Genetic Association of Interleukin 33/ST2 Polymorphisms With Behcet's Uveitis.
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ABSTRACT:
SUBMITTER: Pei M
PROVIDER: S-EPMC8043080 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Interleukin (IL)-33/ST2 pathway plays crucial roles in tumour growth and metastasis. The aim of this study was to investigate the association of two functional polymorphisms (IL-33 rs7025417 and ST2 rs3821204) with osteosarcoma (OS) risk. The rs7025417 and rs3821204 were genotyped by Taqman assay. IL-33mRNA and protein levels were measured by real-time PCR or enzyme-linked immunosorbent assay. The luciferase activity was measured by a dual luciferase reporter gene assay. The allele-specific transcription factor binding for rs7025417 was examined by ChIP-seq. The IL-33 rs7025417 CC genotype was significantly associated with a decreased risk of OS (CC vs TT: OR = 0.59, 95% CI, 0.41-0.85; recessive model: OR = 0.68, 95% CI, 0.49-0.94; C vs T: OR = 0.76, 95% CI, 0.63-0.91). Combined analysis showed that the IL-33 rs7025417CT/CC-ST2 rs3821204CG/CC and the IL-33 rs7025417CT/CC-ST2 rs3821204GG genotypes also had a decreased risk of OS. IL-33mRNA and protein levels in OS patients were significantly higher than controls. Patients with the rs7025417 CC genotype exhibited lower levels of IL-33 (P = .03). The rs7025417 C allele presented a lower transcriptional activity by disrupting the binding site to c-Myb (P < .01). Moreover, the rs3821204 G/C influences the transcriptional activity and ST2mRNA expression by altering the binding site of miR-202-3p. These findings suggest that the rs7025417 and rs3821204 may have a combined effect to protect against the development of OS by decreasing the expression levels of IL-33 or ST2.
| S-EPMC6050508 | biostudies-literature
Project description:InstructionInterleukin 27 (IL-27) is an important regulator of the proinflammatory T-cell response. In this study, we investigated its role in the pathogenesis of Behçet's disease (BD).MethodsIL-27 mRNA in peripheral blood mononuclear cells (PBMCs) was examined by performing RT-PCRs. Cytokine levels in sera or supernatants of PBMCs, naïve CD4(+) T cells, dendritic cells (DCs) and DC/T cells were determined by enzyme-linked immunosorbent assay. We used RNA interference in naïve CD4(+) T cells to study the role of interferon regulatory factor 8 (IRF8) in the inhibitory effect of IL-27 on Th17 cell differentiation. Flow cytometry was used to evaluate the frequency of IL-17- and interferon γ-producing T cells.ResultsThe expression of IL-27p28 mRNA by PBMCs and IL-27 in the sera and supernatants of cultured PBMCs were markedly decreased in patients with active BD. A higher frequency of IL-17-producing CD4(+) T (Th17) cells and increased IL-17 production under Th17 polarizing conditions were observed in patients with active BD. IL-27 significantly inhibited Th17 cell differentiation. Downregulation of IRF8 by RNA interference abrogated the suppressive effect of IL-27 on Th17 differentiation. IL-27 inhibited the production of IL-1β, IL-6 and IL-23, but promoted IL-10 production, by DCs. IL-27-treated DCs inhibited both the Th1 and Th17 cell responses.ConclusionsThe results of the present study suggest that a decreased IL-27 expression is associated with disease activity in BD patients. Low IL-27 expression may result in a higher Th1 and Th17 cell response and thereby promote the autoinflammatory reaction observed in BD. Manipulation of IL-27 may offer a new treatment modality for this disease.
| S-EPMC4095700 | biostudies-literature
Project description:BackgroundUveitis is an eye inflammatory disease, which is sometimes associated with underlying systemic disease. Interleukin-23 plays an important role in autoimmune disease. The aim of this meta-analysis was to evaluate the association between the interleukin-23 receptor (IL-23R) and susceptibility to uveitis.MethodsPublished literature from PUBMED and EMBASE were retrieved. Seven studies were included in this meta-analysis, covering a total of 1309 cases of uveitis and 2400 controls. Meta-analyses were conducted on the associations between uveitisand rs7517847, rs17375018, and rs11209032 polymorphisms in the IL-23R gene.ResultsThere were no significant associations between IL-23R polymorphisms and uveitis with regard to the following alleles: for G allele vs. T allele of rs7517847, OR 1.01, 95% CI 0.92-1.12, P = 0.83; for A allele vs. G allele of rs17375018, OR 0.68, 95% CI 0.47-0.99, P = 0.05; rs11209032 OR 1.12, 95% CI 0.84-1.51, P = 0.43. In contrast, there were significant associations between the AA + AG gene versus GG gene of rs17375018 and the AA gene versus AG + GG gene of rs11209032 polymorphism with uveitis (OR 0.59, 95% CI 0.35-0.99, P = 0.04; OR 1.32, 95% CI 1.10-1.59, P = 0.003).ConclusionsThis meta-analysis suggests that each allele of IL-23R, including rs7519847, rs17375018 and rs11209032 was negatively associated with uveitis. However, homozygote models, including the rs17375018 GG genotype and rs11209032 AA genotype, were significantly associated with uveitis.
| S-EPMC5450396 | biostudies-literature
Project description:Epidemiological studies have demonstrated that interleukin-10 (IL-10) polymorphisms may be associated with the development of Behcet's disease (BD). However, the published results were inconsistent. Therefore, this meta-analysis was conducted to derive a more precise relationship between IL-10 polymorphisms and BD susceptibility. Online databases (PubMed, Embase, Science Citation Index (SCI), CNKI, and WanFang) were searched to identify eligible studies. Odds ratio (OR) and a 95% confidence interval (CI) were applied to assess the relationship strength between IL-10 -1082A>G (rs1800896), -819T>C (rs1800871), and -592A>C (rs1800872) polymorphisms and BD susceptibility. Publication bias, sensitivity, and cumulative analyses were conducted to measure the robustness of our findings. Finally, fifteen articles (36 independent case-control studies) involving 5,971 patients and 8,913 controls were included. Overall, significant associations between -819T>C polymorphisms and BD risk were observed in the total population (C vs. T: OR = 0.72, 95%CI = 0.67-0.77, P < 0.01, I 2 = 36.6%; TC vs. TT: OR = 0.73, 95%CI = 0.66-0.80, P < 0.01, I 2 = 23.0%; CC vs. TT: OR = 0.52, 95%CI = 0.39-0.70, P < 0.01, I 2 = 53.7%; TC+CC vs. TT: OR = 0.67, 95%CI = 0.61-0.71, P < 0.01, I 2 = 22.1%; and CC vs. TT+TC: OR = 0.66, 95%CI = 0.53-0.82, P < 0.01, I 2 = 57.8%). Moreover, the IL-10 -592 A>C polymorphism and the ACC haplotype exhibited a significant, protective effect against BD susceptibility. In summary, our meta-analysis suggested that IL-10 gene polymorphisms may play a salient role for BD development.
| S-EPMC7321531 | biostudies-literature
Project description:Idiopathic inflammatory myopathies (IIM) are rare connective tissue diseases, which can lead to internal organ involvement. IL-33/ST2 pathway is involved in the pathogenesis of numerous diseases including autoimmune disorders. IL-33 fulfils cardioprotective function, while soluble ST2 (sST2) is a decoy receptor that reduces protective impact of IL-33. The aim of the study was to evaluate the concentrations of sST2 and IL-33 in sera of patients with IIM and evaluate its associations with the clinical course of the disease. Patients with IIM as well as age- and sex-matched healthy controls were recruited. Concentrations of sST2 and IL-33 were assessed with ELISA in sera of both patients and controls. Patients were asked to fill in the questionnaires concerning clinical symptoms and physical functioning. Concentrations of sST2 and IL-33 were correlated with the results of laboratory tests and clinical symptoms. Concentrations of sST2 were significantly higher in IIM group than in healthy subjects (median sST2 in IIM 26.51 vs in healthy controls 21.39; p?=?0.03). In the majority of patients, IL-33 concentrations did not exceed the detection limit. Anti-SRP-positive patients presented significantly higher concentrations of sST2 as compared to anti-SRP-negative patients (p?=?0.04). In patients with anti-Ro52 antibodies, sST2 concentrations were significantly lower than in anti-Ro52-negative patients (p?=?0.02). Concentrations of sST2 correlated with the degree of disability evaluated with Health Assessment Questionnaire. sST2 is increased in patients with IIM and its concentration correlates with the degree of disability. In patients with anti-SRP antibodies, levels of sST2 are exceptionally high.
| S-EPMC7256085 | biostudies-literature
Project description:This study identified a novel phenomenon that dendritic cells (DCs) produced interleukin (IL)-33 via Toll-like receptor (TLR)-mediated innate pathway. Mouse bone marrow-derived DCs were treated with or without microbial pathogens or recombinant murine IL-33. IL-33 mRNA and protein were found to be expressed by DCs and largely induced by several microbial pathogens, highly by lipopolysaccharide (LPS) and flagellin. Using two mouse models of topical challenge by LPS and flagellin and experimental allergic conjunctivitis, IL-33-producing DCs were observed in ocular mucosal surface and the draining cervical lymph nodes in vivo. The increased expression levels of myeloid differentiation primary-response protein 88 (MyD88), nuclear factor (NF)-?B1, NF-?B2, and RelA accompanied by NF-?B p65 nuclear translocation were observed in DCs exposed to flagellin. IL-33 induction by flagellin was significantly blocked by TLR5 antibody or NF-?B inhibitor quinazoline and diminished in DCs from MyD88 knockout mice. IL-33 stimulated the expression of DC maturation markers, CD40 and CD80, and proallergic cytokines and chemokines, OX40L, IL-4, IL-5, IL-13, CCL17 (C-C motif chemokine ligand 17), TNF-? (tumor necrosis factor-?), and IL-1?. This stimulatory effect of IL-33 in DCs was significantly blocked by ST2 antibody or soluble ST2. Our findings demonstrate that DCs produce IL-33 via TLR/NF-?B signaling pathways, suggesting a molecular mechanism by which local allergic inflammatory response may be amplified by DC-produced IL-33 through potential autocrine regulation.
| S-EPMC3904307 | biostudies-literature
Project description:Occupational exposure to mechanical vibration can produce the hand-arm vibration syndrome (HAVS), whose most disabling symptom is persistent muscle pain. Unfortunately, the pathophysiology of HAVS pain is still poorly understood, precluding the development of mechanism-based therapies. Since interleukin 33 (IL-33) is essential for inflammation and recovery that follows skeletal muscle injury, we explored its role in muscle pain in a model of HAVS, in adult male rats. Concomitant to mechanical hyperalgesia, an increase in IL-33 in the ipsilateral gastrocnemius muscle was observed 24 hours after vibration. A similar hyperalgesia was produced by intramuscular injection of recombinant rat IL-33 (rrIL-33, 10-300 ng). Intrathecal administration of an oligodeoxynucleotide antisense to IL-33R/ST2 mRNA decreased the expression of ST2 in DRG and attenuated both rrIL-33 and vibration-induced mechanical hyperalgesia. Together these data support the suggestion that IL-33 plays a central role in vibration-induced muscle pain by action, at least in part, on skeletal muscle nociceptors. PERSPECTIVE: Our findings provide evidence of the contribution of IL-33, acting on its canonical receptor, in nociceptors, to muscle pain induced by ergonomic vibration. This suggests that targeting IL-33/ST2 signaling may be a useful strategy for the treatment of muscle pain in HAVS.
| S-EPMC7093240 | biostudies-literature
Project description:We sought to develop an IL-33 vaccine and evaluate its efficacy in a mouse model of asthma. The full-length molecules of putative mature IL-33 were inserted into the immunodominant epitope region of hepatitis B core antigen using gene recombination techniques. The expressed chimeric protein presented as virus-like particles (VLPs) under observation using an electron microscopy. To investigate immunization characteristics of the VLPs, mice were immunized by using different doses, adjuvants, and routes. The VLPs induced sustained and high titers of IL-33-specific IgG and IgA even without the use of a conventional adjuvant, and the lowered ratio of IgG1/IgG2a in vaccinated mice indicated a shift from Th2 to Th1-like responses. To assess the vaccine effects on blocking the signaling of IL-33/ST2 pathway, mice receiving 3 vaccinations subjected to intraperitoneal sensitization and intranasal challenge with ovalbumin (OVA). Control animals received carrier or PBS in place of the vaccine. Immunization with the VLPs significantly suppressed inflammatory cell number and IL-33 level in BALF. OVA -induced goblet cell hyperplasia and lung tissue inflammatory cell infiltration were significantly suppressed in vaccinated mice. Our data indicate that IL-33 molecule-based vaccine, which may block IL-33/ST2 signaling pathway on a persistent basis, holds potential for treatment of asthma and, by extension, other diseases where overexpressed IL-33 plays a pivotal role in pathogenesis.
| S-EPMC4896802 | biostudies-literature
Project description:The interplay between inflammation and lymphangiogenesis is mediated by various cytokines. However, most of these molecules and their associated mechanism are yet to be defined. Here, we explored the role of IL-33 in modulating inflammation-induced lymphangiogenesis (ILA) and its underlying mechanisms using an ILA mouse model and a lymphatic endothelial cell (LEC) line. Our results show that IL-33 promoted the proliferation, migration and tube formation of LECs and ILA in vivo. The pro-lymphangiogenic activity of IL-33 was abolished by ST2 blockage. In mechanisms, IL-33 induced the phosphorylation of Akt/eNOS to produce NO in LECs. The IL-33-induced Akt/eNOS activation was suppressed by the PI3K-specific-inhibitor wortmannin, and NO-production was inhibited by both wortmannin and the NO synthase-inhibitor NMA. Knock-down of ST2 or TRAF6 suppressed Akt/eNOS phosphorylation and NO production. The reduction of NO treated with wortmannin or NMA abolished the promoting effects of IL-33 on the chemotactic motility and tube formation of HDLECs. In vivo, IL-33-induced ILA was also impaired in eNOS-/- mice. In conclusion, our study is the first to show that IL-33 promotes inflammation-induced lymphangiogenesis via a ST2/TRAF6-mediated Akt/eNOS/NO signalling pathway. This findings may provide us more opportunities to treat inflammation and lymphangiogenesis associated diseases.
| S-EPMC5587532 | biostudies-literature
Project description:Type 2 innate lymphoid cells (ILC2) in lungs produce interleukin (IL)-5 and IL-13 in response to IL-33 and may contribute to the development of allergic diseases such as asthma. However, little is known about negative regulators and effective inhibitors controlling ILC2 function. Here, we show that soluble ST2, a member of the IL-1 receptor family, suppresses the effect of IL-33 on lung ILC2 in vitro. Stimulation with IL-33 to naïve ILC2 induced morphological change and promoted cell proliferation. In addition, IL-33 upregulated expression of cell surface molecules including IL-33 receptor and induced production of IL-5 and IL-13, but not IL-4. Pretreatment with soluble ST2 suppressed IL-33-mediated responses of ILC2. The results suggest that soluble ST2 acts as a decoy receptor for IL-33 and protects ILC2 from IL-33 stimulation.
| S-EPMC5600343 | biostudies-literature