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Daifan San intervenes in forkhead box P3 and the interleukin(IL)-23/IL-17A signaling pathway to help prevent and treat primary biliary cirrhosis

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Journal of Traditional Chinese Medicine 2020年第4期40卷 571-583页

作者： Zhan Kai Xu Yan Han Mengling Cheng Liangbin The Second Clinical College of Guangzhou University of Chinese Medicine Guangzhou 510000China Department of Internal Medicine Hubei Rongjun HospitalWuhan 430079China Department of Hepatology the Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510000China Department of Hepatology Hubei Provincial Hospital of Chinese MedicineWuhan 430061China

OBJECTIVE:To investigate the mechanism by which Daifan San(DFS)prevents and treats primary biliary cirrhosis(PBC)via the forkhead box P3(FoxP3)and interleukin(IL)-23/IL-17A signaling pathways.METHODS:Ninety C57BL/6 mice were randomly divided into the control,model,DFS low-dose,DFS middle-dose,DFS high-dose and ursodeoxycholic acid(UDCA)groups(n=15 per group).A mouse model of PBC was induced using polyinosinic polycytidylic acids(poly I:C).Lymphocyte subset expression in the peripheral blood was analyzed via flow cytometry.The inflammatory cytokines and antimitochondrial autoantibody(AMA)levels were detected via enzyme-linked immunosorbent assays.The expressions and location of typeⅠcollagen,typeⅢcollagen,cytokeratin 19 and FoxP3 in the liver tissue were evaluated via immunohistochemistry.FoxP3,IL-23 and IL-17 expressions in the peripheral blood and liver tissue were evaluated via real-time polymerase chain reaction and western blotting.RESULTS:IL-17,IL-23,IL-8,IL-33,TNF-α,and AMA expressions were significantly increased in the model group and decreased in the DFS and UDCA groups.Conversely,Treg cell and FoxP3 expressions were significantly decreased in the model group and increased in the DFS and UDCA groups.The IL-23/IL-17A signaling pathway was closely correlated with chronic inflammation of the bile duct in PBC and functional deletion of Treg cells,leading to reduced FoxP3 levels and mediating the loss of tolerance in PBC.CONCLUSION:DFS may delay the occurrence and relieve the symptoms of PBC by downregulating IL-23/IL-17A signaling pathway expression and upregulating FoxP3 expression.

关键词： Liver cirrhosis,biliary interleukin-23 interleukin-17 Signal transduction FoxP3 protein,mouse Daifan San

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Increased interleukin-23 is associated with increased disease activity in patients with rheumatoid arthritis

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Chinese Medical Journal 2013年第5期126卷 850-854页

作者： GUO Ying-ying WANG Nai-zhi ZHAO Shuai HOU Lin-xin XU Yan-bing ZHANG Ning Department of Rheumatism Shengjing Hospital China MedicalUniversity Shenyang Liaoning 110004 China

Background interleukin-23 （IL-23） is a pro-inflammatory cytokine that is thought to be central to the development of autoimmune diseases. This study was conducted to determine whether or not the serum concentration of IL-23 is elevated in patients with rheumatoid arthritis （RA）, and to determine the relationship between the IL-23 level and disease activity in RA patients. Methods Serum samples were obtained from 59 patients with RA and 30 healthy controls. The clinical parameters of disease activity were determined, including the 28-joint disease activity score （DAS28）, C-reactive protein （CRP）, rheumatoid factor （RF） levels, and the degree of bony erosions based on X-rays. The levels of IL-23 and IL-17 were determined by enzyme-linked immunosorbent assay （ELISA）. The correlations between the serum levels of IL-23 and disease activity parameters of patients with RA were determined. Results The serum IL-23 level was significantly elevated in patients with RA compared to healthy controls. The serum IL-23 levels in the RA patients correlated with IL-17 and CRP levels, and the DAS28. The levels of IL-23 based on X-ray classification phase I, II, III, and IV were gradually elevated in RA patients. Conclusions The levels of serum IL-23 in RA patients were higher than in healthy controls. Thus, elevated serum IL-23 levels may be useful markers to detect active RA. In addition, IL-23 is involved in disease progression and bony erosions in patients with RA.

关键词： rheumatoid arthritis interleukin-23 interleukin-17 C-reactive protein

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Immunotherapeutic effects on murine pancreatic carcinoma by β-elemene combined with dendritic cells modified with genes encoding interleukin-23

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Frontiers of Medicine 2007年第1期1卷 41-45页

作者： TAN Guang WANG Zhongyu CHE Luanqing YIN Shuo Department of General Surgery First Affiliated HospitalDalian Medical UniversityDalian 116011China

The dendritic cell vaccine is a treatment vaccine with potent clinical applications.Functional cytokines can enhance dendritic cell anti-tumor immune responses.This experiment was conducted to study the effects of bone marrow-derived dendritic cells(BM-DCs)modified with genes encoding murine interleukin-23(IL-23)on murine pancreatic carcinoma,and effects of the treatment of pancreatic carcinoma with β-elemene combined with IL-23-modified dendritic cell vaccine.The murine IL-23 cDNA was sub-cloned into a dual-expression vector.DCs were pulsed with tumor cell lysate after being modified wth IL-23.Mice were divided into groups which were injected with IL-23-transduced DC vaccine,non-transduced DC vaccine and sodium respectively.The preventive immune and immunotherapeutic effects of DC vaccines on mice and cytokine release in vivo were then assessed.Results showed inhibitory effects on tumor cells and increased survival time in the experimental group treated with the vaccine combined with β-elemene.The IL-23 protein apparently increases the antigen presenting ability of DCs.After injection with DC vaccines,IFN-γ production in the treatment group was significantly increased as compared with that in the control group(P23-modified dendritic cell vaccines enhance specific Th1-type and cytotoxic T lymphocyte(CTL)responses against pancreatic carcinoma cells,and induce not only auto-immune ability but also preventive immunity against pancreatic carcinoma implanted in mice.β-elemene has great anti-tumor collaborative functions.

关键词： interleukin-23 dendritic cell pancreatic carcinoma immune response β-elemene

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High IL-23^(+)cells infiltration correlates with worse clinical outcomes and abiraterone effectiveness in patients with prostate cancer

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Asian Journal of Andrology 2022年第2期24卷 147-153页

作者： Zheng Liu Jun-Yu Zhang Yun-Jie Yang Kun Chang Qi-Feng Wang Yun-Yi Kong Bo Dai Department of Urology Fudan University Shanghai Cancer CenterShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China Department of Pathology Fudan University Shanghai Cancer CenterShanghai 200032China

Individualized treatment of prostate cancer depends on an accurate stratification of patients who are sensitive to various treatments.interleukin-23(IL-23)was reported to play a significant role in prostate cancer.Here,we aimed to explore the clinical value of IL-23-secreting(IL-23^(+))cells in prostate cancer patients.We evaluated interleukin-23A(IL-23A)expression in The Cancer Genome Atlas database and retrospectively enrolled 179 treatment-naive metastatic prostate cancer patients diagnosed in our institute between June 2012 and December 2014.IL-23^(+)cells were stained and evaluated via immunohistochemistry.Further,survival and multivariate Cox regression analyses were conducted to explore the prognostic value of IL-23^(+)cells.We found that IL-23A expression correlated with disease progression,while IL-23^(+)cells were clearly stained within prostate cancer tissue.Patients with higher Gleason scores and multiple metastatic lesions tended to have more IL-23^(+)cell infiltration.Further analyses showed that patients with higher levels of IL-23^(+)cells had significantly worse overall survival(hazard ratio[HR]=2.996,95%confidence interval[95%CI]:1.812–4.955;P=0.001)and a higher risk of developing castration resistance(HR=2.725,95%CI:1.865–3.981;P=0.001).Moreover,subgroup analyses showed that when patients progressed to a castration-resistant status,the prognostic value of IL-23^(+)cells was observed only in patients treated with abiraterone instead of docetaxel.Therefore,we showed that high IL-23^(+)cell infiltration is an independent prognosticator in patients with metastatic prostate cancer.IL-23^(+)cell infiltration may correlate with abiraterone effectiveness in castration-resistant prostate cancer patients.

关键词： abiraterone acetate interleukin-23 prognosis prostate cancer

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IL-23-induced macrophage polarization and its pathological roles in mice with imiquimod-induced psoriasis

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Protein & Cell 2018年第12期9卷 1027-1038页

作者： Yuzhu Hou Linnan Zhu Hongling Tian Hai-Xi Sun Ruoyu Wang Lianfeng Zhang Yong Zhao State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesUniversity of Chinese Academy of SciencesBeijing 100101China Department of Oncology The Affiliated Zhongshan Hospital of Dalian UniversityDalian 116001China Key Laboratory of Human Diseases Comparative Medicine Ministry of HealthInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Macrophages are roughly categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation driven by IL-23 with a distinct gene expression profile including defined types of cytokines. The freshly isolated resting mouse peritoneal macrophages were stimulated with different cytokines in vitro, the expression of cytokines and chemokines were detected by microarray, real-time PCR, ELISA and multiple colors flow cytometry. Adoptive transfer of macrophages and imiquimod-induced psoriasis mice were used. In contrast to M1- and M2-polarized macrophages, IL-23-treated macrophages produce large amounts of IL-17A, IL-22 and IFN-γ. Biochemical and molecular studies showed that IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) pathway. T-bet mediates the IFN-γ production in IL-23-treated macrophages. Importantly, IL-23-treated macrophages significantly promote the dermatitis pathogenesis in a psoriasis-like mouse model. IL-23-treated resting macrophages express a distinctive gene expression prolife compared with M1 and M2 macrophages. The identification of IL-23-induced macrophage polarization may help us to understand the contribution of macrophage subpopulation in Th17-cytokines-related pathogenesis.

关键词： imiquimod-induced psoriasis interferon-gamma interleukin-17 interleukin-23 macrophage polarization

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Risk of hepatitis B virus reactivation in patients with autoimmune diseases undergoing non-tumor necrosis factor-targeted biologics

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World Journal of Gastroenterology 2021年第19期27卷 2312-2324页

作者： Shintaro Akiyama Thomas G Cotter Atsushi Sakuraba Section of Gastroenterology Hepatology and NutritionDepartment of MedicineUniversity of ChicagoChicagoIL 60637United States

Hepatitis B virus reactivation(HBVr)can occur in patients treated with immunosuppressive medications.Risk stratification for HBVr based on hepatitis B virus(HBV)serology and viral load is an important strategy to determine appropriate HBV monitoring and antiviral prophylaxis use.Recent advances in the understanding of pathophysiology of autoimmune diseases have led the development of cytokine-targeted therapies.Tumor necrosis factor(TNF)-αinhibitors have been widely used for patients with inflammatory bowel disease,psoriasis,and rheumatic diseases.Further,the clinical benefits of interleukin(IL)-12/23,IL-17,or Janus kinases inhibitors have been demonstrated in these patients.It is well known that TNF-αinhibitor use can lead to HBVr,however,the risk of HBVr in patients undergoing non-TNF-targeted biologics have not been fully understood.In this review,we discuss the risk of HBVr in patients treated with non-TNF-targeted biologics,and immunological mechanisms of these medications causing HBVr.

关键词： Hepatitis B virus Autoimmune diseases Biological therapy interleukin-23 interleukin-17 Janus kinases

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大黄素对病毒性心肌炎小鼠IL-23/IL-17炎症轴、Th17细胞及病毒复制的影响

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南方医科大学学报 2014年第3期34卷 373-378页

作者：蒋娜廖雯婷匡希斌南华大学附属第二医院湖南衡阳421001 南方医科大学病理学系广东广州510515

目的探讨大黄素对病毒性心肌炎(VMC)小鼠心肌的保护作用及其分子机制。方法 55只雄性BALB/c小鼠随机分为对照组(n=15)、模型组(n=20)及大黄素组(n=20),模型组、大黄素组小鼠腹腔接种0.1 ml内含柯萨奇病毒B3(CVB3)的Eagle's液建立VMC模型... 详细信息

目的探讨大黄素对病毒性心肌炎(VMC)小鼠心肌的保护作用及其分子机制。方法 55只雄性BALB/c小鼠随机分为对照组(n=15)、模型组(n=20)及大黄素组(n=20),模型组、大黄素组小鼠腹腔接种0.1 ml内含柯萨奇病毒B3(CVB3)的Eagle's液建立VMC模型,对照组仅注射Eagle’s液,于接种当天,大黄素组以3 mg/ml大黄素溶液0.1 ml灌胃,其余2组以0.1 ml蒸馏水灌胃,1次/d,共21 d,记录实验期间小鼠死亡数目,比较各组死亡率。第7天每组处死5只小鼠,取心脏,测定病毒滴度。第22天称体质量(BW)后处死全部小鼠,收集外周血,剥离心脏,称心脏质量(HW),计算HW/BW,行HE染色计算心肌病理积分,采用荧光实时定量PCR、Western blotting分别检测心肌白介素-23(IL-23)、白介素-17(IL-17)mRNA和蛋白表达,通过酶联免疫吸附法测定血清IL-23、IL-17浓度,流式细胞术分析Th17细胞频率,利用Western blotting测定心肌细胞核内核因子-κB(NF-κB)p65表达,ELISA分析心肌白介素-1β(IL-1β)、白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)含量。结果大黄素组死亡率、心肌病理积分及病毒滴度较模型组减少(P23及IL-17 mRNA与蛋白表达水平、血清IL-23和IL-17浓度、Th17细胞频率、胞核NF-κB p65表达水平及心肌IL-1β、IL-6、TNF-α含量显著高于对照组(P23/IL-17炎症轴、Th17细胞增殖及病毒复制发挥抗VMC作用。

关键词：大黄素病毒性心肌炎白介素-23 白介素-17 Th17细胞 interleukin-23 interleukin-17

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Susceptibility to ulcerative colitis in Hungarian patients determined by gene-gene interactions

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World Journal of Gastroenterology 2014年第1期20卷 219-227页

作者： Patricia Sarlos Dalma Varszegi Veronika Csongei Lili Magyari Luca Jaromi Lajos Nagy Bela Melegh 1~(st) Department of Internal Medicine University of Pecs7623 PecsHungary Department of Dermatology Venereology and OncodermatologyUniversity of Pecs7624 PecsHungary Department of Immunology and Biotechnology University of Pecs7624 PecsHungary Szentagothai Research Centre 7624 PecsHungary Department of Medical Genetics University of Pecs7624 PecsHungary Institute of Family Medicine University of Pecs7632 PecsHungary

AIM:To study the inflammatory bowel disease-5 locus(IBD5)and interleukin-23 receptor(IL23R)gene variants in UC patients and test for gene-gene interaction.METHODS:The study population(n=625)was comprised of 320 unrelated ulcerative colitis(UC)patients with Caucasian origin and 316 age-and gendermatched,healthy controls.Five variants in the IBD5 locus(IGR2198a_1 rs11739135,IGR2096a_1 rs12521868,IGR2230a_1 rs17622208,SLC22A4 rs1050152 and SLC22A5 rs2631367)and two of the IL23R gene(rs1004819,rs2201841)were analysed.PCR and restriction fragment length polymorphism methods were used for genotyping,the SLC22A4 rs1050152 genotypes were determined by direct sequencing.Interactions and specific genotype combinations of the seven variants were tested by binary logistic regression analysis.The IL23R genotypes were stratified by IBD5 genotypes for further interaction analyses.RESULTS:For the IL23R rs1004819 A allele we found significantly higher allele frequency(P=0.032)in UC patients compared to control subjects.The SNP rs1004819 showed significant association with UC risk for carriers(P=0.004,OR=1.606;95%CI:1.160-2.223)and the SNP rs2201841 for homozygotes(P=0.030,OR=1.983;95%CI:1.069-3.678).Individually none of the IBD5 markers conferred risk to UC development.There was no evidence for statistical interaction either between IBD5 loci and IL23R genes using logistic regression analysis.After genotype stratification,we could detect a positive association on the background of rs1004819 A allele for SLC22A4 T,SLC22A5 C,IGR2198a_1 C or IGR2096a_1 T allele,the highest OR was calculated in the presence of SLC22A4T allele(P=0.005,OR=2.015;95%CI:1.230-3.300).There was no association with UC for any combinations of rs1004819 and IGR2230a_1.The IL23R rs2201841homozygous genotype and IBD5 carrier status together did not confer susceptibility for UC.CONCLUSION:The present study has shown that UC susceptibility genes are likely to act in a complex interactive manner similar to CD.

关键词： Gene-gene interaction interleukin-23 receptor gene

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Relationship between vitamin D and IL-23,IL-17 and macrophage chemoattractant protein-1 as markers of fibrosis in hepatitis C virus Egyptians

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World Journal of Hepatology 2012年第8期4卷 242-247页

作者： Noha M El Husseiny Hala M Fahmy Waleed A Mohamed Hisham H Amin Internal Medicine Department Faculty of MedicineCairo UniversityCairo 11111Egypt Internal Medicine Department Faculty of MedicineCairo University Cairo 11111Egypt Department of Chemistry Cairo UniversityCairo 12534Egypt Clinical Pathology Department Faculty of Medicine AL Azhar UniversityCairo 15533Egypt

AIM:To assess vitamin D in hepatitis C patients and its relationship to interleukin (IL)-23, IL-17, and macrophage chemoattractant protein-1 (MCP-1). METHODS:The study was conducted on 50 Egyptian hepatitis C virus (HCV) genotype number IV-infected patients and 25 ageand gender-matched healthy subjects. Venous blood samples were obtained. Samples were allowed to clot and sera were separated by centrifugation and stored at -20 ℃. A 25 hydroxy vitamin D assay was carried out using solid phase RIA. A 1,25 dihydroxy vitamin D assay was carried out using a commercial kit purchased from Incstar Corporation. IL-17 and -23 and MCP-1 were assayed by an enzyme immunoassay. Quantitative and qualitative polymerase chain reaction for HCV virus were done by TaqMan technology. Only HCV genotype IV-infected subjectswere included in the study. The mean ± SD were determined, a t-test for comparison of means of different parameters was used. Correlation analysis was done using Pearson's correlation. Differences among different groups were determined using the Kruskal-Wallis test. RESULTS:The mean vitamin D level in HCV patients (groupⅠ) was 15 ± 5.2 ng/mL while in control (group Ⅱ) was 39.7 ± 10.8. For active vitamin D in groupⅠas 16.6 ± 4.8 ng/mL while in group Ⅱ was 41.9 ± 7.9. IL-23 was 154 ± 97.8 in group Ⅰ and 6.7 ± 2.17 in group Ⅱ. IL-17 was 70.7 ± 72.5 in cases and 1.2 ± 0.4 in control. MCP-1 was 1582 ± 794.4 in group Ⅰand 216.1 ± 5.38 in group Ⅱ. Vitamin D deficiency affected 72% of HCV-infected patients and 0% of the control group. Vitamin D insufficiency existed in 28% of HCV-in-fected patients and 12% of the control group. One hundred percent of the cirrhotic patients and 40% of non cirrhotic HCV-infected patients had vitamin D deficiency. IL-23, IL-17, and MCP-1 were markedly increased in HCV-infected patients in comparison to controls.A significant negative correlation between vitamin D and IL-17 and-23 and MCP-1 was detected. HCV-infected males and females showed no differences with respect to viral load, vitamin D le

关键词： Vitamin D Macrophage chemoattractant protin-1 Liver cirrhosis interleukin-23 interleukin-17

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Expression of toll-like receptor 4 gene polymorphism and inflammatory factors in peripheral blood on patients with sepsis

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Discussion of Clinical Cases 2020年第4期7卷 15-21页

作者： Tieying Tian Xiyuan Xu Jingping Yang Department of Respiratory and Critical Medicine the Third Affiliated Hospital of Inner Mongolia Medical University(Baogang Hospital)BaotouInner MongoliaChina

Objective:To observe the presence of toll-like receptor 4(TLR4)gene polymorphism in the venous blood in patients with sepsis,meanwhile,to observe the expression and the diagnostic value of TLR4 mRNA,interferon-(IFN-),interleukin-23(IL-23),procalcitonin(PCT)and C-reactive protein(CRP)in patients with different degrees of sepsis.Methods:The peripheral blood samples from the subjects were collected to extract genomic DNA,gene sequencing and enzyme digestion method were applied to the detection of TLR4 Asp299Gly loci polymorphism.The expression of TLR4 mRNA in the peripheral blood was detected by reverse transcriptase polymerase chain reaction(RT-PCR).The expression levels of IFN-,IL-23,PCT and CRP were measured by enzyme linked immunosorbent assay(ELISA).Results:(1)The gene polymorphism was not present in TLR4 Asp299Gly loci;(2)The expression of TLR4 mRNA in the peripheral blood in patients with sepsis:on d1,there were statistically significant differences between the normal group and the group(APACHE II≤20),between the normal group and the group(APACHE II>20),between the group(APACHE II≤20)and the group(AAPACHE II>20)(t=5.741,14.780 and 10.500,all p20),between the group(APACHE II≤20)and the group(APACHE II>20)(t=4.186,13.830 and 9.645,all p23,PCT and CRP were obviously upregulated(all p23(all p23 at baseline was 861μg/L,with a sensitivity of 100%and a diagnostic specificity of 97%.Conclusions:(1)The Asp299Gly polymorp

关键词： Sepsis Toll-like receptor 4 interleukin-23 Gene polymorphism

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