Role of IL-17 family cytokines in the progression of IPF from inflammation to fibrosis

Idiopathic pulmonary fibrosis(IPF)is a fatal chronic interstitial lung disease with no established treatment and is characterized by progressive scarring of the lung tissue and an irreversible decline in lung function.Chronic inflammation has been demonstrated to be the pathological basis of fibrosis.Emerging studies have revealed that most interleukin-17(IL-17)isoforms are essential for the mediation of acute and chronic inflammation via innate and adaptive immunity.Overexpression or aberrant expression of IL-17 cytokines contributes to various pathological outcomes,including the initiation and exacerbation of IPF.Here,we aim to provide an overview of IL-17 family members in the pathogenesis of IPF.

A Novel LNP-Based <i>Chlamydia</i>Subunit Vaccine Formulation That Induces Th1 Responses without Upregulating IL-17 Provides Equivalent Protection in Mice as Formulations That Induced IL-17 and Th1 Cytokines

We evaluated novel Chlamydial vaccines, consisting of major outer membrane protein (MOMP) alone or in combination with polymorphic membrane proteins D (PmpD) and G (PmpG) using a C57BL/6 mouse model. Native MOMP (nMOMP) isolated from C. muridarum elementary bodies (EBs) and recombinant PmpD and PmpG proteins were adjuvanted with Monophosphoryl lipid A (MPLA), with either lipid nanoparticles (LNPs) or the cationic lipid dimethyldioctadecylammonium bromide (DDA). Antibody titers to C. muridarum nMOMP, and EBs were evaluated by ELISA, and T-cell responses were analyzed by intracellular cytokine staining (ICS). Protection from challenge was determined by qPCR. Vaccine immunized mice showed significantly higher antibody titers to nMOMP (P < 0.001) and C. muridarum EBs (P < 0.001), when compared to the adjuvant alone group. Antibody titers in vaccine groups with Monophosphoryl lipid A (MPLA) + LNP were higher as compared to the MPLA + DDA group (P < 0.001) except for (Cm nMOMP + PmpG + PmpD p73 + PmpD p82 + MPLA + DDA) vs (Cm nMOMP + PmpG + PmpD p73 + PmpD p82 + MPLA + LNP) for both C. muridarum EBs and PmpG. ICS analysis showed more robust CD4 + T-cell responses (IFN-γ/IL-2/TNF-a) in the DDA and LNP groups compared to the adjuvant alone group. The DDA + MPLA gave robust Th17 responses in comparison to MPLA and LNP group. Mice immunized with Chlamydia antigens also showed protection from C. muridarum challenge, by reduction in bacterial shedding for all groups (P < 0.003) compared to shedding from the adjuvant control. Both vaccine formulations generated robust immunological responses, and both were protective by reducing bacterial shedding after challenge. This data indicates equal protection can be achieved without the induction of Th17 responses.

Cytokines Elicited by HSP60 in Periodontitis with and without Coronary Heart Disease

The human 60 kDa and microbial 65 kDa heat shock proteins (HSP) have been implicated in the pathogenesis of chronic periodontitis (CP) and coronary heart disease (CHD). We have studied 100 subjects: Group (a) consisted of patients with gingivitis (n = 25), group (b) were patients with CP (n = 25), group (c) patients with CHD and gingivitis (n = 25) and group (d) patients with CHD and CP (n = 25). PBMCs separated from peripheral blood were stimulated with medium, PMA/ionomycin, human HSP60, microbial HSP65, or no stimulus for 18 hours before intracellular IL-2, IFN-γ, TNF-α, IL-4, IL-5, or IL-17 were detected by flow cytometry. The mean fluorescence intensity (MFLI) for intracellular TNF-α was significantly increased when PBMC were stimulated with human HSP60 amongst the four groups (p = 0.001, ANOVA);pairwise comparisons revealed significant differences in MFLI between the gingivitis group and the CP (p = 0.017);between gingivitis and ging/CHD (p = 0.001) as well;but no significant difference between the CP and CP/CHD (p = 0.442). There was no significant difference in intracellular expression of IL-17, or any of the other cytokines tested;and the MFLI for HSP-stimulated were comparable to unstimulated cultures. When heat-labile human HSP60 was heated, intracellular cellular TNF-α expression was abrogated. In contrast, heat-stable LPS elicited TNF-α expression from monocytes in bulk cultures in all groups. These results suggest that the cytokine expression was dependent on human HSP60 and not LPS. Serum CRP was significantly associated with MFLI of intracellular TNF-α in CP patients (rs = 0.665, p = 0.026) and CP/CHD (rs = 0.699, p = 0.011). We conclude that human HSP60 elicits increased monocytic expression of TNF-α in patients with CP, CP/CHD or ging/CHD compared to patients with gingivitis. Since the marker of inflammation, namely CRP correlates with CP with or without CHD and not with mild chronic gingivitis or ging/CHD, this suggests that human HSP60-induced production of TNF-α is associated with CP and not CHD. There was no significant difference in intracellular expression of IL-17.

白细胞介素-17与肝癌家族聚集性的关系

目的探讨细胞因子白细胞介素(IL)-17的表达水平与广西肝癌家族聚集性的相关性。方法在广西肝癌高发现场配对选取112对肝癌高发家族和无癌家族成员,共224例,以高发家族成员为观察组,无癌家族成员为对照组,采用酶联免疫吸附(ELISA)法检测两组外周血清IL-17的水平。结果无论从总体水平还是分层(性别、年龄、名族、HBs Ag感染状况)比较,观察组IL-17表达水平均显著高于对照组,差异有统计学意义(P=0.000)。观察组中,不同亲缘系数的成员之间IL-17表达水平差异无统计学意义(Z=4.831,P=0.185)。肝癌高发家族中随着患肝癌例数增加,IL-17表达水平下降,差异无统计学意义(t=0.580,P=0.563)。结论肝癌高发家族成员IL-17表达水平升高与肝癌家族聚集现象存在相关性。

Uncoupling tumor necrosis factor-αand interleukin-10 at tumor immune microenvironment of breast cancer through miR-17-5p/MALAT-1/H19 circuit

Triple Negative Breast Cancer(TNBC)immunotherapy has recently shown promising approach.However,some TNBC patients presented with resistance.One of the reasons was attributed to the excessive release of cytokines at the tumor microenvironment(TME)such as Tumor necrosis factor alpha(TNF-α)and Interleukin-10(IL-10).Fine regulation of these cytokines’levels via non-coding RNAs(ncRNAs)might alleviate the immune quiescent nature of TME at TNBC tumors.However,the extrapolation of ncRNAs as therapeutic tools is highly challenging.Therefore,disentanglement the nature for the isolation of natural compounds that could modulate the ncRNAs and their respective targets is an applicable translational therapeutic approach.Hence,this study aimed to targeting the chief immune suppressive cytokines at the TME(TNF-αand IL-10)via ncRNAs and to examine the effects of Rosemary aerial parts extract on the expression levels of these ncRNAs in TNBC.Results revealed miR-17-5p as a dual regulator of TNF-αand IL-10.Moreover,an intricate interaction has been shown between miR-17-5p and the oncogenic lncRNAs:MALAT1 and H19.Knocking down of MALAT1 and/or H19 caused an induction in miR-17-5p and reduction in TNF-αand IL-10 expression levels.miR-17-5p was found to be down-regulated,while TNF-α,IL-10,MALAT1 and H19 were up-regulated in BC patients.Forced expression of miR-17-5p in MDA-MB-231 cells reduced TNF-α,IL-10,MALAT1 and H19 expression levels,as well as several BC hallmarks.In a translational approach,ursolic acid(UA)isolated from rosemary induced the expression of miR-17-5p,MALAT1 and decreased H19 expression levels.In conclusion,this study suggests miR-17-5p as a tumor suppressor and an immune-activator miRNA in BC through tuning up the immunological targets TNF-α,IL-10 at the TME and the oncological mediators MALAT1 and H19 lncRNAs.

Fhe roles and functional mechanisms of interleukin-17 amily cytokines in mucosal immunity

The mucosal immune system serves as our front-line defense against pathogens. It also tightly maintains immune tolerance to self-symbiotic bacteria, which are usually called commensals. Sensing both types of microorganisms is modulated by signalling primarily through various pattern-recognition receptors （PRRs） on barrier epithelial cells or immune cells. After sensing, proinflammatory molecules such as cytokines are released by these cells to mediate either defensive or tolerant responses. The interleukin-17 （IL-17） family members belong to a newly characterized cytokine subset that is critical for the maintenance of mucosal homeostasis. In this review, we will summarize recent progress on the diverse functions and signals of this family of cytokines at different mucosal edges.

Neutralization of interleukin-17A alleviates burn-induced intestinal barrier disruption via reducing pro-inflammatory cytokines in a mouse model

Background:The intestinal barrier integrity can be disrupted due to burn injury,which is responsible for local and systemic inflammatory responses.Anti-inflammation strategy is one of the proposed therapeutic approaches to control inflammatory cascade at an early stage.Interleukin-17A(IL-17A)plays a critical role in inflammatory diseases.However,the role of IL-17A in the progression of burn-induced intestinal inflammation is poorly understood.In this study,we aimed to investigate the effect of IL-17A and associated pro-inflammatory cytokines that were deeply involved in the pathogenesis of burn-induced intestinal inflammatory injury,and furthermore,we sought to determine the early source of IL-17A in the intestine.Methods:Mouse burn model was successfully established with infliction of 30%total body surface area scald burn.The histopathological manifestation,intestinal permeability,zonula occludens-1 expression,pro-inflammatory cytokines were determined with or without IL-17A-neutralization.Flow cytometry was used to detect the major source of IL-17A^(+)cells in the intestine.Results:Burn caused intestinal barrier damage,increase of intestinal permeability,alteration of zonula occludens-1 expressions,elevation of IL-17A,IL-6,IL-1βand tumor necrosis factor-α(TNF-α),whereas IL-17A neutralization dramatically alleviated burn-induced intestinal barrier disruption,maintained zonula occludens-1 expression,and noticeably,inhibited pro-inflammatory cytokines elevation.In addition,we observed that the proportion of intestinal IL-17A^(+)Vγ4^(+)T subtype cells(but not IL-17A^(+)Vγ1^(+)T subtype cells)were increased in burn group,and neutralization of IL-17A suppressed this increase.Conclusions:The main original findings of this study are intestinal mucosa barrier is disrupted after burn through affecting the expression of pro-inflammatory cytokines,and a protective role of IL-17A neutralization for intestinal mucosa barrier is determined.Furthermore,Vγ4^(+)T cells are identified as the major early producers of IL-17A that orchestrate an inflammatory response in the burn model.These data suggest that IL-17A blockage may provide a unique target for therapeutic intervention to treat intestinal insult after burn.

Three paralogous clusters of the miR-17-92 family of microRNAs restrain IL-12-mediated immune defense

MicroRNAs(miRNAs)have been widely implicated in immune regulation,but evidence for the coordinated function of paralogous miRNA clusters remains scarce.Here,by using genetically modified mice with individual or combined cluster deficiencies,we found that three paralogous clusters of the miR-17-92 family of miRNAs collectively suppressed IL-12 production in macrophages.Accordingly,miR-17-92 family miRNAs deficiencies resulted in heightened production of IL-12 and thus enhanced the host defense against intracellular pathogen Listeria monocytogenes in vivo.Mechanistically,different members of the miR-17-92 family of miRNAs acted on a common target,PTEN,to inhibit IL-12 expression by modulating the PI3K-Akt-GSK3 pathway.In addition,the expression of miR-17-92 family miRNAs was collectively inhibited by the transcription factor RBP-J,and RBP-J-associated macrophage functional defects were genetically rescued by deleting three clusters of miR-17-92 family miRNAs on a RBP-J null background.Thus,our results illustrated key roles of three clusters of miR-17-92 family miRNAs in cooperatively controlling IL-12-mediated immune responses and identified miR-17-92 family miRNAs as functional targets of RBP-J in macrophages.

IL-17家族与气道慢性炎症性疾病

气道慢性炎症性疾病如慢性阻塞性肺疾病、支气管哮喘等是在各种内外界刺激因素作用下由气道固有细胞、炎症细胞和炎症因子参与的非特异性炎症性疾病。目前，人们已经发现6个IL-17家族成员，它们在慢性气道炎症性疾病的发展中发挥重要作用。故深入认识IL-17家族与慢性气道炎症性疾病的关系将为临床治疗提供新的思路。

IL-17C 在全身的真菌的感染期间为致命的发炎被要求

Within the interleukin-17 （IL-17） family of cytokines, IL-17A is known to be critical in the host defense against fungal infections; however, the function of the other IL-17 family members in anti-fungal immunity remains largely unknown. Here, we show that IL-17C expression was highly induced in kidney epithelial cells after fungal infection. Mice that lacked IL-17C exhibited increased survival and attenuated kidney tissue damage, although they had similar fungal loads. IL-17C deficiency resulted in decreased pro-inflammatory cytokine expression compared with wild-type control mice. Additionally, IL-17C directly acted on renal epithelial cells in vitro to promote pro-inflammatory cytokine production. Taken together, our data demonstrate that IL-17C is a critical factor that potentiates inflammatory responses and causes host injury during fungal infection.

开发应用于Bio-Plex悬液芯片系统抗IL-17A的单克隆抗体

利用大肠杆菌(E.coli)表达的IL-17A单体蛋白免疫小鼠,通过杂交瘤技术获得针对IL-17A的单克隆抗体,用Bio-Plex悬浮芯片技术筛选出能通过双抗夹心法识别IL-17A的高亲和力单克隆抗体对,最终实现用Bio-Plex悬浮芯片技术定量检测样品中IL-17A含量的研究目标。

Chlamydia muridarum respiratory tract infection induces the proliferation of γδT cells and the secretion of IFN-γ and IL-17

Objective To investigate the proliferation,activation and cytokine production ofγδT cells during different periods of Chlamydia muridarum(Cm)respiratory tract infection.Methods C57BL/6 mice were inoculated intranasally with 3×103inclusion-forming units(IFU)of Cm strains to induce the murine model of

白介素17细胞因子家族与支气管哮喘

白介素17（IL-17）家族的提出,揭示了又一独特的受、配体信号系统.目前,IL-17A（IL-17）和IL-17F作为该家族的重要成员,其与哮喘的发生发展已经引起人们的关注,然而基于IL-17家族分子特性的支气管哮喘发生机制研究尚缺乏深度和系统性.本文就IL-17与IL-17F细胞因子的分子结构、受体、信号转导途径、功能及其与支气管哮喘关系的研究进展作一简要综述.