INTRODUCTION

Chlamydia species are obligate intracellular parasites which cause several complications [1]. It has been evidenced that immune responses to Chlamydia species participate in Chlamydia complications [2]. Moreover, previous studies demonstrated that Chlamydia species are able to regulate immune responses via modulated expression of some immune system molecules including cytokines [3, 4]. These studies also demonstrated that cytokines play important roles in the regulation of immune responses against infectious agents which have been revealed to be important in either eradication or pathogenesis of microbial infections [5]. IL-10 is the main anti-inflammatory cytokine which is produced by several immune cells (see next section). This cytokine plays pivotal roles in the induction of either immune-tolerance against self antigen or immune-homeostasis after microbe elimination [6–8]. Additionally, there are studies indicating that up-regulation of IL-10 is associated with several chronic infectious diseases and their complications [9, 10]. Therefore, it can be hypothesized that alteration in the expression of this cytokine can be associated with infection of pathologic Chlamydia species and their associated complications. Thus, the main aim of this review was to collect the recent information regarding the association and relationship of IL-10 with Chlamydia infections. Additionally, studies reported that single nucleotide polymorphisms (SNPs) within IL-10 gene are associated with the regulation of IL-10 expression [11]; hence, another aim of this review article was to address recent data regarding the association of genetic variations (polymorphisms) of IL-10 and Chlamydia infections.

IL-10

IL-10 is an anti-inflammatory cytokine which is produced by several types of immune cells including B and T regulatory and Th2 lymphocytes, activated macrophages and other cells [12]. Two transcription factors, Sp1 and Sp3, are responsible for the regulation of IL-10 expression by immune cells. The IL-10 gene is located on 1q31–1q32 and is approximately 5.2 kB. There are five exons within IL-10 gene [13] which encodes a 178 amino acid protein that is called pro-IL-10 [14]. Pro-IL-10 is activated after cleavage of 18 amino acids, the signal peptide, from the N-terminal of the cytokine [14]. IL-10 affects target cells via interaction with its corresponded receptor, IL-10 receptor (IL-10R) [15]. IL-10R belongs to type II cytokine receptor and consists of two chains, α and β [15]. IL-10/IL-10R interaction leads to activation of several intracellular signaling pathways which are discussed in the next section. IL-10 is the most important regulatory factor to suppress the inflammatory functions of Th1, Th2, and B lymphocytes, NK cells, macrophages, and dendritic cells [14, 16]. Therefore, it appears that this cytokine plays key roles in the suppression of immune responses during prolonged course of infections.

IL-10 RECEPTOR INTRACELLULAR SIGNALING

As mentioned in the previous section, IL-10 has immunoregulatory functions which regulate the activities of many of the immune cells [7]. IL-10 binding to the extracellular domain of α chain of IL-10R results in phosphorylation of two protein kinases, JAK1 (Janus kinase-1) and TYK2 (tyrosine kinase-2), which are associated with IL-10R α and β chains, respectively [17]. Interestingly, the phosphorylated (activated) kinases then phosphorylate tyrosine residues at Y446 and Y496 positions of IL-10R α chain intracellular domain [18]. Signal transducer and activator of transcription 3 (STAT3) binds to phosphorylated Y446 and Y496 via its SH2 (Src homology-2) domain, and the receptor-associated JAKs phosphorylate STAT3 tyrosine residues [19]. Following tyrosine phosphorylations, STAT3 homodimerizes and translocates into the nucleus and interacts with STAT-binding element (SBE) regions within the promoters of IL-10 target genes which leads to the up-regulation of target genes including suppressor of cytokine signaling 3 (SOCS3), anti-apoptotic, cell-cycle-progression genes, and so on [20]. It has also been documented that IL-10/IL-10R interaction also activates another pathway (PI3K (phosphoinositide-3 kinase) as well as its downstream substrates p70S6K (p70 S6-kinase) and Akt/PKB (protein kinase-B)) which leads to the survival of target cells [21]. IL-10 also regulates the p38/MAPK (mitogen-activated protein kinase) pathway (Fig. 1) [22].

Fig. 1
figure 1

Intracellular signaling of IL-10 receptor (IL-10R). The figure shows that IL-10/IL-10R interaction leads to the phosphorylation of STAT3 as well as activation of MAPK and AKT/PKB pathways. Activated STAT3 is translocated to the nucleus and bind to SEB region that result in transcription from SOCS3. SOCS3 inhibits intracellular signaling of pro-inflammatory cytokines and Jak molecules.

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IL-10 GENE POLYMORPHISMS

According to the fact that IL-10 expression is genetically regulated by promoter region [23, 24], so, it appears that the polymorphisms within this region can be considered as potential candidates for studying in the immune system related diseases. It has been reported that there are three biallelic polymorphisms including -1082G/A (rs1800896), -829C/T (rs1800871), and -592C/A (rs1800872) within promoter region of IL-10 [25]. Since, these single nucleotide polymorphisms (SNPs) are associated with changes in IL-10 expression [26], alteration in the expression of IL-10, which is reported in chronic infectious diseases, can be associated with the polymorphisms within this region of IL-10 gene. Next sections present recent data regarding the association between Chlamydia infections and the polymorphisms within the promoter region of IL-10 gene.

CHLAMYDIA

The order Chlamydiales currently comprises four families including Chlamydiaceae, Parachlamydiaceae, Simkaniaceae, and Waddliaceae [27]. Chlamydiaceae family is divided into two genera including Chlamydophila and Chlamydia [28]. The genus Chlamydia has four species as follows: (1) Chlamydia trachomatis, (2) Chlamydia suis, (3) Chlamydia muridarum, and (4) Chlamydia pecorum [28]. Chlamydia species as obligate intracellular bacterial pathogens with a unique and host-cell dependent biphasic developmental cycle has caused a great health problem throughout the world [29]. Latest studies from the World Health Organization (WHO) indicated that there were an estimated 101.5 million new cases per year of Chlamydia infection among adults aged 15 to 49 years [30]. In Europe, the prevalence of Chlamydia infection among unscreened asymptomatic women ranges between 1.7 and 17 % [31], with sexually active women and men under the age of 20 and 25 years respectively being most affected. Chlamydia infections are asymptomatic in up to 90 % of women and more than 50 % of men [32]. In Italy, the prevalence of chlamydial infection among infertile couples was reported about 8 % [33]. Recent studies from North America and Europe revealed that the role of C. trachomatis in pelvic inflammatory disease (PID) is greater than Neisseria gonorrhea [34]. In the Middle East countries, few data regarding the epidemiologic aspects of this infection is available. Two studies performed in the United Arab Emirates and Jordan reported that the frequency of C. trachomatis infection was 3 and 5 % respectively [35]. Also, limited studies in Iran demonstrated a wide range of frequency among female patients from 3 to 15.5 % [36]. Despite this wide range of contamination, only a minority of infected individuals develop severe long-term complications such as trachoma or tubal factor infertility (TFI). A number of factors may be involved in the occurrence of these consequences including the presence of different strains among infected patients, pathogen genetic variability, the pathogen burden of each infected individual, and polymorphisms in host genetic risk factors [37]. This pathogen comprises different serovar groups causing diverse diseases in terms of severity and tissue tropism. To date, three well-known serovar groups are; lymphogranuloma venereum (L1–L3), ocular (A–C), and genital (D–K), serovars. C. trachomatis genital infections are global and cause considerable morbidities including PID and infertility, especially in women [38]. Since different C. trachomatis serovars can infect and survive in diverse host cells, they are responsible for a wide range of diseases in humans. For example, genital serovars contaminate genital tract epithelial cells causing a number of male and female genital tract infections while ocular serovars infect conjunctival epithelial cells affecting people with poor healthcare and resulting in trachoma, and the lymphogranuloma venereum (LGV) serovars infect macrophages and spread systemically through lymph nodes [38]. Several studies have investigated the correlation between host genetic factors and Chlamydial disease severity.

IL-10 AND CHLAMYDIA INFECTION

According to the aforementioned information, Chlamydia species may result in distributed infection in some patients, while, some of the infected patients are able to limit the infection. Researchers believe that the differences in genetic and immunological factors determine the outcome of infections in the Chlamydia infected patients. Due to the fact that IL-10 plays important roles in the regulation of immune responses (see previous sections), hence, it appears that this cytokine may be involved in the pathogenesis of Chlamydia infection. Interestingly, previous studies demonstrated that IL-10 suppresses expression of several pro-inflammatory molecules which are involved in immune responses against Chlamydia infections [39]. Additionally, Gao et al. reported that IL-10 suppresses expression of inducible co-stimulator-ligand (ICOS-L), an activator of T lymphocytes, on DC in an animal model with C. muridarum lung infection [40]. Yilma and colleagues also revealed that exogenous IL-10 is able to inhibit the secretion of TNF, IL-6, and IL-8 by C. trachomatis infected human epithelial cells and mouse macrophages [41]. Therefore, it appears that IL-10 up-regulation can be used by Chlamydia species to modulate immune responses. Interestingly, investigations demonstrated that IL-10 expression was increased during Chlamydia infections. For example, our previous study revealed that expression levels of IL-10 in the semen of patients suffering from C. trachomatis were significantly increased when compared to healthy controls [3]. Fedina et al. revealed that C. trachomatis induces expression of IL-10 by human monocytes [42]. Another study demonstrated that C. trachomatis-infected macrophages, Jurkat cells, and THP-1 cells present more IL-10 receptors than non-infected cells [43]. Campbell and co-workers also reported that single intra-nasal inoculation of Chlamydia pneumonia results in increased serum levels of IL-10 in C57BL/6J mice [40]. A study by Azenabor and York demonstrated that C. trachomatis induces IL-10 production by infected macrophages via increasing of intracellular Ca(2+) levels [42]. Moniz and colleagues indicated that C. muridarum induces expression of IL-10 by plasmacytoid dendritic cells [44]. Interestingly, another study reported that infection of human gingival fibroblasts with Chlamydia pneumoniae leads to up-regulation of IL-10 [45]. Moreover, several studies also confirmed that there is a positive correlation between Chlamydia infections and production of IL-10 by immune cells [46]. Vats and co-authors revealed that stimulation of peripheral blood mononuclear cells (PBMCs), which were obtained from C. trachomatis infected women, with the Chlamydial antigen resulted in a higher production of IL-10 compared to the PBMCs from healthy controls [47]. Several studies also reported that the immune cells derived from Chlamydia species infected patients produce higher IL-10 than non-infected individuals [48–52].

Gupta et al. also showed that IL-10 serum levels were increased in C. trachomatis infected infertile, but not fertile, women [41]. Therefore, it appears that increased expression of IL-10 not only is associated with persistent Chlamydia infection but also may be associated with Chlamydia infection complications such as infertility. Interestingly, Agrawal and colleagues reported that cervical lymphocyte infection with C. trachomatis leads to up-regulation of IL-10 by the infected cells which support the findings from the previous studies [53]. It has been also documented that C. trachomatis 60 kDa heat shock protein (CHSP60) induces IL-10 production in infertile women [54, 55]. Therefore, it may be concluded that Chlamydia modulate immune responses via up-regulation of IL-10 through its damage associated molecular patterns (DAMPs), such as CHSP60, and pathogen associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS). It has been also reported that toll-like receptors play important roles in the Chlamydia infections which recognize Chlamydia-derived DAMPs and PAMPs. Moreover, as mentioned before, variations in IL-10 gene may be associated with different expression of IL-10; hence, the polymorphisms within IL-10 gene may also be considered as another risk factor for persistence of Chlamydia infections. Although, there are three functional polymorphisms within promoter region of IL-10 gene, but previous studies reported the polymorphisms at position -1082 only in Chlamydia infected patients. For example, Ohman and colleagues demonstrated that C. trachomatis infected patients carried out IL-10–1,082 GG genotype produced higher levels of IL-10 in comparison to the patients with AA genotypes [56]. Another study revealed that the IL-10 -1082 AA genotype is associated with an increased risk of severe tubal damage in unfertilized C. trachomatis infected women [43]. Based on the fact that tubal damages are associated with lower expression of IL-10, hence, it appears that IL-10 -1082 AA genotype is associated with the lower expression of IL-10. Natividad et al. and Wang et al. also revealed that IL-10 -1082 G allele is associated with higher expression of IL-10 productions [57, 58]. Interestingly, Kinnunen and colleagues showed that IL-10 -1082 AA genotype were significantly associated with C. trachomatis tubal factor infertility, which is an inflammatory condition [59]. Therefore, it confirmed that this genotype is associated with lower expression of IL-10. In parallel with the results, a study by Mozzato-Chamay et al. revealed that IL-10 -1082 G allele is associated with higher levels of IL-10 in C. trachomatis endemic population [60]. Thus, based on these considerations, it may be concluded that IL-10 -1082 G allele and GG genotype can be considered as a risk factor for the up-regulation of IL-10 which is associated with persistent Chlamydia infection. Additionally, since there are other polymorphisms within IL-10 gene which have not yet been evaluated in infected patients, it appears that future investigations are essential to complete our knowledge.

CONCLUSION

Due to the aforementioned studies, it seems that IL-10 plays critical roles in the pathogenesis of Chlamydia infections and accordingly, Chlamydia species up-regulate this anti-inflammatory cytokine to suppress immune responses against their antigens. In addition to bacterial factors which up-regulate IL-10, genetic variations within IL-10 gene also determine the outcome of Chlamydia infection. Additionally, it has also been documented that Chlamydia infections are responsible for the severe damage of Fallopian tube tissue resulting in tubal infertility and ectopic pregnancy [61]. It appears that inflammation processes induced by Chlamydia infections are responsible for several complications including fallopian tube tissue damages. Hence, it may be hypothesized that IL-10 is also involved in the incidence of the complications of Chlamydia infections. On the other hand, IL-10 can reduce the pathologic effects of C. trachomatis infection on the Fallopian tube tissue [61]. Another study demonstrated that, although, the lack of anti-inflammatory action of IL-10 is associated with enhanced Chlamydia eradication, but leads to severe inflammation in IL-10 knock out (IL-10 KO) mice [62]. Thus, it seems that modulation of IL-10 expression in the Chlamydia infected patients is cautiously performed.