SLE and healthy subjects (11, 22). The IL-1A and IL-1B proteins are pro-inflammatory cytokines and play important role in many biological extensive activities. The IL-1A and IL-1B are binding to the IL-1 receptor and lead to signal transduction and biological effects. In contrast, the IL-1Ra protein is a competitive inhibitor and binding to IL-1 receptors and leads to inhibition of intracellular signaling (51) . It is believed that interfere in balance between these three proteins and their receptors may play important roles in creation of autoimmune diseases.
4. Interleukin 1 and SLE
The IL-1 protein family is a polypeptide include IL-1 alpha (IL-1α), IL-1 beta (IL-1β) and IL receptor antagonist (IL-RA). The IL-1 was located on human chromosome 2 (2q13-21), in 430-kb region, and IL-1α and IL-1β genes are very close together (52). The IL-1α and IL-1β are pro-inflammatory cytokines and involved in many biological activities. Studies suggested that imbalance between IL-1α, IL-1β and IL-RA proteins causes autoimmune response (51). Many studies reported significant relationship in production of IL-1 family with SLE patients (53-55).
Abnormal expression of the IL-1 family members has been involved in progression of SLE, which is revealed since 1983 (56). But so far, many studies have not been performed to investigate the relationship between IL-1 member’s polymorphisms and SLE. In one study performed by Chua et al. (2009), they showed that patients with SLE are susceptible to IL-1β -511C/T polymorphism in Malaysian population; they reported that C allele and its homozygous increases the SLE risk (57). On the other hands, Parks et al. (2004) reported that T allele increases susceptibility of SLE in African Americans population (56). Also Huang et al. (2002), reported no relationship between IL-1β -511C/T polymorphism and SLE in Taiwan population (58). In a similar study Chua et al. (2009), reported a significant association between IL-1β +3954E1/E2 polymorphism in exon 5 and patient with SLE in Malaysian population and E1 allele increases the SLE risk (57). Also this result have seen in patients with SLE Columbian population, but not seen in Chines population (59, 60).
The activity and production of IL-1α and IL-1β are controlled by IL-receptor antagonist (IL-1RA or IL-1RN). The dysregulation in expression of IL-1 by IL-1RA abnormal activity leads to high inflammatory response and cause damage to tissues. The tissues damages are one of the SLE symptoms. Many studies performed to evaluation of association between IL-1RN gene polymorphisms and SLE. The IL-1RA variable numbers tandem repeat -86bp (VNTR 86-bp) polymorphism in intron 2 is relevant with SLE risk (61, 62). Our previous study in association between VNTR 86-bp polymorphism and SLE showed that IL-1RN∗2 allele no association with SLE (11). On the other hands, Blakemore et al. reported association between IL-1RN∗2 allele and SLE susceptibility (62). Also Lian et al. showed that IL-1RN∗2 allele was associated with SLE in Malaysian population (63).
In this present study, we have considered some interleukins which play important roles in SLE pathogenesis. Our study showed some cytokines, which have important roles in SLE pathogenesis. SLE is an autoimmune disorder with many heterogeneous symptoms. The main mechanism of this disorder remains unknown. However, many studies suggested that SLE is a multi-factorial disease, which involve genetic, environmental and immunological agents. These factors lead to sensitivity of the body toward antigens; therefore, immunologic responses become out of control in some body tissues and cause damage to these tissues. Many studies performed on SLE patients and SLE animal models showed that over expression of some interleukin families play important roles in the SLE progression. Over expression of some inflammatory interleukins lead to increase of auto reactive B cells, which cause to increase the production of autoantibodies in body. In addition many genetic antigens, which involved in immune response process, TLR signal transduction to IFN type I production and lymphocytes signal transduction are well-known as important factors in pathogenesis of SLE disorder.
Declaration of Interest
The authors declare that they have no conflicts of interest.
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