H19 Increases IL-17A/IL-23 Releases via Regulating VDR by Interacting with miR675-5p/miR22-5p in Ankylosing Spondylitis.
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SUBMITTER: Zhang X
PROVIDER: S-EPMC6938967 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). Blocking IL-17A is expected to inhibit bony ankylosis. Here, we investigated the effects of anti IL-17A agents in AS.MethodsTNF?, IL-17A, and IL-12/23 p40 levels in serum and synovial fluid from patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteoarthritis (OA), or healthy controls (HC) were measured by ELISA. Bone tissue samples were obtained at surgery from the facet joints of ten patients with AS and ten control (Ct) patients with noninflammatory spinal disease. The functional relevance of IL-17A, biological blockades, Janus kinase 2 (JAK2), and non-receptor tyrosine kinase was assessed in vitro with primary bone-derived cells (BdCs) and serum from patients with AS.ResultsBasal levels of IL-17A and IL-12/23 p40 in body fluids were elevated in patients with AS. JAK2 was also highly expressed in bone tissue and primary BdCs from patients with AS. Furthermore, addition of exogenous IL-17A to primary Ct-BdCs promoted the osteogenic stimulus-induced increase in ALP activity and mineralization. Intriguingly, blocking IL-17A with serum from patients with AS attenuated ALP activity and mineralization in both Ct and AS-BdCs by inhibiting JAK2 phosphorylation and downregulating osteoblast-involved genes. Moreover, JAK2 inhibitors effectively reduced JAK2-driven ALP activity and JAK2-mediated events.ConclusionsOur findings indicate that IL-17A regulates osteoblast activity and differentiation via JAK2/STAT3 signaling. They shed light on AS pathogenesis and suggest new rational therapies for clinical AS ankylosis.
| S-EPMC5992730 | biostudies-literature
Project description:Ankylosing spondylitis is the most common form of the chronic inflammatory disease group known as spondyloarthritides. Recent discoveries of the CD4+ Th17 cells and IL-23/IL-17 axis have changed the paradigms in many autoimmune diseases. In this study, we aimed to evaluate the importance of IL-23/IL-17 pathway and IL-23 receptor polymorphism in the pathogenesis of ankylosing spondylitis. Blood samples for this study were obtained from 109 ankylosing spondylitis patients and 40 healthy control subjects. Serum levels of TNF-α, IL-6, IL-17, and IL-23 were measured by the ELISA method. The IL-23R gene polymorphisms rs11209026 (Arg381Gln) and rs4131362 (Val362Ile) were performed by the Sanger Sequence method. IL-6 levels were higher in the active and inactive ankylosing spondylitis groups than in the control group. However, levels of IL-17 and IL-23 were lower in the patient group. The frequency of IL-23R gene rs11209026 and rs4131362 polymorphism were 3.7% and 8.3% in the patient, respectively. As a result, dysregulation of the IL-23 / IL-17 pathway, which is caused by reduced levels of IL-17 and IL-23 in systemic circulation in patients with ankylosing spondylitis, may contribute to the pathogenesis of the disease by systemically producing chronic autoimmune inflammation.
| S-EPMC7050057 | biostudies-literature
Project description:The association between the IL-23R and IL-17A polymorphisms and ankylosing spondylitis (AS) in the Southwest Chinese Population is still unclear. The purpose of this study is to detect the association between IL-23R and IL-17A polymorphisms and AS. A case-control study consisting of 486 AS patients and 480 healthy controls was performed. We used the high-resolution melting methods (HRM) to genotype five selected single nucleotide polymorphisms (SNPs), rs6693831, rs7517847, rs1884444, rs10889677 in the IL-23R gene and rs2275913 in the IL-17A gene. Meanwhile, the laboratory indexes were recorded. In this study, patients with genotype CC (p = 8.574E-8) and allele C (p = 3.206E-31) on SNP rs6693831 (IL-23R) showed decreased risk of AS. The genotype TT (p = 4.551E-6) and allele T (p = 0.02) on SNP rs1884444 (IL-23R) showed significant lower risk of AS. Individuals carrying the allele A of rs2275913 showed higher morbidity of AS (p = 0.04). We first detected that rs6693831 and rs1884444 in IL-23R gene and rs2275913 in IL-17A gene have genetic association with AS.
| S-EPMC5642556 | biostudies-literature
Project description:Ankylosing spondylitis (AS) is a chronic autoimmune inflammatory disease that mainly affects the axial and sacroiliac joints. Single-nucleotide polymorphisms (SNPs) in genes encoding cytokines have been associated with AS, which can interfere with the production of these cytokines and contribute to the development of AS. In order to contribute to a better understanding of the pathology of AS, our objective was to investigate a possible association of the IL10 -1082 A>G SNP (rs1800896) with AS and to evaluate the serum levels of TNF-α, IL-10, IL-17A, and IL-17F in AS patients and controls comparing them with their respective genotypes (TNF rs1800629, IL10 rs1800896, IL17A rs2275913, and IL17F rs763780). Patients and controls were selected from the Maringá University Hospital and the Maringá Rheumatism Clinic, in Paraná State, Southern Brazil, and they were diagnosed by the ASAS Criteria. In total, 149 patients and 169 controls were genotyped for the IL10 -1082 A>G polymorphism using a polymerase chain reaction with sequence specific primers (PCR-SSP); the measurement of TNF-α serum levels was performed through the immunofluorimetric test and IL-10, IL-17A, and IL-17F using an ELISA test. There was a high frequency of the IL10 -1082 G allele in AS patients compared with controls with an odds ratio of 1.83 and 95% confidence interval of 1.32 to 2.54, and a significant difference in the genotype frequencies of the IL10 -1082 A/G+G/G between patients and healthy controls, with an odds ratio of 3.01 and 95% confidence interval of 1.75 to 5.17. In addition, increased serum levels of IL-10 were observed in AS patients: 2.38 (IQR, 0.91) pg/ml compared with controls 1.72 (IQR 0.93) pg/ml (P = 0.01). Our results also showed an association between IL17F rs763780 C/T+T/T genotypes and increased serum levels of IL-17F in patients with AS and also in controls. We can conclude that patients with the A/G and G/G genotypes for -1082 A>G (rs1800896) in the IL10 gene are three times more likely to develop AS, that the serum level of IL-10 was higher in AS patients and that the IL17F rs763780 polymorphism can affect the levels of IL-17F in the serum of patients and controls in the same way.
| S-EPMC8287882 | biostudies-literature
Project description:It is very important to understand the communication and interaction mechanisms between the host and its resident microorganisms on host physiology and for precise diagnosis and treatment. Although intestinal fungi and bacteria dysbiosis is increasingly linked to ankylosing spondylitis (AS), their mechanisms of action have been rarely illustrated. In this paper, fecal samples from 10 AS monkeys and 10 healthy controls were collected to systematically characterize the gut mycobiota and microbiota in AS monkeys by 16S rRNA and ITS2 DNA sequencing. Our results showed the gut fungi of Kazachstania pintolopesii, Saccharomycetaceae, Kazachstania, and Saccharomyceteles. Saccharomycetes were specially enriched in AS, and the microbiota of AS monkeys was characterized by an increased abundance of Clostridia, Clostridiales, Ruminococcaceae, and Prevotella 2, using Line Discriminant Analysis Effect Size. Compared to healthy controls, decreased ITS2/16S biodiversity ratios and altered bacterial-fungal interkingdom networks were observed in AS monkeys. Oral administration of K. pintolopesii activates IL-17RA pathway and induce inflammatory reaction in the colonic tissue of C57BL/6 mice, as well as multiple AS phenotypes, including fungal and bacterial dysbiosis, immune responses of NK cells, platelets, T cells, leukocytes, B-cell activation, rheumatoid arthritis, and inflammatory bowel disease. We also found the secreted products of K. pintolopesii could activate the IL-17RA pathway, which induces PANoptosis in macrophage RAW264.7 cells. Much worse, the PANoptosis products could promote the proliferation and morphological changes of K. pintolopesii, which resulted in much more K. pintolopesii and a severe inflammatory reaction. Interestingly, the inflammatory factor TNF-α can promote the morphological transformation of Candida albicans and K. pintolopesii, which is worthy of further study. The characteristic fungi in all these findings implied that fungal and bacterial dysbiosis have a close link to AS and that their communication and interaction indeed play an important role in autoimmune responses, and K. pintolopesii could be a potential marker microorganism in AS, although its specific mechanism is not fully elucidated.
| S-EPMC9808786 | biostudies-literature
Project description:IL-17A and IL-17F together with their coreceptor (IL-17RA/RC) were reported to play a significant role in the pathogenesis of spondyloarthritis. The group of axial spondyloarthritis comprises ankylosing spondylitis (AS), a rheumatic disease characterized by chronic inflammation of the joints in the spine. This study is aimed at investigating IL-17A, IL-17F, IL-17RA, and IL-17RC polymorphisms as potential biomarkers of disease susceptibility, clinical parameters, and anti-TNF treatment outcome in a cohort of Polish ankylosing spondylitis patients. In total, 328 subjects, including 138 AS patients and 190 healthy volunteers, participated in the study. Genotyping of IL-17A rs2275913 (G/A), IL-17F rs763780 (A/G), IL-17RA rs4819554 (A/G), and IL-17RC rs708567 (G/A) was performed on real-time PCR instrument using LightSNiP assays. No significant differences were revealed in genotype and allele distribution between patients and controls despite the association of the IL-17RC rs708567 AA homozygosity with the earlier onset of the disease. Moreover, some relationships between IL-17F rs763780 and IL-17RA rs4819554 polymorphisms with clinical parameters related to the disease activity and anti-TNF treatment outcome were observed. IL-17F rs763780 G allele was found to be associated with high disease activity and BASDAI after 6 months and poor response to the treatment while higher VAS values were more common among IL-17RA rs4819554 G variant carriers. In conclusion, the IL-17F rs763780 polymorphism should be considered as a promising biomarker of disease activity and anti-TNF treatment outcome. The IL-17RA rs48419554 G allele may serve as a potential marker of disease severity in Polish AS patients.
| S-EPMC8566063 | biostudies-literature
Project description:Biologics that neutralize specific cytokines have improved outcomes for several immune-mediated disorders but may also increase risks for particular side effects. This article postulates potential immunologic consequences of inhibiting components of the IL-23/T-helper cell 17 pathway-the target of next-generation biologics for treating psoriasis-based on clinical phenotypes of inherent or acquired deficiencies in this pathway. Generally, downstream deficiencies (e.g., IL-17A, IL-17F) are associated with fewer disorders compared with upstream deficiencies, suggesting that selectively blocking downstream targets may result in a narrower range of side effects. However, safety of these specific inhibitions must be established in long-term studies.
| S-EPMC4580732 | biostudies-other
Project description:Background: Anti-IL-17A therapy is generally effectively applied in patients with Ankylosing Spondylitis (AS) to achieve and maintain remission. However, the influence of anti-IL-17A on the composition of the immune system is not apparent. Our prospective study was to explore the changes in immune imbalance regarding T cell, B cell and natural killer (NK) cell subsets after secukinumab treatment in AS patients. Methods: Immune cell distribution of 43 AS patients treated with secukinumab for 12 weeks and 47 healthy controls (HC) were evaluated. Flow cytometry using monoclonal antibodies against 25 surface markers was accomplished to explore the frequencies of lineage subsets. The differences between HC, AS pre-treatment, and post-treatment were compared using the paired Wilcoxon test, Mann-Whitney U test, and ANOVA. Results: AS patients had altered immune cell distribution regarding T cell and B cell subsets. Apart from activated differentiation of CD4+ T cell, CD8+ T cell and B cell, higher levels of cytotoxic T (Tc) two cells and Tc17 cells were noted in AS patients. We confirmed that helper T (Th) one cell became decreased; however, Th17 cells and T follicular helper (Tfh) 17 cells went increased in AS. After 12 weeks of secukinumab therapy, CRP and ASDAS became significantly decreased, and meanwhile, the proportions of Th1 cells, Tfh17 cells and classic switched B cells were changed towards those of HC. A decreased CRP was positively correlated with a decrease in the frequency of naïve CD8+ T cells (p = 0.039) and B cells (p = 0.007) after secukinumab treatment. An elevated level of T cells at baseline was detected in patients who had a good response to secukinumab (p = 0.005). Conclusion: Our study confirmed that AS patients had significant multiple immune cell dysregulation. Anti-IL-17A therapy (Secukinumab) could reverse partial immune cell imbalance.
| S-EPMC8551761 | biostudies-literature
Project description:BackgroundDental implantation has been practiced since ancient times and has gone through several stages. Dentists use dental implants to support dental prostheses such as crowns, bridges, dentures, face prostheses, or as an orthodontic anchor. Thus, the purpose of this study is to detect the role of the immune-genetic variation of IL-17A and related inflammatory cytokine (IL-23) in the initiation and progress of peri implantitis.Material and methodsThis cross-sectional study included 80 subjects (15 peri-implantitis patients, 35 successful implants, and 30 healthy controls); their mean age was (43.91 ± 11.33) years. Blood samples and Peri-implant sulcus fluid (PISF) were collected from all subjects (patients with peri-implantitis, successful implants, and healthy controls) attending the Department of Oral and Maxillofacial Surgery in the Dental College Teaching Hospital, Baghdad University, Baghdad, Iraq. The blood sample detects gene polymorphisms in interleukin-17A by a polymerase chain reaction (PCR). An enzyme-linked immunosorbent assay (ELISA) was carried out to estimate the Peri-implant sulcus fluid (PISF) levels of interleukin-23.ResultThe current study revealed an obvious significant elevation in the mean level of interleukin-23 in the peri-implantitis patient's group more than its level in the successful implant and control groups (P < 0.05). In addition, the result showed that A/A genotype is associated significantly with peri-implantitis OR (95%confidence interval) =6.9 (1.7121 to 27.4638) folds increase risk of peri-implantitis) (p = 0.0065), while G/A genotype had OR 4.9 (0.9539-24.9394) folds increased risk of peri-implantitis, (p = 0.0572). But it was not statistically significant and G/G genotype had a one-fold increase risk of peri-implantitis.ConclusionThe increased level of inflammatory cytokine (interleukin-23) might add to the systemic inflammatory burden a predisposing factor, which may lead to impaired osseointegration and subsequent bone loss or implant failure. In addition, IL-17A gene polymorphism may play a role in peri-implant disease susceptibility, especially in persons carrying the rs2275913 A allele at a higher risk of developing peri-implantitits as compared with those carrying the G allele.
| S-EPMC10899656 | biostudies-literature
Project description:To comprehensively evaluate the association between rs7517847 and rs2201841 polymorphisms in the Interleukin-23 (IL-23) receptor gene and ankylosing spondylitis (AS), a meta-analysis was performed. The Pubmed, Embase, MEDLINE, Cochrane, China National Knowledge Infrastructure (CNKI), VIP, Wanfang and China Biology Medicine disc (CBMdisc) databases were searched to identify eligible studies on rs7517847 and rs2201841 polymorphisms in the IL-23 receptor gene and AS that were published through September 2014. Data of interest were extracted from each study, and the meta-analysis was performed using STATA 12.0. Four studies were eligible for the meta-analysis and included a total patient population of 2,465. With regards to rs7517847, the current study showed that the genotype GG and allele G might play a protective role during AS (OR = 0.76, 95% CI [0.59-0.99]; OR = 0.88, 95% CI [0.78-0.99] for homozygote and allelic models, respectively). However, according to the meta-analysis, there was no statistical association between the genotype or allele of rs2201841 and an individual's susceptibility to AS in all genetic models. In conclusion, it was the IL-23 rs7517847 polymorphism rather than the rs2201841 polymorphism that had a statistical association with AS. Nevertheless, more evidence is needed to confirm this result. Consequently, it is necessary to carry out more high-quality studies to confirm the associations between these two single nucleotide polymorphisms and AS.
| S-EPMC4411516 | biostudies-literature