1.Potential Role of Interleukin-25/Interleukin-33/Thymic Stromal Lymphopoietin-Fibrocyte Axis in the Pathogenesis of Allergic Airway Diseases.
Xiu-Juan YAO ; Xiao-Fang LIU ; Xiang-Dong WANG
Chinese Medical Journal 2018;131(16):1983-1989
Objective:
Allergic airway diseases (AADs) are a group of heterogeneous disease mediated by T-helper type 2 (Th2) immune response and characterized with airway inflammation and remodeling, including allergic asthma, allergic rhinitis, and chronic rhinosinusitis with allergic background. This review aimed to discuss the abnormal epithelial-mesenchymal crosstalk in the pathogenesis of AADs.
Data Sources:
Articles referred in this review were collected from the database of PubMed published in English up to January 2018.
Study Selection:
We had done a literature search using the following terms "allergic airway disease OR asthma OR allergic rhinitis OR chronic sinusitis AND IL-25 OR IL-33 OR thymic stromal lymphopoietin OR fibrocyte". Related original or review articles were included and carefully analyzed.
Results:
It is now believed that abnormal epithelial-mesenchymal crosstalk underlies the pathogenesis of AADs. However, the key regulatory factors and molecular events involved in this process still remain unclear. Epithelium-derived triple cytokines, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), are shown to act on various target cells and promote the Th2 immune response. Circulating fibrocyte is an important mesenchymal cell that can mediate tissue remodeling. We previously found that IL-25-circulating fibrocyte axis was significantly upregulated in patients with asthma, which may greatly contribute to asthmatic airway inflammation and remodeling.
Conclusions
In view of the redundancy of cytokines and "united airway" theory, we propose a new concept that IL-25/IL-33/TSLP-fibrocyte axis may play a vital role in the abnormal epithelial-mesenchymal crosstalk in some endotypes of AADs. This novel idea will guide potential new intervention schema for the common treatment of AADs sharing common pathogenesis in the future.
Asthma
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metabolism
;
physiopathology
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Cytokines
;
physiology
;
Humans
;
Interleukin-17
;
physiology
;
Interleukin-33
;
physiology
2.Dual role of interleukin-33 in tumors.
Qianqian LIU ; Di LU ; Jiahua HU ; Junchao LIANG ; Huoying CHEN
Journal of Central South University(Medical Sciences) 2021;46(2):169-175
Interleukin-33 (IL-33) is a new member of the IL-1 cytokine family which plays roles in the nucleus as a nuclear factor and is released by damaged or necrotic cells to act as a cytokine. It can be released via damaged or necrotic cells and functions as a cytokine. The released IL-33 activates the downstream NF-κB and MAPKs signaling pathways through the isomers of the specific receptor ST2 and the interleukin-1 receptor accessory protein (IL-1RAcP), resulting in danger signals and the activated multiple immune responses. IL-33 is abnormally expressed in various tumors and involves in tumorigenesis, development, and metastasis. Moreover, IL-33 can play both pro-tumor and anti-tumor roles in the same type of tumor.
Cytokines
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Humans
;
Interleukin-33/genetics*
;
MAP Kinase Signaling System
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NF-kappa B/metabolism*
;
Neoplasms
3.Expression of IL-25 and IL-33 and the count of EOS in peripheral blood of children with allergic rhinitis receiving immunotherapy.
Hua FAN ; Tai Jie QIN ; Lin Song YE ; Feng Ti LI ; Gan Sheng LIN ; You Qiong LIANG ; Shen Hong QU
Journal of Clinical Otorhinolaryngology Head and Neck Surgery 2018;32(6):443-446
OBJECTIVES:
To investigate the expression of IL-25,IL-33 and EOS in children with allergic rhinitis (AR).
METHODS:
Ninety-four AR children receiving immunotherapy and 23 healthy people were concluded in the study. The serum levels of IL-25 and IL-33 were detected by Enzyme-linked Immunosorbent Assay (ELISA), and a count of EOS were measured.
RESULTS:
The serum levels of IL-25 and IL-33 in the mild group were higher than control group (<0.05). The count of EOS showed no difference between the mild group and the control group (>0.05). The serum levels of IL-25 and IL-33 in the severe group were higher than those in mild group (<0.05). The serum levels of IL-25 and IL-33 in the severe group were higher than control group (<0.05). The count of EOS in the severe group were higher than those in mild group (<0.05). The count of EOS in the severe group were higher than those in control group (<0.05). Spearman test showed the serum levels of IL-25 in the children with AR patients have positive correlation with the serum levels of IL-33 (<0.05, =0.238).
CONCLUSIONS
Expression of IL-25 levels, IL-33 levels and the count of EOS in patients with AR are enhanced, which shows that IL-25, IL-33 and the count of EOS are involved in the AR. If we can understand the mechanism of them, it will profound implications for treatment.
Child
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Enzyme-Linked Immunosorbent Assay
;
Eosinophils
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Humans
;
Immunotherapy
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Interleukin-17
;
metabolism
;
Interleukin-33
;
metabolism
;
Rhinitis, Allergic
;
immunology
;
therapy
4.Discussion IL-33 and its receptor ST2 associated with the pathogenesis of allergic rhinitis.
Yunyan DU ; Ying LUO ; Chunping YANG ; Jiali LIU ; Jun WAN ; Kun WANG
Journal of Clinical Otorhinolaryngology Head and Neck Surgery 2015;29(9):811-814
OBJECTIVE:
To study the expression of IL-33 and its receptor ST2 in the nasal mucosa of allergic rhinitis (AR) patients, and to explore the role of IL-33 and ST2 in the pathogenesis of AR.
METHOD:
Collected 24 cases of nasal septum deviation of patients with AR as AR group,and selected 20 patients with simple septum deviation as normal control. In addition, collected 20 cases diagnosed with AR, who accepted standardized specific immunotherapy(SIT).
RESULT:
Immunohistochemical results found more positively stained cells of IL-33 and ST2 in AR patients than normal control group, the difference was statistically significant (P < 0.05), Western-Blot detected that IL-33 and ST2 protein level were significantly higher in AR than the normal control group (P < 0.01), PCR detected that the expression of IL-33mRNA and ST2mRNA were increased in AR group compared with the control group, the difference was statistically significant (P < 0.05). While, the serum IL-33 levels in AR were decreased before treatment (72.37 ± 16.18) ng/L than after six months of SIT (47.35 ± 10.59) ng/L,and the difference was statistically significant (P < 0.05).
CONCLUSION
IL-33 and its receptor ST2 were highly expressed in the nasal mucosa of patients with AR, suggesting that IL-33/ST2 may play an important role in the pathogenesis of allergic rhinitis. Serum levels of IL-33 were significantly decreased after SIT treatment, suggesting that IL-33 may have a positive correlation with the severity of AR.
Case-Control Studies
;
Humans
;
Immunotherapy
;
Interleukin-33
;
metabolism
;
Nasal Mucosa
;
metabolism
;
Nasal Septum
;
abnormalities
;
Receptors, Interleukin
;
metabolism
;
Rhinitis, Allergic
;
drug therapy
;
metabolism
;
pathology
5.Bioinformatics analysis of nasal epithelial cell gene expression in seasonal and perennial allergic rhinitis.
Li Wei SUN ; Zi Yu LIU ; Ji Chao SHA ; Cui Da MENG ; Dong Dong ZHU
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2022;57(4):425-432
Objective: Transcriptome sequencing and bioinformatics analysis were performed on the gene expression of nasal epithelial cells in patients with seasonal allergic rhinitis (AR) and perennial AR, so as to obtain the differences in the gene expression of nasal epithelial cells between seasonal AR and perennial AR. Methods: The human nasal epithelial cell line(HNEpC) was cultured in vitro, treated with 100 μg/ml mugwort or house dust mite (HDM) extracts for 24 hours. Total cell RNA was extracted, and quantitative real-time polymerase chain reaction (qPCR) was used to detect the expression of cytokines, including IL-6, IL-8, IL-33 and thymic stromal lymphopoietin (TSLP). From November 2019 to November 2020, 3 seasonal AR patients, 3 perennial AR patients, and 3 healthy controls who attended the Department of Otolaryngology Head and Neck Surgery, China-Japan Union Hospital of Jilin University were analyzed. The patients' primary nasal epithelial cells were cultured in vitro, treated with corresponding allergens for 24 hours. Total RNA was extracted for transcriptome sequencing, and the sequencing results were analyzed by bioinformatics. Results: The qPCR results showed that the cytokines IL-6, IL-8, IL-33 and TSLP of HNEpC treated with mugworts extracts and HDM extracts had the same trend of change. After the nasal epithelial cells from patients with seasonal AR and perennial AR were treated with corresponding allergens, there were differences in biological processes and signal pathways between those and control. Gene ontology (GO) enrichment analysis showed that the differentially expressed genes (DEG) in AR patients allergic to mugwort were mainly enriched in the oxidation-reduction process, the negative regulation of apoptosis process, and the cell adhesion; the DEG in AR patients allergic to HDM were mainly enriched in cell adhesion, the negative regulation of cell proliferation and the response to drug. Enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway showed that the DEG of AR patients allergic to mugwort were significantly enriched in arachidonic acid metabolism, p53 signaling pathway and transforming growth factor β (TGF-β) signaling pathway, while the DEG of AR patients allergic to HDM were mainly enriched in cells cycle, Fanconi anemia pathway and DNA replication. Gene Set Enrichment Analysis (GSEA) showed that the inflammatory response, TNF-α/NF-κB signaling pathway and IL-2/STAT5 signaling pathway were significantly up-regulated in AR patients allergic to mugwort, indicating the promotion of inflammatory response; and AR patients allergic to HDM had significant down-regulation of G2M, E2F, and MYC, indicating the inhibition of cell proliferation. The protein-protein interaction network showed that TNF and CDK1 were the most interacting proteins in mugwort and HDM allergic AR patients, respectively. Conclusion: Seasonal AR and perennial AR may affect the different biological processes and signal pathways of nasal epithelial cells, leading to differences in the occurrence and development of AR.
Allergens
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Animals
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Computational Biology
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Cytokines/metabolism*
;
Epithelial Cells/metabolism*
;
Gene Expression
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Humans
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Interleukin-33/metabolism*
;
Interleukin-6/metabolism*
;
Interleukin-8
;
Nasal Mucosa/metabolism*
;
Plant Extracts/metabolism*
;
Pyroglyphidae
;
RNA/metabolism*
;
Rhinitis, Allergic/metabolism*
;
Rhinitis, Allergic, Perennial
;
Rhinitis, Allergic, Seasonal
;
Seasons
6.Regulating the immune response to carbon tetrachloride-induced liver fibrosis in mice by blocking inducible co-stimulatory molecules and interleukin-33.
Bo WANG ; Wen Na LI ; Xin LI ; Hui Yan LI ; Yue Tong CHEN ; Yuan LI ; Hai Tao DING
Chinese Journal of Hepatology 2023;31(5):504-508
Objective: To investigate the effects of combined blockade of interleukin-33 (IL-33) and inducible co-stimulatory molecule (ICOS) on carbon tetrachloride-induced chronic liver fibrosis and imbalance of T helper lymphocyte subsets in mice. Methods: There were 40 BALB/c mice in each model and control group. Flow cytometry was used to determine the proportion of Th1/Th2/Th17 cells in the splenic lymphocyte suspension of mice, the expression levels of interferon γ, IL-4, and IL-17 in the splenic lymphocyte suspension of liver fibrosis mice after combined blockade of IL-33 and ICOS, and the pathological changes of liver histopathology in mice with liver fibrosis. Two independent sample t-test was used to compare data between groups. Results: Compared with the non-blocking group, the proportion of Th2 and Th17 cells in the IL-33/ICOS blocking group was significantly down-regulated (Th2: 65.96% ± 6.04% vs. 49.09% ± 7.03%; Th17: 19.17% ± 4.03% vs. 9.56% ± 2.03%), while the proportion of Th1 cells and Th1/Th2 ratio were up-regulated (Th1: 17.14% ± 3.02% vs. 31.93% ± 5.02%; Th1/Th2: 0.28 ± 0.06 vs. 0.62 ± 0.23), and the difference was statistically significant (t = 5.15, 6.03, 7.14, 4.28, respectively, with P < 0.05). After entering the chronic inflammation stage of liver fibrosis in mice (10 weeks), compared with the non-blocking group, the expression levels of IL-4 and IL-17 in the blockade group were significantly down-regulated [IL-4: (84.75 ± 14.35) pg/ ml vs. (77.88 ± 19.61) pg/ml; IL-17: (72.38 ± 15.13) pg/ml vs. (36.38 ± 8.65) pg/ml], while the expression of interferon γ was up-regulated [(37.25 ± 11.51) pg/ml vs. (77.88 ± 19.61) pg/ml], and the difference was statistically significant (t: IL-4: 4.71; IL-17: 5.84; interferon γ: 5.05, respectively, with P < 0.05). Liver histopathological results showed that hepatic necrosis, hepatic lobular structural disorder, and fibrous tissue hyperplasia were significantly lower in the blockade group than those in the non-blocking group at 13 weeks of liver fibrosis. Conclusion: Combined blockade of the ICOS signaling pathway and IL-33 can regulate Th2 and Th17 polarization, down-regulate the inflammatory response, and inhibit or prevent the occurrence and progression of fibrosis.
Mice
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Animals
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Interferon-gamma/metabolism*
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Interleukin-17/metabolism*
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Interleukin-33/metabolism*
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Cytokines/metabolism*
;
Carbon Tetrachloride
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Th2 Cells
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Interleukin-4/metabolism*
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Liver Cirrhosis/pathology*
;
Th1 Cells
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Th17 Cells/pathology*
;
Immunity
7.Effect of interleukin-33 on Th1/Th2 cytokine ratio in peripheral lymphocytes in asthmatic mice.
Xinliang HE ; Wei WU ; Yan LU ; Yali GUO ; Chaoliang HU ; Yuyun HUANG ; Yuzu XU ; Jungang XIE ; Jianping ZHAO
Chinese Medical Journal 2014;127(8):1517-1522
BACKGROUNDAllergic asthma is a chronic airway inflammatory disease partly characterised by high concentration of T help 2 (Th2) cytokines in bronchoalveolar lavage fluid (BALF). There is no report on the relation of peripherally circulating blood lymphocytes and asthma. We explored the balance of Th2/Th1 cytokines in asthmatic mice. Exogenous recombinant interleukin (IL) 33 acted on murine peripheral circulating blood lymphocytes, IL-5 cytokine was selected for assessing Th2 cytokines and interferon-gamma (IFN-γ) for Th1 cytokines.
METHODSFemale specific pathogen free BABL/c mice were sensitised by intraperitoneal injection of 20 µg of ovalbumin emulsified in 1 mg of aluminium hydroxide gel in a total volume of 200 µl, and challenged for 30 minutes in 7 consecutive days with an aerosol of 2 g ovalbumin in 100 ml of PBS. Then we collected BALF and isolated lymphocytes from the peripheral blood. The lymphocytes were divided into two groups: asthmatic group and normal group. Th1/Th2 cytokines was detected by enzyme-linked immunosorbent assay (ELISA) kits.
RESULTSIn the asthma group, we found numerous eosinophils and lymphocytes on the glass slides. We then confirmed that the optimal concentration of IL-33 was 10 ng/ml and time of IL-33 stimulating lymphocytes was 24 hours. In the asthma group, the production of IL-5 was significantly increased over normal group after stimulation with IL-33 (P < 0.05) and the production of IFNγ was supressed from IL-33 stimulated lymphocytes (P < 0.05).
CONCLUSIONIL-33 acts on lymphocytes of peripheral blood increasing secretion of Th2 cytokines and inhibiting secretion of Th1 cytokines.
Animals ; Asthma ; chemically induced ; immunology ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Interferon-gamma ; immunology ; metabolism ; Interleukin-33 ; Interleukin-5 ; immunology ; metabolism ; Interleukins ; immunology ; metabolism ; Lymphocytes ; immunology ; metabolism ; Mice ; Mice, Inbred BALB C
8.Pretreatment with interleukin-33 reduces warm hepatic ischemia/reperfusion injury in mice.
Shu LI ; Feng-Xue ZHU ; Hong-Bin ZHANG ; Hui LI ; You-Zhong AN
Chinese Medical Journal 2013;126(10):1855-1859
BACKGROUNDInterleukin (IL)-33 is a recently identified member of the IL-1 family that binds to the receptor, ST2L. This study examined IL-33 production in mouse liver and investigated its role in hepatic ischemia/reperfusion (I/R) injury.
METHODSMale BALB/c mice ((22 ± 3) g) were subjected to 90 minutes partial hepatic ischemia, followed by 6 hours reperfusion. First, mice were randomized into two groups: control group (laparotomy only, without blocking blood supply) and ischemia model group. IL-33 mRNA and serum protein levels were measured at 30, 60, 90 minutes after ischemia and 2 and 6 hours after reperfusion. Second, mice were randomized into four groups: control, model (injection of rabbit IgG polyclonal antibody), recombinant IL-33 intervention and anti-ST2L antibody intervention group. Mice were sacrificed 6 hours after reperfusion. Liver pathology was observed via transmission electron microscopy. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), IL-4, IL-5, IL-13, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were measured.
RESULTSLevels of IL-33 mRNA and protein did not change during ischemia (P > 0.05) but increased significantly during reperfusion (P < 0.05). After reperfusion for 6 hours, serum levels of ALT, AST, IL-4, IL-5, IL-13, IFN-γ and TNF-α were significantly increased (P < 0.05), and hepatocellular ultrastructure was damaged. Pretreatment with IL-33 attenuated severity of liver damage compared with controls, but pretreatment with anti-ST2L antibody increased severity. Serum levels of IL-4, IL-5 and IL-13 protein increased whereas IFN-γ decreased following IL-33 pretreatment. Pretreatment with anti-ST2L antibody significantly decreased serum IL-4, IL-5, IL-13 levels and increased serum IFN-γ levels compared with controls (P < 0.05). There was no change in the level of TNF-α.
CONCLUSIONIL-33 is produced systematically and locally in liver during I/R injury. Pretreatment with IL-33 is therapeutic for hepatic I/R injury, possibly via inducing a Th1 to Th2 shift.
Animals ; Humans ; Interleukin-33 ; Interleukins ; blood ; genetics ; therapeutic use ; Liver ; drug effects ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred BALB C ; Reperfusion Injury ; blood ; drug therapy ; genetics
9.Expression and role of IL-33 and its receptor ST2 in eosinophilic and non-eosinophilic chronic rhinosinusitis with nasal polyps.
Tiancong LIU ; Changlong LV ; Zhiwei CAO
Journal of Clinical Otorhinolaryngology Head and Neck Surgery 2015;29(15):1350-1371
OBJECTIVE:
To investigate the expression and role of Interleukin-33 (IL-33) and ST2 in the nasal polyps of human Eosinophilic and non-Eosinophilic chronic rhinosinusitis with nasal polyps (ECRS and non-ECRS).
METHOD:
IL-33 and ST2 protein expression in nasal polyps of ECRS and non-ECRS as well as in seemingly normal mucosa of the inferior turbinate tissue was investigated by immunohistochemical staining and messenger RNA (mRNA) expression of IL-33 and ST2 was assessed by realtime polymerase chain reaction (PCR) in 27 subjects with ECRS, 33 subjects with non-ECRS, and 11 control subjects.
RESULT:
(1) The ST2 was found both in nasal polyps of ECRS and non-ECRS,especially in ECRS, yet hardly found in the normal mucosa of the inferior turbinate tissue; (2) The expression of ST2 mRNA in nasal polyps of ECRS was higher than that in non-ECRS and normal inferior turbinate tissue, and the difference was both prominent in statistics (P<0.01); (3) The expression patterns of IL-33 at both mRNA and protein levels were not significantly different among the three groups (P>0.05).
CONCLUSION
The IL-33 and its receptor ST2 were both expressed in human nasal polyps including ECRS and non-ECRS, meanwhile the expression patterns of ST2 at both mRNA and protein levels were significantly higher in nasal polyps of ECRS. The current study suggests that IL-33 and its receptor ST2 may play important roles in the pathogenesis of chronic rhinosinusitis with nasal polyps, especially in ECRS through the increased expression of ST2 in Eosinophils as a hypothesis.
Chronic Disease
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Eosinophils
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immunology
;
Humans
;
Interleukin-1 Receptor-Like 1 Protein
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Interleukin-33
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metabolism
;
Nasal Mucosa
;
metabolism
;
Nasal Polyps
;
immunology
;
RNA, Messenger
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Real-Time Polymerase Chain Reaction
;
Receptors, Cell Surface
;
metabolism
;
Rhinitis
;
immunology
;
Sinusitis
;
immunology
;
Turbinates
;
metabolism
10.Association of IL33/ST2 signal pathway gene polymorphisms with myocardial infarction in a Chinese Han population.
Jin-hua YANG ; Fang-qin WU ; Qiang WEN ; Wen-cai ZHANG ; Yang-e WANG ; Xin XIONG ; Yan-wen SU ; Long-xian CHENG
Journal of Huazhong University of Science and Technology (Medical Sciences) 2015;35(1):16-20
This study investigated the relationship between IL-33/ST2 signal pathway gene polymorphisms and myocardial infarction (MI) in Han Chinese. A case-control association analysis was performed on a total of 490 MI patients (MI group) and 929 normal subjects (NC group). Sequenom Mass Array and Taqman genotyping technique were used to analyze the tag single nucleotide polymorphisms (SNPs) in the genes encoding IL-33, ST2, and IL-1RaP (rs11792633, rs1041973 and rs4624606). The results showed that the frequencies of rs4624606 genotypes AA, TT, AT were 0.031, 0.647, 0.322 in MI group and 0.026, 0.712, 0.263 in NC group, and the allele frequencies of A and T were 0.192, 0.808 in MI group and 0.157, 0.843 in NC group. There were significant differences in rs4624606 genotypes and allele frequencies between MI group and NC group (P<0.05). For rs11792633, the allele frequencies of C and T were 0.45, 0.55 in MI group and 0.454, 0.546 in NC group with no significant differences found between the two groups. Compared with genotype CC+TC, rs11792633 genotype TT had an increased risk of hypertension (P<0.05). However, there were no significant differences in the frequencies of rs11792633 genotypes between the two groups. No significant differences were noted in the frequencies of rs1041973 genotype and allele between the two groups. Logistic regression analysis showed that rs4624606 genotypes AT and AA+AT were both significantly associated with MI (AT: OR=1.325, P=0.029, 95% CI=1.03-1.705; AA+AT: OR=1.316, P=0.028, 95% CI=1.03-1.681) after factors such as age, gender, smoking, drinking, body mass index (BMI), triglyceride (TG) and cholesterol were adjusted. Those carrying rs4624606 genotype AT or AA+AT had an increased risk of MI. No associations were found between the polymorphisms of the other two loci with MI. It was concluded that, in the IL33/ST2 signal pathway, the A allele of rs4624606 polymorphism of IL-1RaP gene is a potential independent risk factor for MI, and the genotypes AA+AT and AT are associated with the incidence of MI.
China
;
Ethnic Groups
;
genetics
;
Female
;
Humans
;
Interleukin-1 Receptor-Like 1 Protein
;
Interleukin-33
;
Interleukins
;
genetics
;
metabolism
;
Male
;
Myocardial Infarction
;
genetics
;
Receptors, Cell Surface
;
genetics
;
metabolism
;
Signal Transduction
;
genetics