肥大细胞释放生物活性介质促进TNCB致敏淋巴细胞分泌IL-17

氯化苦咪酸(TNCB)是诱导接触性超敏反应(CHS)实验模型的常用试剂,IL-17参与CHS的致病过程。利用TNCB致敏C57BL/6小鼠,4d后无菌分离淋巴结细胞。同时制备并体外活化同源小鼠成熟骨髓来源的肥大细胞(BMMC),成熟的BMMC具有肥大细胞特异性表型(FcεRI+/c-kit+),活化后可分泌TNF-α和IL-6等生物活性介质。在抗原提呈细胞存在下,活化的BMMC与淋巴结细胞体外共同培养72h,结果显示,与未致敏淋巴细胞共同培养组相比,BMMC与TNCB致敏淋巴细胞的共同培养上清中IL-17分泌水平显著增高(P0.01)。由此提示,活化的肥大细胞通过释放生物活性介质,促进TNCB致敏淋巴细胞IL-17的分泌。     

Upregulation of IL-17A/F from human lung tissue explants with cigarette smoke exposure: implications for COPD

Background

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder marked by relative resistance to steroids. The IL-17 superfamily, which mediates cross-talk between the adaptive and innate immune systems, has been associated with diminished responses to steroids. Increasing evidence supports elevated IL-17 expression in the lung of COPD subjects. However, whether cells of the immune system (systemic) and/or local lung cells are contributing to the elevated IL-17 remains unclear. To address this issue, we utilized a human parenchymal lung tissue explant culture system with cigarette smoke exposure to investigate the expression of IL-17 and the mechanisms involved.

Methods

Parenchymal lung tissue removed from 10 non-COPD and 8 COPD patients was sectioned and cultured with different concentrations of cigarette smoke extract (CSE) for 3 or 6 hours. Tissue viability was evaluated by LDH (lactate dehydrogenase) in culture supernatants. Western blot and real-time PCR were performed to evaluate IL-17A/F expression. To investigate the mechanisms, pharmacological inhibitors for MAPK p38, ERK1/2, NF-κB and PI3K pathways were added into the culture media.

Results

No tissue damage was observed after the cigarette smoke exposure for 3 h or 6 h compared with the control media. At the protein level, the expression of both IL-17A (2.4 ± 0.6 fold) and IL-17 F (3.7 ± 0.7 fold) in the tissue from non-COPD subjects was significantly increased by 5% of CSE at 3 h. For COPD subjects, IL-17A/F expression were significantly increased only at 6 h with 10% of CSE (IL-17A: 4.2 ± 0.8 fold; IL-17 F: 3.3 ± 0.8 fold). The increased expression of IL-17A/F is also regulated at the mRNA level. The inhibitors for NF-κB and PI3K pathways significantly inhibited CSE-induced IL-17A/F expression from lung tissue of non-COPD subjects.

Conclusions

We found the evidence that the expression of both IL-17A and IL-17 F is increased by the cigarette smoke exposure in explants from both non-COPD and COPD subjects, supporting that local lung cells contribute IL-17 production. The elevated IL-17A/F expression is dependent on NF-κB and PI3K pathways. These observations add to the growing evidence which suggests that Th17 cytokines play a significant role in COPD.     

TGF-β is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23

TGF-β and IL-6 induce Th17 differentiation, and IL-23 is required for expansion and maintenance of Th17 cells. Recently, it was shown that IL-6 up-regulates IL-23R mRNA in naive CD4⁺ T cells and therefore IL-6 and IL-23 synergistically promote Th17 differentiation. However, the molecular mechanism whereby IL-6 and IL-23 induce Th17 differentiation and the relevance to TGF-β remain unknown. Here, we found that IL-6 up-regulated IL-23R mRNA expression, and IL-6 and IL-23 synergistically augmented its protein expression. The combination induced Th17 differentiation, and TGF-β1 further enhanced it. IL-6 augmented endogenous TGF-β1 mRNA expression, whereas the amount of TGF-β produced was not enough to induce Th17 differentiation by IL-6 alone. However, unexpectedly, the up-regulation of IL-23R and induction of Th17 differentiation by IL-6 and IL-23 were almost completely inhibited by anti-TGF-β. These results suggest that the induction of IL-23R and Th17 differentiation by IL-6 and IL-23 is mediated through endogenously produced TGF-β.     

Cyclosporin A inhibits the production of IL-17 by memory Th17 cells from healthy individuals and patients with rheumatoid arthritis

Recent evidence from several studies indicated that IL-17-producing Th17 cells can represent the key effector cells in the induction and development of autoimmune disorders. Cyclosporine A (CsA) is a commonly used immunosuppressant to treat lots of autoimmune diseases including rheumatoid arthritis (RA). Here, we demonstrated that PBMCs and purified CD4⁺ T cells from healthy individuals and patients with RA could be induced to produce large amounts of IL-17 after stimulation with anti-CD3 plus anti-CD28 mAbs. Phenotypic analysis indicated that the majority of IL-17-producing cells were Th17 cells with memory phenotype. The addition of CsA into cell cultures significantly inhibited the IL-17 production by Th17 cells at protein and at mRNA levels. Compared to the PBMCs from normal individuals, PBMCs from the patients with RA produced higher levels of IL-17 that was also significantly inhibited by CsA both at protein and at mRNA levels. The mechanism might be the effect of CsA on the T cells activation because the expression of CD69 and CD25 molecules on T cells was markedly reduced in the presence of CsA. Taken together, these results demonstrated that CsA suppressed the IL-17 production and inhibited the Th17 cells differentiation from both healthy individuals and patients with RA.     

靶定IL-17 治疗类风湿关节炎研究进展

IL-17作为前炎症因子参与类风湿关节炎,系统性红斑狼疮等自身免疫性疾病的病理过程。它主要由CD4+T细胞的一个亚群--Th17细胞分泌释放。目前,IL-17在类风湿关节炎的病理过程中的作用引起了医学界广泛的关注,抗IL-17A抗体已经生产并进入临床实验,用于治疗类风湿关节炎、银屑病关节炎等疾病。但其在类风湿关节炎病理过程中的作用尚需进一步研究,其有效性亦尚需进一步探讨。本文主要针对IL-17家族的各个亚型的表达、调控、生物学作用及与类风湿关节炎发病的关系进行阐述,为类风湿关节炎的治疗提供新的思路。     

IL-17作为分子佐剂增强蛋白疫苗细胞免疫应答的研究

目的:为了进一步增强重组蛋白质疫苗的细胞免疫应答,利用重组的IL-17作为分子佐剂,与卵清蛋白(ovalbumin,OVA)一起免疫小鼠,研究IL-17作为分子佐剂对适应性免疫的影响,探索IL-17对蛋白疫苗诱导的免疫反应,特别是细胞免疫应答的影响.方法:用OVA作为特异性蛋白疫苗,与不同剂量的IL-17联合免疫C57...     

Inhibition of IL-17 prevents the progression of traumatic heterotopic ossification

Traumatic heterotopic ossification (HO) is the abnormal formation of bone in soft tissues as a consequence of injury. However, the pathological mechanisms leading to traumatic HO remain unknown. Here, we report that aberrant expression of IL-17 promotes traumatic HO formation by activating β-catenin signalling in mouse model. We found that elevated IL-17 and β-catenin levels are correlated with a high degree of HO formation in specimens from patients and HO animals. We also show that IL-17 initiates and promotes HO progression in mice. Local injection of an IL-17 neutralizing antibody attenuates ectopic bone formation in a traumatic mouse model. IL-17 enhances the osteoblastic differentiation of mesenchymal stem cells (MSCs) by activating β-catenin signalling. Moreover, inhibition of IL-17R or β-catenin signalling by neutralizing antibodies or drugs prevents the osteogenic differentiation of isolated MSCs and decreases HO formation in mouse models. Together, our study identifies a novel role for active IL-17 as the inducer and promoter of ectopic bone formation and suggests that IL-17 inhibition might be a potential therapeutic target in traumatic HO.     

川芎嗪对类风湿性关节炎患者外周血IL-17 和Foxp3 的影响

目的:探究川芎嗪对类风湿性关节炎患者外周血IL-17、Foxp3的影响。方法:选取我院风湿科收治的类风湿性关节炎住院患者共60例,随机分为对照组30例,给予甲氨喋吟片与乐松片治疗,实验组30例,在对照组的基础上给予盐酸川芎嗪注射液,连续14 d。治疗期间观察患者有无不良反应,注意饮食,忌烟酒。治疗结束后,RT-PCR检测外周血RORTt、Foxp3 m RNA的表达;免疫组化检测外周血IL-17、Foxp3水平。结果:与治疗前相比,治疗后两组患者的RORTt水平明显降低,Foxp3水平明显增高,RORTt/Foxp3比值明显减小,治疗后,与对照组相比,RORTt、RORTt/Foxp3比值较低,Foxp3水平较高(P0.05);与治疗前相比,治疗后两组患者的IL-17水平降低,Foxp3水平均升高(P0.05),与对照组相比,上述指标改善更为明显(P0.05)。结论:川芎嗪对类风湿性关节炎明显下调外周血RORTt水平,降低IL-17,升高Foxp3水平,提高患者免疫功能,从而减轻炎症反应,改善患者临床症状及不良预后,临床值得推广应用。     

Combination of sepsis biomarkers may indicate an invasive fungal infection in haematological patients

Background: Invasive fungal infections are a major threat to a large cohort of immunocompromised patients, including patients with chemotherapy-associated neutropenia. Early differential diagnosis with bacterial infections is often complicated, which leads to a delay in empirical antifungal therapy and increases risk for adverse outcome. Accessibility and performance of specific fungal antigen and PCR-tests are still limited, while sepsis biomarkers are more broadly used in most settings currently.

Methods: Haematological patients hospitalized to receive chemotherapy with proven or probable invasive fungal infection or microbiologically proven bacterial bloodstream infection were included in the study. C-reactive protein was assessed daily during the profound neutropenia period, while procalcitonin or presepsin were measured during the first 48?hours after the onset of febrile episode.

Results: There were totally 64 patients included in the study, 53 with bacterial bloodstream infections and 11 with invasive fungal infections. Combination of CRP >120 with PCT <1.25 or presepsin <170 was shown to be a possible combined biomarker for invasive fungal infections in immunocompromised patients, with areas under the ROC-curves: 0.962 (95% CI 0.868 to 0.995) for PCT-based combination and 0.907 (95% CI 0.692 to 0.990) for presepsin-based combination.     

5%环孢菌素霜对银屑病合并代谢综合征患者血清IL-17 及IL-18 水平的 影响

目的:探讨5%环孢菌素霜对银屑病合并代谢综合征患者外周血IL-17、IL-18水平及PASI评分的影响。方法:选择我院收治的寻常型银屑病合并代谢综合症患者68例,分为实验组和对照组。对照组予以复方甘草酸苷和卡泊三醇治疗,实验组在此基础上加用制备好的5%环孢菌素霜,观察并比较两组患者治疗前后外周血IL-17及IL-18水平的变化情况以及血压、空腹血糖、血脂及PASI评分结果。结果:与治疗前比较,两组患者治疗后IL-17及IL-18水平、血压、FPG、TG及PASI评分均显著降低,而HDL-C明显升高,差异均具有统计学意义(P0.05);与对照组比较,实验组治疗后IL-17及IL-18水平、血压、FPG、TG及PASI评分较低,而HDL-C较高,差异均具有统计学意义(P0.05)。结论:5%环孢菌素霜辅助治疗可调节银屑病合并代谢综合征患者外周血IL-17、IL-18水平,降低其PASI评分,改善患者机体代谢紊乱状态,对银屑病合并代谢综合症有显著临床疗效。     

寻常型银屑病患者血清IL-17、IL-18、VEGF的表达及与病情严重程度的相关性研究

目的:探讨寻常型银屑病患者血清白介素17(IL-17)、白介素18(IL-18)、血管内皮生长因子(VEGF)的表达及与病情严重程度的相关性。方法:选取2015年8月到2017年4月在我院接受治疗的寻常型银屑病患者86例为研究组,另选取同期在我院体检结果为健康的志愿者40例作为健康对照组,并根据临床症状和病情变化对研究组患者进行分组,其中进行期银屑病组32例,静止期银屑病组24例,退行期银屑病组30例。对比研究组和健康对照组血清中IL-17、IL-18、VEGF水平,对比不同严重程度的寻常型银屑病患者血清中IL-17、IL-18、VEGF水平和PASI评分,采用Spearman相关性分析IL-17、IL-18、VEGF的表达与PASI评分的相关性。结果:研究组患者血清中的IL-17、IL-18、VEGF水平显著高于健康对照组(P0.05),进行期银屑病组患者血清中IL-17、IL-18、VEGF水平和PASI评分显著高于静止期银屑病组和退行期银屑病组,静止期银屑病组患者血清中IL-17、IL-18、VEGF水平和PASI评分显著高于退行期银屑病组(P0.05),Spearman相关性分析结果显示,研究组患者血清中IL-17、IL-18、VEGF水平与PASI评分均呈正相关(P0.05)。结论:寻常型银屑病患者血清中IL-17、IL-18、VEGF水平异常升高,且其水平与病情严重程度有关,对上述三种指标进行监测有助于临床治疗寻常型银屑病。     

IL-17 与狼疮性肾炎关系的研究新进展

系统性红斑狼疮是一种涉及多系统损害的自身免疫性疾病,其主要并发症及死亡原因之一是狼疮性肾炎。研究表明,IL-17和产IL-17细胞可以浸润肾脏,与其他细胞因子协同作用,引起肾脏局部炎症反应。拮抗IL-17的生物制剂已应用于银屑病、强制性脊柱炎等免疫介导炎症性疾病,但在系统性红斑狼疮及狼疮性肾炎的研究尚少。本文对IL-17与狼疮性肾炎的关系进行综述,探讨IL-17及其抑制剂在狼疮性肾炎治疗的作用及发展前景。     

早产产妇血清和胎盘IL-17、IL-21及IL-22表达水平与新生儿感染发生的相关性研究

摘要 目的：分析早产产妇血清和胎盘IL-17、IL-21及IL-22表达水平与新生儿感染发生的相关性。方法：选择2020年7月至2021年12月在我院分娩的120例早产产妇作为观察组,另选同期的120例足月分娩产妇作为对照组。检测两组产妇血清和胎盘IL-17、IL-21及IL-22表达水平,根据观察组产妇分娩的新生儿是否发生感染,分为感染组和非感染组,比较两组母体血清和胎盘IL-17、IL-21及IL-22表达水平,使用多因素Logistic回归分析和受试者工作特征曲线(ROC)分析早产产妇血清和胎盘IL-17、IL-21及IL-22与新生儿感染的关系。结果：观察组血清和胎盘IL-17、IL-21及IL-22表达水平均高于对照组（P＜0.05）;感染组母体血清和胎盘IL-17、IL-21及IL-22表达水平均高于非感染组（P＜0.05）;经多因素Logistic回归分析,早产产妇血清和胎盘IL-17、IL-21及IL-22均是新生儿感染发生的独立预测因素（P＜0.05）;经Pearson相关性分析,早产产妇血清IL-17与胎盘IL-17 mRNA、血清IL-21与胎盘IL-21 mRNA、血清IL-22与胎盘IL-22 mRNA均呈正相关（P＜0.05）;经ROC曲线分析,早产产妇血清IL-17、IL-21联合IL-22预测新生儿感染发生的AUC为0.910。结论：早产产妇血清和胎盘IL-17、IL-21及IL-22表达水平升高均与新生儿感染发生密切相关,其中血清IL-17、IL-21联合IL-22预测新生儿感染的效能较高,值得进一步研究应用。     

Interleukin-17 (IL-17)-induced MicroRNA 873 (miR-873) Contributes to the Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting A20 Ubiquitin-editing Enzyme

Interleukin 17 (IL-17), produced mainly by T helper 17 (Th17) cells, is increasingly recognized as a key regulator in various autoimmune diseases, including human multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although several microRNAs (miRNAs) with aberrant expression have been shown to contribute to the pathogenesis of MS and EAE, the mechanisms underlying the regulation of abnormal miRNA expression in astrocytes upon IL-17 stimulation remain unclear. In the present study, we detected the changes of miRNA expression profiles both in the brain tissue of EAE mice and in cultured mouse primary astrocytes stimulated with IL-17 and identified miR-873 as one of the co-up-regulated miRNAs in vivo and in vitro. The overexpression of miR-873, demonstrated by targeting A20 (TNFα-induced protein 3, TNFAIP3), remarkably reduced the A20 level and promoted NF-κB activation in vivo and in vitro as well as increasing the production of inflammatory cytokines and chemokines (i.e. IL-6, TNF-α, MIP-2, and MCP-1/5). More importantly, silencing the endogenous miR-873 or A20 gene with lentiviral vector of miR-873 sponge (LV-miR-873 sponge) or short hairpin RNA (shRNA) of A20 (LV-A20 shRNA) in vivo significantly lessened or aggravated inflammation and demyelination in the central nervous system (CNS) of EAE mice, respectively. Taken together, these findings indicate that miR-873 induced by IL-17 stimulation promotes the production of inflammatory cytokines and aggravates the pathological process of EAE mice through the A20/NF-κB pathway, which provides a new insight into the mechanism of inflammatory damage in MS.     

B cell infiltration is associated with the increased IL-17 and IL-22 expression in the lungs of patients with tuberculosis

Although it has been recognized that ectopic follicle-like B cell aggregate formation is common in the lungs of patients with tuberculosis, the role of infiltrated B cells in human tuberculosis remains to be elucidated. In the present study, we showed that ectopic B cell aggregate formation was associated with containment of Mycobacterium tuberculosis. The area ratio of ectopic B cell aggregates was correlated with localized IL-17 mRNA expression and peripheral TGF-β and IL-6 mRNA expression. Depletion of B cells from pleural fluid mononuclear cells resulted in significantly diminished M. tuberculosis antigen-specific IL-17 and IL-22 production, but not in IFN-γ secretion. Therefore, ectopic lung B cell formation is important for containment of M. tuberculosis, and up-regulation of IL-17 and IL-22 responses may be an important mechanism underlying the protective role B cells in human tuberculosis.     

Age-dependent rates of infection of cassava green mites by a fungal pathogen in Brazil

Age-specific effects of invertebrate pathogens on their hosts can greatly influence the population dynamics in such interactions. Explanations for such differences are usually sought within differing intrinsic susceptibilities of the host life stages but we present data which indicate that host size, behaviour and life history may be the overriding factors determining age-specific effects of a fungal pathogen, Neozygites floridana (Entomophthorales: Neozygitaceae) on spider mites (Mononychellus tanajoa Bondar, Acari: Tetranychidae). Epizootics of N. floridana in spider mites are characterised by much greater relative mortality of adult females compared with other life stages (ca. 99%), despite similar physiological susceptibilities. We present empirical data that demonstrate encounter rates of mites with N. floridana increasing with life stage during an epizootic on cassava in northeastern Brazil. Estimates of the size, walking speeds and patterns, and life history of different life stages (and adult sexes) were used to calculate expected relative encounter rates which were found not to be different from the observed values (although not testable for larvae). This helps explain the different apparent susceptibility of host life stages in the field. Given the low ecological susceptibility of younger life stages to this pathogen, we predict that the interaction time between host and pathogen, determined by climatic conditions, will be critical in determining the degree of host population control in an epizootic. We further hypothesise that such variation in ecological susceptibility to pathogens can generate selection pressures on basic host traits, contributing to the sessile nature of many microarthropods. This revised version was published online in July 2006 with corrections to the Cover Date.