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Journal of Biomedicine and Biotechnology
Volume 2010 (2010), Article ID 838390, 11 pages
IL-10 and TNFα Genotypes in SLE
1Department of Functional Biology, Immunology Area, University of Oviedo, 33006 Oviedo, Asturias, Spain
2Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (CSIC), 33300 Villaviciosa, Asturias, Spain
3Department of Immunology, Hospital Universitario Central de Asturias, 33006 Oviedo, Asturias, Spain
Received 15 January 2010; Accepted 20 April 2010
Academic Editor: Timothy B. Niewold
Copyright © 2010 Patricia López et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The production of two regulators of the inflammatory response, interleukin 10 (IL-10) and tumor necrosis factor (TNF), has been found to be deeply deregulated in SLE patients, suggesting that these cytokines may be involved in the pathogenesis of the disease. Genetic polymorphisms at the promoter regions of IL-10 and TNF genes have been associated with different constitutive and induced cytokine production. Given that individual steady-state levels of these molecules may deviate an initial immune response towards different forms of lymphocyte activation, functional genetic variants in their promoters could influence the development of SLE. The present review summarizes the information previously reported about the involvement of IL-10 and TNF genetic variants on SLE appearance, clinical phenotype, and outcome. We show that, in spite of the heterogeneity of the populations studied, the existing knowledge points towards a relevant role of IL-10 and TNF genotypes in SLE.
In spite of its unknown etiology, it is accepted that genetics and environmental factors contribute to systemic lupus erythematosus (SLE) susceptibility and outcome. The levels of various cytokines have been found elevated in SLE patients; so they have been considered essential elements in the etiopathology of the disease. Given that the production of these molecules is controlled at genetic level, functional polymorphisms in their promoters could influence the development and severity of the disease. In particular, the production of interleukin 10 (IL-10) and tumor necrosis factor (TNF), two mutually regulated cytokines that play complex and predominantly opposite roles in systemic inflammatory responses, has been found to be deregulated in SLE patients (Figure 1). Besides its stimulated production, various cell types are constitutively capable of producing detectable amounts of these cytokines, mainly cells of myeloid origin and less abundantly T and B lymphocytes. It has been reported that individual steady-state levels of these molecules may deviate an initial immune response towards different forms of T cell activation, influencing the likelihood to transform a limited autoimmune response into an autoimmune disease.
Several evidences suggest that IL-10 could be a strong candidate gene influencing SLE susceptibility. IL-10 is an important immunoregulatory cytokine that inhibits T cell function by suppressing the expression of proinflammatory cytokines such as TNF, IL-1, IL-6, IL-8, and IL-12 [1, 2]. It also inhibits antigen presenting cells by downregulating major histocompatibility complex class II (MHC-II) and B7 expression . In addition to these inhibitory actions, IL-10 promotes B-cell-mediated functions, enhancing survival, proliferation, differentiation, and antibody production . Hence, increased production of IL-10 could thus explain B cell hyperactivity and autoantibody production, two main features of the immune dysregulation in SLE. In fact, elevated levels of this molecule have been currently reported in SLE patients, frequently associated with indicators of disease activity [5, 6]. Moreover, it has been demonstrated that IL-10 plays an important role in murine lupus. Ishida et al.  reported that continuous administration of anti IL-10 antibodies in the murine lupus model New Zealand black/white (NZB/W) F1 delayed the onset of autoimmunity and improved the survival rate from 10 to 80%. Interestingly, Llorente et al.  demonstrated that constitutive IL-10 production by monocytes and B cells in healthy members of multicase families with SLE was significantly higher than that of healthy unrelated controls, but was similar to that of SLE patients, thus suggesting that a genetically controlled high innate IL-10 production may predispose to SLE development.
In the same way, TNF is a well-known cytokine for its role in the regulation of inflammation and apoptosis, two processes involved in the pathogenesis of SLE. This molecule stimulates the production of inflammatory cytokines, enhances neutrophil activation and expression of adhesion molecules and acts as a costimulator for T-cell activation and antibody production. Accordingly, in vivo and in vitro studies demonstrated that high levels of TNF lead to exacerbation of the inflammatory response. These effects, together with its potent immunomodulator activities [9–11], could support the involvement of TNF in the pathogenesis of SLE . However, initial studies in murine models of SLE showed contradictory results, probably because different strains of lupus prone mice have different phenotypic features. Thus, whereas the (NZB/W) F1 strain produces relatively low level of TNF and treatment with recombinant TNF caused a significant delay in the onset of nephritis and an improved survival rate , MRL-lpr/lpr and BXSB strains constitutively produce relatively high amounts of TNF, being its effect deleterious in the outcome of the disease .
Nevertheless, a number of studies showed higher serum levels of TNF in SLE patients compared with controls, which were frequently linked to SLE activity  or to specific immunological or clinical features, such as elevated autoantibody production [10, 11, 16]. All these data lead to suspect that TNF has an important role in SLE susceptibility or outcome [17, 18].
2. Functional IL-10 and TNF Genetic Polymorphisms
Human IL-10, encoded by a gene located at chromosome 1, is secreted by a variety of cell types in response to several activation stimuli. This cytokine could be also constitutively produced at low levels by immune cells, mainly monocytes, macrophages and dendritic cells. In fact, in contrast to many other cytokines, the synthesis of IL-10 is regulated by the transcription factors Sp1 and Sp3, which are constitutively expressed by different cell types . The striking interindividual differences detected in IL-10 levels at both in vivo constitutive and in vitro following cellular stimulation , suggest that its production is genetically controlled. A number of genetic polymorphisms at the promoter region of the IL-10 gene have been reported, some of them associated with different constitutive and induced cytokine production. Among them, the most widely studied include two areas of multiple (CA)n repeats, the microsatellites IL10.R ( Kb) and IL10.G ( Kb) [21, 22] with probable association with IL-10 production, and three single nucleotide polymorphisms (SNPs) located at (G/A), (C/T) and (C/A) positions upstream of the transcription start site . A complete linkage disequilibrium exists between the alleles present at and positions; so these polymorphisms occurred in tandem and only three haplotypes have been found in Caucasian populations (GCC, ACC and ATA). These SNPs have been associated with variability in IL-10 production [24–26] and carriers of the GCC/GCC genotype are considered as genetically high producers, being G the most relevant allele [24, 27, 28] (Table 1) [29–46].
The gene encoding TNF is located at the MHC class III region, placed on chromosome 6p21. Similarly to IL-10, an important genetic diversity at the TNF promoter has been detected. In vitro studies indicated that TNF production varied among different alleles of the five microsatellite markers described (a, b, c, d and e). In addition, several SNPs have been identified [47–49], being G/A and G/A the most extensively examined. The polymorphic variant A is associated with DR3 and DR7 in extended haplotypes [50, 51], but no consistent data about their functionality were reported. Polymorphism present at position , identified by Wilson et al. , has been associated with different levels of cytokine production. The less common TNF2 allele (A) has been related to higher TNF transcription rate than the TNF1 allele (G) after in vitro activation of lymphocytes with different stimuli [52, 53]. In vivo studies on mRNA constitutive levels confirmed this association  (Table 1). TNF2 is part of the extended haplotype HLA-A1-B8-DR3-DQ2 , associated with high TNF production [56, 57] and with predisposition to several autoimmune diseases. Nevertheless, carriage of TNF2 allele—in the presence or absence of other loci—leads to an increase in TNF production that could modify cytokine homeostasis in favor of the development of pathogenic situations.
3. IL-10 Genetic Polymorphisms and SLE Susceptibility
The IL-10 gene is situated in a major SLE susceptibility locus (1q31-32) . However, in spite of the considerable number of genetic studies performed, no definitive result about its involvement in SLE susceptibility was achieved. Some works showed significant associations between IL-10 microsatellites or SNPs with SLE susceptibility or with the development of certain clinical or immunological features, while other studies indicated that these polymorphisms did not appear to have any relevance in the disease (Table 2) [27–31, 34, 45, 59–71]. With respect to microsatellite variants, different alleles of IL10.G have been reported to be associated with SLE incidence in various populations. Thus, frequency of IL10.G9 allele (21 CA repeats) was significantly decreased in European [30, 66, 71] and Mexican-American  SLE patients, whereas the long alleles IL10.G10, G11 and G13 (with a CA repeat number greater than 21) were significantly increased in Mexican-American , Italian [30, 66] and British  patients respectively. On the contrary, an increase in IL10.G4 (short allele) was reported in Chinese patients  whereas no significant differences in IL10.G alleles were detected in other cohorts [65, 68, 72, 73]. In addition, a meta-analysis study showed only association of the IL10.G11 allele with SLE susceptibility in the populations analyzed (OR = 1.279; 95% CI: 1.027–1.593; ) . It has been reported that LPS-stimulated cells from individuals carriers of the IL10.G allele with 26 CA repeats presented higher IL-10 production than those from carriers of short alleles , suggesting that long alleles might be responsible for a high IL-10 production. Thus, accordingly to these data, high IL-10 producer genotypes (with more than 21 CA repeats) could be associated with SLE susceptibility, while presence of short alleles could confer a protective effect [60, 66].
Conflicting results were also obtained after examining the possible association between SLE susceptibility and SNPs at , and positions of IL-10 gene in the different populations in which they were investigated. The frequency of high IL-10 producers (carriers of G allele or GCC haplotype) was found to be increased in several works with Asian [62, 74] or European [59, 75] patients, although most of the studies performed in Caucasian populations did not show significant associations [27, 31, 34, 45, 64, 67, 69, 76].
4. TNF Genetic Polymorphisms and SLE Susceptibility
Less controversial data exist with regard to TNF SNPs, since genotypes associated with high cytokine production have been linked to SLE susceptibility in different populations (Table 3) [31, 38–46, 74, 77–90]. Thus, an increased risk of developing SLE, independent of the HLA-DR genotype, has been reported for carriers of TNF2 allele in Caucasian [31, 44–46, 78, 81, 90], African American , Chinese [82, 85], Colombian [31, 38, 92] and Mexican  populations, while no relation was found in a few works analyzing mestizo Mexican , Caucasian [39, 84], African Americans  or Asian [41, 60, 74, 85] cohorts. In fact, the allele-based comparisons of 21 studies , after stratification by ethnicity, detected a significant association of the A allele in the European-derived groups, but not in Asian-derived or African-derived populations. Conversely, no association between TNF SNP and SLE was observed in the great majority of the populations analyzed [42, 44, 74, 81, 89, 92]. On the other hand, the influence of TNF microsatellite variants in SLE incidence has been poorly investigated. Alleles a2, b3 and d2 have been found to be increased in SLE patients from various European populations [86, 87, 93], showing linkage disequilibrium with HLA-DR3 haplotypes associated with SLE risk. On the contrary, no association was found in a study with Japanese patients .
5. Influence of IL-10 and TNF Genotypes on Autoantibody Production
The presence of autoantibodies, mainly directed against nuclear antigens (ANAs), is one of the most characteristic features of SLE. It has been observed that the incidence of ANAs is more frequent among nonaffected family members of SLE patients than in the healthy population, suggesting that presence of autoantibodies may be, at least in part, genetically controlled [94–96]. The effect of IL-10 genotypes did not seem to be especially relevant, although it has been reported an increased prevalence of antibodies against several extractable nuclear antigens (anti-ENA) in patients with the allele IL-10.G9 , and the presence of anti-Sm antibodies was found significantly overrepresented among patient carriers of G14 and G15 alleles and R2-G15 and R2-G14 haplotypes .
On the other hand, an association of the high producer TNF genotypes ( AA or AG) with the presence of autoantibodies has been consistently reported. It has been described an association between carriage of the TNF2 allele and presence of anti-SSa or anti-SSb antibodies [45, 82, 85]. This finding is in accordance with the increased frequency of TNF2 allele reported in patients with cutaneous lupus erythematosus [76, 97], congenital heart block  and cutaneous neonatal lupus , all of them being pathologies linked to the presence of anti-SSa antibodies. However, it is important to consider that the actions of cytokines may be profoundly conditioned by the presence of other cytokines, and this is particularly true in the case of IL-10 and TNF, two mutually regulated molecules which have opposite roles in the inflammatory reactions. In fact, the investigations about the effect of combined IL-10 and TNF genotypes in SLE supported this interaction. Specifically, the highest percentage of antibodies against SSa and SSb was found among carriers of the combined genotype “low IL10 (AA-AG)/high TNF (AA-AG)” , the genotype linked to the highest TNF production . Association of high TNF genotypes, alone or in combination, and autoantibody appearance has also been described in patients with other autoimmune pathologies such as inflammatory bowel disease or Sjögren`s syndrome [101–103]. This effect of TNF could be mediated by its highly proapoptotic activity since, as it has been reported, sera from SLE patients react with proteins phosphorylated during apoptosis , probably by recognising new epitopes generated by phosphorylation or proteolysis . Thus, we can hypothesize that the proapoptotic properties of elevated TNF levels could not be counterbalanced by the low amounts of IL-10 in patients with the high TNF/low IL-10 genotype, thus triggering an autoimmune response to antigenically modified autoproteins generated during the apoptotic process.
6. Genetic Polymorphisms and Clinical Outcome
Increased circulating levels of IL-10 and TNF have been consistently reported in the sera of patients with SLE. However, there were no definitive data on the association of IL-10 or TNF polymorphisms and specific clinical manifestations, probably due to the heterogeneity of the disease. For instance, renal involvement has been associated with both high (GCC) [27, 106] and low (ATA)  IL-10 producer genotypes. High prevalence of neuropsychiatric  and cardiovascular disorders  has been reported in patients with low genetic production whereas high IL-10 production has been linked to an increased incidence of serositis, hematological disorder , SLICC/ACR Damage Index  and presence of discoid or mucocutaneous lesions [45, 68]. This last association was supported by the increased frequency of the high producer G allele observed in patients with discoid lupus erythematosus [45, 67] and by the fact that cutaneous manifestations improved in SLE patients under anti IL-10 monoclonal antibody treatment .
With respect to TNF genotype, most works did not find relevant relationships with clinical parameters, although it has been reported an increased frequency of the TNF2 allele in patients with nephritis , central nervous system involvement  and presence of malar rash, discoid lesions, photosensitivity, oral ulcers or serositis . However, it is worth noting the interesting association detected between TNF genotype and clinical outcome after antimalarial treatment. Antimalarial drugs (hydroxychloroquine, chloroquine, and quinacrine) have been widely used as disease-modifying antirheumatic agents mainly in the treatment of SLE and rheumatoid arthritis . Nevertheless, their beneficial mechanisms have not been fully defined. Several in vitro experiments have demonstrated that antimalarials decreased the production of proinflammatory cytokines induced by LPS or CpG oligonucleotides in monocytes and macrophages [111–114] by a nonlysosomotropic mechanisms  and/or by blocking the interaction between TLR9 and CpG in monocyte endosomes . More recently, this valuable antiinflammatory effect has been documented in patients with SLE, in whom antimalarial-treatment has been shown to downregulate serum levels of TNF [100, 117]. But the most interesting finding was that antimalarial effect seems to be influenced by polymorphisms of the genes encoding TNF and IL-10. Specifically, the greatest beneficial effect of antimalarial treatment appeared in patients carriers of the combined genotype low IL-10/high TNF, since they presented better clinical response, lower amount of circulating TNF and increased number and function of Treg cells  as compared with other genotypes. Of note, antimalarial treated SLE patients which were carriers of the opposite high IL-10/low TNF genotype, presented higher circulating IFN levels, thus suggesting an interesting relationship between TNF and IFN in lupus disease .
7. Conclusions and Perspectives
It seems to be clear that carriage of the high producer TNF2 allele is a risk factor for SLE appearance in Caucasian populations. However, in spite of the wide number of studies performed, conclusive data on the involvement of IL-10 genetic variants have not been obtained. Nevertheless, the inverse relationship existing between both cytokines, could determine a role for IL-10 in the phenotype and/or outcome of the disease. SLE patients carriers of the high TNF genotype probably developed the disease due to the effect of environmental or genetic factors added to their high TNF production. The elevated levels of this cytokine may be involved in diverse pathological mechanisms and, therefore, a clinical benefit could be expected under a treatment that diminishes TNF production. In fact, a strong association was found between carriage of this genotype, in combination with low IL-10 producer alleles, and good response to antimalarial therapy, a treatment that downregulated TNF levels. Thus, we would expect that carriage of the proinflammatory genotype low IL-10/ high TNF may predispose to develop anti-SSa/SSb antibodies and mild disease presenting a good course under antimalarial therapy. In addition, the conflicting data about the association of IL-10 and TNF genotypes with clinical features which were observed by the various studies performed supports the heterogeneity of the disease and the involvement of diverse etiopathogenic factors. Thus, treatments and management of the disease might be individualized depending on IL-10 and TNF genotypes.
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