Clinical associations between IL-17 family cytokines and periodontitis and potential differential roles for IL-17A and IL-17E in periodontal immunity

Objective

IL-17A is implicated in periodontitis pathogenesis. The roles of IL-17B–IL-17F and IL-17A/F are unknown. This study aimed to determine clinical associations between IL-17 family cytokines and periodontitis and to investigate the biological roles of IL-17A and IL-17E using in vitro model systems.

Materials and methods

Samples from 97 patients with periodontitis and 77 healthy volunteers were used in the study. Serum, saliva and gingival crevicular fluid (GCF) levels of IL-17 family cytokines were measured by ELISA. Oral keratinocytes were stimulated with a P. gingivalis biofilm, or IL-17A, in the presence and absence of IL-17E and the expression of IL-8 and CXCL5 were investigated by ELISA and real-time-PCR. NF-κB phosphorylation in similar experiments was also measured using a cell-based ELISA.

Results

Serum, saliva and GCF IL-17A levels were higher in periodontitis patients and correlated positively with clinical parameters of attachment loss, pocket depth and bleeding on probing. Serum IL-17E levels were lower in periodontitis patients and the serum IL-17A:IL-17E ratio correlated positively with clinical parameters. In vitro, IL-17E inhibited Porphyromonas gingivalis and IL-17A induced expression of chemokines by reducing phosphorylation of the NF-κB p65 subunit.

Conclusions

Serum IL-17A:IL-17E may be a marker of disease severity. IL-17E may have opposing roles to IL-17A in periodontitis pathogenesis. IL-17E can negatively regulate IL-17A and periodontal pathogen induced expression of chemokines by oral keratinocytes.     

Recent progress in host immunity to avian coccidiosis: IL-17 family cytokines as sentinels of the intestinal mucosa

The molecular and cellular mechanisms leading to immune protection against coccidiosis are complex and include multiple aspects of innate and adaptive immunities. Innate immunity is mediated by various subpopulations of immune cells that recognize pathogen associated molecular patterns (PAMPs) through their pattern recognition receptors (PRRs) leading to the secretion of soluble factors with diverse functions. Adaptive immunity, which is important in conferring protection against subsequent reinfections, involves subtypes of T and B lymphocytes that mediate antigen-specific immune responses. Recently, global gene expression microarray analysis has been used in an attempt to dissect this complex network of immune cells and molecules during avian coccidiosis. These new studies emphasized the uniqueness of the innate immune response to Eimeria infection, and directly led to the discovery of previously uncharacterized host genes and proteins whose expression levels were modulated following parasite infection. Among these is the IL-17 family of cytokines. This review highlights recent progress in IL-17 research in the context of host immunity to avian coccidiosis.     

IL-17B: A new area of study in the IL-17 family

The interleukin (IL)-17 superfamily, a relatively new family of cytokines, consists of six ligands (from IL-17A to IL-17F), which bind to five receptor subtypes (from IL-17RA to IL-17RE) and induce downstream signaling. IL-17A, a prototype member of this family, has been reported to be involved in the pathogenesis of allergies, autoimmune diseases, allograft transplantations, and malignancies. Unlike IL-17A, which is mainly produced by T helper 17 cells, IL-17B is widely expressed in various tissues. Recently, the biological function of IL-17B in diseases, particularly tumors, has attracted the attention of researchers. We previously reported that the expression of IL-17RB increased in gastric cancer tissues and demonstrated that IL-17B/IL-17RB signaling plays a critical role in gastric tumor progression. However, studies on IL-17B are scant. In this review, we detail the structural characteristics, expression patterns, and biological activities of IL-17B and its potential role in the pathogenesis of diseases.     

Neuromedin U: potential roles in immunity and inflammation

Since the discovery of neuromedin U (NmU) from porcine spinal cord in 1985, this neuropeptide has been subsequently identified in many other species with multiple physiological and pathophysiological roles detected, ranging from smooth muscle contraction, feeding, energy balance to tumorigenesis. Intriguingly, NmU is also emerging to play pro‐inflammatory roles involving immune cell activation and cytokine release in a neuron‐dependent or neuron‐independent manner. The NmU‐mediated inflammatory responses have already been observed in worm infection, sepsis, autoimmune arthritis and allergic animal models. In this review, we focus on the roles of NmU in immunity and inflammation by highlighting the interactions between NmU and immune cells, summarizing the signalling mechanism involved in their reactions and discussing its potential contributions to inflammatory diseases.     

IL-17 and related cytokines involved in systemic sclerosis: Perspectives

Systemic sclerosis (SSc) is a multisystemic, complex, and rare disease of connective tissue, with high morbidity and mortality, and without specific treatment. The disease is characterized by three main principles: vascular disease, autoantibody production and inflammation, and fibrosis. Since it is well defined that SSc is characterized by elevated production of TGF-β, IL-6, and IL-1, all of them cytokines related to Th17 differentiation, the hypothesis is that this disease may be strongly related to a polarization of the immune response towards the Th17 pathway. Considering the importance of a better understanding of the pathophysiology of Th17 pathway in SSc, this article aims to propose an update for a better understanding of current knowledge on main cytokines secreted by the Th17 cells (IL-17?A, IL-21, and IL-22) and the future prospects in the current disease.     

IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens

Interleukin 17 receptor E (IL-17RE) is an orphan receptor of the IL-17 receptor family. Here we show that IL-17RE is a receptor specific to IL-17C and has an essential role in host mucosal defense against infection. IL-17C activated downstream signaling through IL-17RE-IL-17RA complex for the induction of genes encoding antibacterial peptides as well as proinflammatory molecules. IL-17C was upregulated in colon epithelial cells during infection with Citrobacter rodentium and acted in synergy with IL-22 to induce the expression of antibacterial peptides in colon epithelial cells. Loss of IL-17C-mediated signaling in IL-17RE-deficient mice led to lower expression of genes encoding antibacterial molecules, greater bacterial burden and early mortality during infection. Together our data identify IL-17RE as a receptor of IL-17C that regulates early innate immunity to intestinal pathogens.     

Differential roles for IFN-gamma and IL-17 in experimental autoimmune uveoretinitis

IL-17-producing CD4(+) T cells, so called T(h)17 cells, constitute a newly identified inflammatogenic cell population, which is critically involved in some inflammatory diseases. To explore the role of T(h)17 cells in murine experimental autoimmune uveoretinitis (EAU), a model of human autoimmune uveitis where T(h)1 responses predominantly participate in the pathogenesis, IL-17(-/-) mice were immunized with interphotoreceptor retinoid-binding protein peptide 1-20 for disease induction. Funduscopic examination revealed that EAU was induced in IL-17(-/-) mice just like in wild-type (WT) mice at early phases of the disease. However, at later/maintenance phases, the severity was significantly reduced in IL-17(-/-) mice. Expression of IFN-gamma and MCP-1 was comparable between WT and IL-17(-/-) mice during the time course. In vivo blockade of IFN-gamma and IL-4 resulted in exacerbation of EAU at later phases with augmented IL-17 production. Taken together, our data demonstrated that IL-17/T(h)17 participates in the late phases of EAU and also that T(h)1 and T(h)17 responses are differentially required for EAU.     

Contrasting roles for IL-10 in protective immunity to different life cycle stages of intestinal nematode parasites

Expulsion of the gastro-intestinal nematode Trichinella spiralis is associated with a pronounced mastocytosis mediated by a T helper (Th) 2 type response involving interleukin (IL)-4 and IL-13. Here we demonstrate that IL-10 is a key regulator of protective immune responses against T. spiralis in vivo. IL-10 knockout mice or normal mice treated with a neutralizing anti-IL-10 receptor antibody are highly susceptible to a primary T. spiralis infection and show significantly delayed adult worm expulsion. Depletion of IL-10 resulted in elevated Th1 and Th2 cytokine responses but significantly reduced numbers of mucosal mast cells in the jejunum. Interestingly, the increase in IFN-gamma detected in the absence of IL-10 resulted in increased immunity to larval stages. Hence, IL-10 has a negative effect on immunity to the tissue dwelling larval stages of T. spiralis but plays a significant biological role as an in vivo regulator of intestinal mast cell responses and is crucially involved in protection against adult stages of intestinal parasites in vivo.     

From genes polymorphisms to mucosal expression of cytokines: evaluating IL-23/IL-17 axis in adult patients with gastritis

Background and ObjectiveChronic inflammation is the typical sign of gastritis that may shift into gastric cancer. IL-17A and IL-17F as a novel inflammatory cytokines subset of CD4+Th play the main role in inflammation. A key cytokine receptor in the inflammatory IL-17/IL-23 axis, the interleukin 23 receptor (IL23R), may be related to gastritis. We evaluated the correspondence between IL-17A G197A, IL-17F A7488G and IL23R+2199 A/C polymorphisms with TGF-β1, IL-6, IL-17, IL-21 and IL-23 mucosal mRNAs expression in uninfected H. Pylori (HP) chronic gastritis patients.Materials and MethodsTotal RNA and genomic DNA were separated from gastric biopsies of 44 patients with gastritis. Subsequently, mucosal mRNAs expression of TGF-β1, IL-6, IL-17, IL-21 and IL-23 were assessed by real-time PCR. To polymorphisms determination of IL-17A G197A, IL-17F A7488G and IL-23R +2199A/C the PCR-RFLP was used in gastric biopsies.ResultsResults point that IL-17A G197A, IL-17F A7488G and IL23R +2199A/C polymorphisms did not influence the mucosal expression of TGF-β1, IL-6, IL-17 and IL-21 (p> 0.05). In an opposite result, we don''t find a correspondence between IL-17A G197A, IL-17F A7488G polymorphisms and mucosal expression of IL-23 (p> 0.05). In a contrary, we found a correlation between IL23R +2199A/C polymorphism and mucosal expression of IL-23 in patients with chronic gastritis (p< 0.05).ConclusionThese findings propose that IL23R +2199A/C polymorphism may change the mucosal expression of IL-23 pattern in patients with gastritis disease in the absence of HP, but to support the conclusion, more research may be required.     

The roles of IL-17A in inflammatory immune responses and host defense against pathogens

Summary: T-helper 17 (Th17) cells are a newly discovered CD4⁺ helper T-cell subset that produces interleukin-17A (IL-17A) and IL-17F. IL-17A plays important roles in allergic responses such as delayed-type hypersensitivity, contact hypersensitivity, and allergic airway inflammation. IL-17A promotes inflammation by inducing various proinflammatory cytokines and chemokines, recruiting neutrophils, enhancing antibody production, and activating T cells. IL-17A expression is also augmented in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Using mouse models of these diseases, we found that IL-17A plays a central role in their development. IL-6 is required for the development of Th17 cells and tumor necrosis factor functions downstream of IL-17A during the effector phase. IL-1 is important both for developing Th17 cells and eliciting inflammation. Th17 cells, like Th1 and Th2 cells, are involved in host defense against infections, but the contribution of these Th subsets to defense mechanisms differs among pathogens. The roles of IL-17F remain largely unknown. In this review, we introduce how IL-17A/IL-17F are involved in inflammatory immune responses and host defense mechanisms and discuss their relationship with other cytokines in the development of inflammatory and infectious diseases.     

IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines.

BACKGROUND: IL-17 is a cytokine that has been reported to be produced by T lymphocytes. In vitro, IL-17 activates fibro-blasts and macrophages for the secretion of GM-CSF, TNF-alpha, IL-1beta, and IL-6. A number of these cytokines are involved in the airway remodeling that is observed within the lungs of asthmatic individuals. OBJECTIVE: In this study, we investigated the expression of IL-17 in sputum and bronchoalveolar lavage specimens obtained from asthmatic subjects and from nonasthmatic control subjects. METHODS: IL-17 was detected through use of immunocytochemistry, in situ hybridization, and Western blot. Bronchial fibroblasts were stimulated with IL-17, and cytokine production and chemokine production were detected through use of ELISA and RT-PCR. RESULTS: Using immunocytochemistry, we demonstrated that the numbers of cells positive for IL-17 are significantly increased in sputum and bronchoalveolar lavage fluids of subjects with asthma in comparison with control subjects (P <.001 and P <.005, respectively). We demonstrated that in addition to T cells, eosinophils in sputum and bronchoalveolar lavage fluids expressed IL-17. Peripheral blood eosinophils were also positive for IL-17, and the level of IL-17 in eosinophils purified from peripheral blood was significantly higher in subjects with asthma than in controls (P <.01). To further investigate the mechanism of action of IL-17 in vivo, we examined the effect of this cytokine on fibroblasts isolated from bronchial biopsies of asthmatic and nonasthmatic subjects. IL-17 did enhance the production of pro-fibrotic cytokines (IL-6 and IL-11) by fibroblasts, and this was inhibited by dexamethasone. Similarly, IL-17 increased the level of other fibroblast-derived inflammatory mediators, such as the alpha-chemokines, IL-8, and growth-related oncogene-alpha. CONCLUSION: Our results, which demonstrate for the first time that eosinophils are a potential source of IL-17 within asthmatic airways, suggest that IL-17 might have the potential to amplify inflammatory responses through the release of proinflammatory mediators such as alpha-chemokines.     

Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation

Interleukin (IL)-17A is a pro-inflammatory cytokine in mice and humans. It is recognized as a key factor for the protection of mice against various pathogens, but it also underlies pathogenic inflammatory responses in numerous mouse models. The inborn errors of IL-17A- and IL-17F-mediated immunity identified in humans in the last decade have revealed that IL-17A and IL-17F are key players in mucocutaneous immunity to Candida albicans, and, to a lesser extent, Staphylococcus aureus. By contrast, there is currently no genetic evidence for a causal link between excess of IL-17 and autoimmunity, autoinflammation, or allergy in humans. We discuss here the physiological and pathological roles of mouse and human IL-17A and IL-17F in host defense and excessive inflammation. We highlight recent advances in our understanding of the consequences of deficient or excessive IL-17 immunity at various mucocutaneous sites, including the oral cavity, skin, intestine, lungs, and vagina.     

Characterization and gene expression analysis of the two main Th17 cytokines (IL-17A/F and IL-22) in turbot,Scophthalmus maximus

This report describes the cloning, characterization and gene expression pattern of two Th17 cytokines, interleukin (IL)-17A/F and -22, in turbot Scophthalmus maximus. The turbot IL-17A/F cDNA contains a 516 bp open reading frame encoding a deduced IL-17A/F protein of 171 amino acid (aa) residues, containing a predicted signal peptide of 31 aa. Turbot IL-22 had a 564 bp ORF coding for a 187 aa protein with a 33 aa signal peptide. The turbot IL-22 protein contained a typical IL-10 family signature. Both cytokines had highest expression levels in the intestine followed by head kidney and gills. Stimulation with the Gram negative bacterium Aeromonas salmonicida was able to modulate IL-17A/F and IL-22 expression in head kidney, spleen and liver but not the intestine. PMA and PHA were also able to induce the expression of both cytokines, suggesting that, as expected, T-cells are likely the main producers of these molecules in turbot as in mammals.     

Association of IL-17A and IL-17F polymorphisms with gastric cancer risk in Asians: A meta-analysis

Increasing number of studies focused on the association of IL-17A rs2275913 and IL-17F rs763780 polymorphisms with gastric cancer (GC) risk. However, the results were inconsistent. To elucidate the exact association, we performed the present meta-analysis. Databases including PubMed, Web of knowledge and Chinese National Knowledge Infrastructure (CNKI) were systematically searched for potentially eligible literatures. Odds ratios (OR) and their 95% confidence interval (CI) were used to evaluate the strength of association. Eight studies for IL-17A rs2275913 (3345 cases and 4427 controls) and five studies for IL-17F rs763780 (1784 cases and 2592 controls) were finally included. The results indicated that individuals with AA genotype of IL-17A rs2275913 polymorphism were associated with increased GC risk compared with wild-type GG (OR = 1.61, 95% CI = 1.17–2.23, P = 0.004); A allele was significantly associated with increased GC risk compared with G allele (OR = 1.22, 95% CI = 1.06–1.41, P = 0.007). IL-17F rs763780 polymorphism was also significantly associated with increased GC risk (CC vs. CT: OR = 1.40, 95% CI = 1.04–1.88, P = 0.025; CT vs. TT: OR = 1.35, 95% CI = 1.16–1.58, P < 0.001; C allele vs. T allele: OR = 1.30, 95% CI = 1.15–1.47, P < 0.001). In summary, IL-17A rs2275913 A/G polymorphism and IL-17F rs763780 C/T polymorphism might be associated with increased GC risk in Asians. Further large-scale studies are still required to confirm the results of this meta-analysis.     

Common variants in IL-17A/IL-17RA axis contribute to predisposition to and progression of congestive heart failure

AIM: Heart failure is characterized by immune activation leading to production and release of proinflammatory cytokines. Interleukin 17A( IL-17A) is a proinflammatory cytokine and multiple lines of evidence from animal and human studies suggest crucial roles of IL-17 A in heart failure. Therefore,we investigated whether common polymorphisms of genes IL17 A and IL17RA( coding interleukin17 receptor A) gene contribute to genetic predisposition to heart failure and adverse clinical outcomes associated with it. METHODS AND RESULTS: A total of 1713 adults patients with congestive heart failure and 1713 age- and sex-matched controls were genotyped for promoter SNPs,rs2275913 and rs8193037 in IL17 A and rs4819554 in IL17 RA,to assess the relationship between individual SNPs and the risk of congestive heart failure. Results showed that rs8193037 in IL17 A was associated with the risk of congestive heart failure(P 0. 01) after adjustment for multiple cardiovascular risk factors including age,sex,smoking status,diabetes,hypertension and dyslipidemia. This association was evident in both ischemic and non-ischemic heart failure( P 0. 05). Furthermore,prospective follow-up of 12. 7 months for the occurrence of adverse clinical outcomes showed that rs4819554 in IL17 RA was significantly associated with cardiovascular mortality( P 0. 05) after adjustments for multiple cardiovascular risk factors and New York Heart Association functional class. CONCLUSION: This study demonstrated associations of rs8193037 in the promoter of IL17 A with the risk of congestive heart failure,and of rs4819554 in the promoter of IL17 RA with the risk of cardiovascular mortality in patients with congestive heart failure. These data lend further support to the notion that immune activation and genetic polymorphisms contribute to heart failure pathogenesis and progression.     

The association between G-197A gene polymorphism of IL-17A with changes in protein interaction of IL-17A,levels of urinary IL-17, and degree of lupus nephritis abnormality

Elevated levels of IL-17 in systemic lupus erythematosus (SLE) patients have been reported to be correlated to renal disorders, but the involvement of the G-197A gene polymorphism of IL 17 in lupus nephritis (LN) and the degree of renal abnormality have not been reported. Therefore, the aim of this study was to investigate these associations. This study involved 30 LN patients and 20 healthy control. Levels of uIL-17 were measured by ELISA, while the G-197A gene polymorphisms of IL-17A were examined using polymerase chain reaction (PCR) and sequence analysis. Changes in the protein structure due to G-197A gene polymorphism of IL-17A were analyzed by in silico investigation. In addition, renal biopsies were performed to determine the degree of renal abnormality (classes I–VI). A significant difference was found between LN patients and the control group in term of uIL-17 levels (p?=?0.004). However, the G-197A gene polymorphism of IL-17A between LN patients and the control group were not significantly different (p?=?0.154). There were no difference in the levels of uIL-17 between patients and control group on G-197A gene polymorphism of IL-17A (p?=?0.682). Also, there were no significant differences in G-197A gene polymorphism of IL-17A toward the degree of nephritis (p?=?0.300). In silico investigation showed that G197A gene polymorphism of IL-17A resulted in changes of the pattern of IRF-4 binding to the promoter, thereby affecting its activity. In conclusion, the levels of uIL-17 in LN patients were significantly higher than those in the control group, but G-197A gene polymorphism of IL-17A did not cause varying levels of IL-17 and did not influence the degree of renal abnormalities in LN.     

Association between polymorphisms in cytokine genes IL-17A and IL-17F and development of allergic rhinitis and comorbid asthma in Chinese subjects

Background

Th17 cell lineage, a distinct pro-inflammatory lineage characterized by preferential synthesis of cytokines IL-17A and IL-17F, is thought to play an important role in the pathogenesis of allergic rhinitis (AR).

Objectives

Our aim was to investigate whether polymorphisms in and around IL-17A and IL-17F genes are associated with AR and comorbid asthma.

Methods

A case-control comparison was performed in a cohort of 279 AR patients, 197 allergic rhinitis with asthma (AR-A) patients and 281 control Chinese subjects, to investigate associations between 19 tagging single-nucleotide polymorphisms (SNPs) in IL-17A and IL-17F gene regions and manifestation of AR or AR-A. Genotyping was performed using the Sequenom MassARRAY platform.

Results

SNP rs3819024 in IL-17A gene, intergenic SNPs rs1892280 and rs10807439 were specifically associated with AR protective or risk effects, while rs3819024 in IL-17A gene, intergenic SNP rs13192563 in IL-17F gene were associated with AR-A protective or risk effects. Haplotype analysis showed significant AR risk in haplotype AA (rs1892280G–rs13192563A) and AR protective effect in haplotype GT (rs7758579A–rs11966760T); the haplotype AT(rs7758579–rs11966760) were considered AR-A risk.

Conclusions

Our findings preliminarily indicate IL17A and IL17F SNPs, and some intergenic variants have the potential association with AR and comorbid asthma in Chinese population.