白介素-19、20和24与银屑病的关系

白介素-19、20和24是新近发现的3种细胞因子，生物功能尚不完全明了，结构上与白介素-10有很高的同源性。相应的受体和基因结构也明显关联，它们及其受体在结构上有同源性，功能上有联系，但又有各自的独特陛。初步研究显示，它们主要分布在银屑病皮损的表皮，在银屑病炎症中发挥重要作用。     

IL-12 and IL-23 affect photocarcinogenesis differently

Induction of DNA damage by UVR is the key event in photocarcinogenesis. IL-12 and IL-23 are related heterodimeric cytokines consisting of a common p40 unit and a p35/IL-12 and a p19/IL-23 chain, respectively. Both exert immunomodulatory activities but are also found to reduce UVR-induced DNA damage presumably via induction of DNA repair. As both cytokines are also produced in the skin, they may mitigate the risk to develop UVR-induced skin cancer. This appears to be the case as mice lacking p40 were previously shown to be at higher risk for skin tumors upon chronic UVR exposure. As these mice express neither IL-12 nor IL-23, the individual effects of IL-12 or IL-23 could not be evaluated. Thus, mice lacking p35 (IL-12p35-/-) or p19 (IL-23p19-/-) were subjected to chronic UVR exposure. The Kaplan-Meier analysis indicated a significantly increased probability of tumor development in IL-23p19-/- but not in IL-12p35-/- mice. Taken together, in our model, loss of IL-23, but not of IL-12, enhances development of UVR-induced skin tumors, indicating that IL-23 but not IL-12 may counteract photocarcinogenesis. This may have impact on the development of future strategies utilizing antibodies against IL-12 and IL-23, respectively, for the treatment of inflammatory dermatoses.     

产妇宫内感染对早产儿IL-1β、IL-6、IL-8、IL-10和TNF-α影响情况研究

目的:探讨产妇宫内感染对早产儿IL-1β、IL-6、IL-8、IL-10和TNF-α的影响。方法:回顾性分析2015年8月至2016年10月在我院接受分娩的宫内感染产妇的早产儿的临床资料,同时选取同期在我院分娩的非宫内感染产妇的早产儿作为对照。观察两组早产儿血清炎症因子水平、NIHSS评分、肾功能、心肌酶指标和出生时一般情况的差异。结果:宫内感染组早产儿的IL-1β、IL-6、IL-8、IL-10和TNF-α水平均高于对照组(t=7.044、12.208、7.289、20.185、5.421,P0.001);宫内感染组早产儿的Sp O2、Pa O2低于对照组(t=-6.353、-35.142,P0.001),Pa CO2水平高于对照组(t=35.720,P0.001);宫内感染组早产儿的NIHSS评分高于对照组(t=50.424,P0.001),出生1min和5min的Apgar评分低于对照组(t=-3.475、-4.398,P0.001);宫内感染组早产儿的尿素氮、肌酐和CK-MB水平均高于对照组(t=49.014、11.611、16.458,P0.001);Pearson相关分析法结果显示,宫内感染早产儿血清IL-1β、IL-6、IL-8、IL-10和TNF-α水平与NIHSS评分、肾功能、心肌酶指标水平正相关,与Apgar评分负相关。结论:宫内感染产妇分娩的早产儿的血IL-1β、IL-6、IL-8、IL-10和TNF-α水平较高,且与患儿的NIHSS评分、肾功能、心肌酶指标密切相关。     

IL-17和IL-23拮抗剂治疗银屑病的研究进展

目前美国食品药品监督局（FDA）批准用于临床的IL-17抗体拮抗剂包括secukinumab、ixekizumab和brodalumab,三者治疗中度至重度斑块状银屑病皮损清除均优于对照组TNF-α拮抗剂,且安全性及耐受性均较好。三种IL-23拮抗剂risankizumab,guselkumab和tildrakizumab目前均在III期临床试验中,初步临床试验结果表明三种药物治疗银屑病较对照组TNF-α拮抗剂具有更快达到皮疹改善、更高皮疹清除率和注射次数更少的优势。本文就上述六种生物制剂治疗银屑病的研究进展进行了综述。     

Role of fibroblasts in the regulation of proinflammatory interleukin IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1

Received: 15 May 1995     

Th17细胞相关因子与寻常性进行期银屑病的相关性研究

目的探讨Th17细胞相关因子白细胞介素(IL)-17A、IL-17F、IL-21、IL-22与寻常性进行期银屑病发病的相关性。方法通过实时定量反转录聚合酶链式反应(RT-PCR)分别检测30例患者和20名正常人外周血单个核细胞(PBMC)、12例患者皮损、12名正常皮肤组织中上述4种细胞因子的mRNA表达水平。结果患者组PBMC中IL-17A、IL-17F、IL-21和IL-22的mRNA表达水平较正常组显著升高(P均0.05),患者组皮损中4种细胞因子的mRNA表达明显高于正常组(P均0.05)。结论 Th17细胞因子IL-17A、IL-17F、IL-21和IL-22的mRNA水平在患者组PBMC及皮肤组织中明显升高,提示Th17细胞因子可能与寻常性银屑病的发病有一定相关性。     

IL-23-mediated epidermal hyperplasia is dependent on IL-6

Psoriasis is a chronic inflammatory skin disease primarily driven by Th17 cells. IL-23 facilitates the differentiation and induces complete maturation of Th17 cells. Lesional psoriatic skin has increased levels of IL-23 and recent studies show that intradermal injections of IL-23 induce a psoriasis-like skin phenotype in mice. We have now characterized the IL-23-induced skin inflammation in mice at the molecular level and found a significant correlation with the gene expression profile from lesional psoriatic skin. As observed in psoriasis, the pathogenesis of the IL-23-induced skin inflammation in mice is driven by Th17 cells. We demonstrate a dramatic upregulation of IL-6 mRNA and protein after intradermal injections of IL-23 in mice. Using IL-6(-/-) mice we show that IL-6 is essential for development of the IL-23-elicited responses. Despite producing high levels of IL-22, IL-6(-/-) mice were unable to express the high-affinity IL-22 receptor chain and produced minimal IL-17A in response to intradermal injections of IL-23. In conclusion, we provide evidence for the critical role played by IL-6 in IL-23-induced skin inflammation and show that IL-6 is required for expression of IL-22R1A.     

Type I IL-1 receptor mediates IL-1 and intracellular IL-1 receptor antagonist effects in skin inflammation

The IL-1 system plays a key role in skin physiology and pathology. In this study, we used mutant mice lacking the type I IL-1 receptor (IL-1RI), lacking IL-1 receptor antagonist (IL-1Ra), or overexpressing the human intracellular (ic) IL-1Ra1 isoform, as well as combinations thereof, to dissect the role of the IL-1 system in phorbol 13-myristate 12-acetate (PMA)-induced skin inflammation. In wild-type (WT) mice, PMA application induced epidermal thickening and dermal inflammation. Skin IL-1alpha production and circulating levels of the acute-phase protein serum amyloid A (SAA) were elevated. In mice lacking IL-1RI or overexpressing icIL-1Ra1, PMA induced similar epidermal thickening as in WT mice, but dermal inflammation was partially prevented. Skin IL-1alpha mRNA expression was similar in PMA-treated IL-1RI-/- and WT mice, whereas the increase in serum SAA was suppressed in IL-1RI-/- mice. Interestingly, PMA-induced IL-1alpha mRNA expression was further enhanced by icIL-1Ra1 overexpression in an IL-1RI-dependent manner. Finally, IL-1Ra-/- mice spontaneously displayed skin lesions characterized by high IL-1beta, but not IL-1alpha, expression. In conclusion, PMA-induced epidermal thickening and skin IL-1alpha expression were independent of IL-1 signaling, in contrast to dermal inflammation and systemic inflammatory response.     

Histamine-induced IL-6 and IL-8 production are differentially modulated by IFN-gamma and IL-4 in human keratinocytes

It is known that large amounts of histamine are stored in mast cells located in the superficial dermis of the skin and can be released upon appropriate stimulation. However, the effects of histamine on keratinocyte function have not been well characterized. We therefore examined the capacity of histamine to modulate the production of interleukin (IL)-6 and IL-8 by keratinocytes. We found that histamine significantly augmented the production of IL-6 and IL-8 in a dose- and time-dependent manner. The enhancing effects of histamine were completely inhibited by a potent H1 receptor (H1R) antagonist, emedastine difumarate. Pyrilamine (a much weaker H1R antagonist) and cimetidine (an H2R antagonist) only partially inhibited the enhancing effects of histamine. The histamine-induced up-regulation of IL-6 and IL-8 production, however, was completely abrogated by a combination of pyrilamine and cimetidine. The IL-6 production was significantly enhanced by interferon (IFN)-gamma. Interestingly, IFN-gamma and IL-4 both significantly augmented the histamine-induced IL-6 production. On the other hand, the production of IL-8 was inhibited by IFN-gamma, and IFN-gamma and IL-4 both completely abrogated the histamine-induced IL-8 production. These results suggest that the histamine-induced IL-6 production and IL-8 production are differentially regulated by IFN-gamma and IL-4. Histamine may be an important modulator of cytokine production in epidermal milieu.     

Role of IL-17 and IL-22 in autoimmunity and cancer

The dysregulation of inflammatory cytokines can cause a variety of diseases, such as autoimmunity and cancer. Since their identification in 2005, Th17 cells and its signature cytokine IL-17, have been implicated in the pathogenesis of autoimmune diseases such as psoriasis and rheumatoid arthritis (RA), and inflammatory associated cancers such as colorectal carcinoma (CRC). Recently, IL-22 a Th17 related cytokine has been shown to be pathogenic in psoriasis and RA. In this review, we will summarize the biological functions of IL-17 and IL-22, their role in autoimmune diseases and briefly review results from clinical trials targeting IL-17 or its receptor for the treatment of autoimmune diseases. Next, we will discuss pre-clinical and clinical data supporting the rationale of targeting other cytokines implicated in the Th17/IL-17 pathway, such as IL-22 and IL-23. Finally, we discuss the role of IL-17, and in particularly IL-22 in tumour immunity and possible therapeutic interventions.     

IL-6 and IL-10 promoter gene polymorphisms in psoriasis vulgaris

Overexpression of IL-6 has been implicated in the pathology of numerous autoimmune and chronic inflammatory diseases, including psoriasis, and relative deficiency of IL-10 in psoriatic patients seems to be important in the development of this disease. The aim of this study was to investigate the association between IL-6 and IL-10 single nucleotide polymorphisms and susceptibility to psoriasis vulgaris. DNA from 78 patients with psoriasis vulgaris and 74 healthy volunteers was investigated. IL-6 promoter gene single nucleotide polymorphisms in position -174, and IL-10 single nucleotide polymorphisms in positions -1082, -819 and -592 were evaluated by polymerase chain reaction using sequence-specific primers. No significant differences were found in the polymorphisms of IL-6 and IL-10 promoter genes between patients with psoriasis and healthy controls.     

IL-27 acts as a priming signal for IL-23 but not IL-12 production on human antigen-presenting cells

IL-27 belongs to the IL-12 family of cytokines and has been described not only to support T-cell polarization along the Th1 lineage, but also to induce important anti-inflammatory responses in later phases of inflammation. We and others have previously shown that the cytokine IL-27 has an important impact on the chronic manifestation of inflammatory skin diseases. Thus, the aim of this study was to specify the effects of IL-27 on the human antigen-presenting cell (APC) subtype inflammatory dendritic epidermal cells (IDEC), which are known to play an important role in eczema. IDEC and blood-derived human macrophages were generated from human peripheral blood and stimulated with IL-27. Functional responses of the cells were analysed by intracellular cytokine staining, ELISA and FlowCytomix. IL-27 was found to be the only IL-12 family member that acts on human APC as a priming signal for IL-23 but not IL-12 production. We confirmed for macrophages that IL-27 limits lipopolysaccharide-induced IL-10 production and detected the same tendency for IDEC. Furthermore, we showed that this also applies to CD40L-induced IL-10 expression in both investigated human APC subsets. We demonstrate that IL-27 exerts pro-inflammatory effects on human APC in particular in the context of a range of bacterial-derived TLR ligands. Hence, our study builds upon the idea that IL-27 exerts a pro-inflammatory effect on innate immune and tissue-resident cells and may drive eczematous reaction - in particular in the context of bacterial superinfection - towards a chronic phase.     

除湿通淋颗粒治疗慢性非细菌性前列腺炎临床疗效及对IL-2、IL-6、IL-8影响观察

目的:观察除湿通淋颗粒治疗慢性前列腺炎的临床疗效以及对按摩前列腺后精确控制的前段尿液(VB3)中IL-2、IL-6、IL-8的影响。方法:将97例慢性非细菌性前列腺炎患者随机分为治疗组48例和对照组49例,治疗组给予除湿通淋颗粒(免煎颗粒),每日2次,每次1袋,开水冲服;对照组给予癃清片,每日3次,每次3g;治疗4周后对比观察两组临床疗效以及采用双抗体夹心ELISA法定量分析VB3内的IL-2、IL-6、IL-8的水平变化,并且与对照组比较。结果:治疗组NIH评分总有效率为85.71%,对照组为69.05%,差异有统计学意义(P0.05);治疗组中医证候积分总有效率为92.86%,对照组为71.43%,差异有统计学意义(P0.05);两组治疗后IL-2较治疗前升高,差异有统计学意义(P0.05),治疗组与对照组相比,差异无统计学意义(P0.05);IL-6、IL-8较治疗前降低,差异有统计学意义(P0.05),治疗组与对照组相比有统计学意义(P0.05)。结论:除湿通淋颗粒治疗慢性非细菌性前列腺炎临床疗效显著,可能通过提高前列腺液中IL-2的水平或者降低IL-6、IL-8的水平而发挥作用。     

Detection of elevated levels of IL-4, IL-6, and IL-10 in blister fluid of bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease with autoantibodies directed against antigens associated with hemidesmosomes of basal keratinocytes. In addition to autoantibodies and activated complement, cellular mechanisms are crucial for blister formation in this disease. Mononuclear cells, which are the first cells infiltrating BP lesions, mainly belong to CD3, CD4⁺ T-helper (Th) cells. Elevated concentrations of IL-2, IFNγ, TNFβ, and IL-5 have been recently demonstrated in BP blister fluid. In this study, we were interested in levels of other Thtype cytokines, including IL-3, IL-4, IL-6, IL-10, and GM-CSF in blister fluid of BP. Cytokines were determined by ELISA or bioassay. Levels in the blister fluid from ten BP patients were compared with those in serum samples taken at the time of blister puncture and with those in suction blister fluid of ten healthy volunteers. In blister fluid of BP, we found significantly elevated concentrations of IL-4, IL-6, and IL-10 relative to both concurrent serum samples and suction blister fluid from controls. No differences were detected for either IL-3 or GM-CSF. Our results suggest that IL-4, IL-6, and IL-10 are released at the site of blister formation in BP.     

白介素-1和银屑病

银屑病的发病机制至今尚未完全明确，银屑病皮损中存在细胞因子的异常表达，IL—1是重要的炎症递质，在银屑病皮损中IL—1表达异常。研究表明，IL—1在银屑病发病中起重要作用。     

IL-17 and infections

IL-17 immunity has been shown to be essential for mucocutaneous protection against Candida albicans in mice and humans. However, mice with defective IL-17 immunity display broader susceptibility, as they are also prone to infections with diverse infectious agents at various sites. Humans with genetic defects affecting their IL-17 immunity usually suffer from chronic mucocutaneous candidiasis (CMC): recurrent or persistent infections of the skin, nails, and mucosae with C. albicans, with or without other clinical signs. Most patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) due to STAT3 deficiency or AD STAT1 gain-of-function display impaired IL-17-producing T-cell development, and CMC is one of their principal clinical manifestations. Similarly, patients with autosomal recessive (AR) autoimmune polyendocrine syndrome type 1 (APS-1) caused by AIRE deficiency have high levels of neutralizing autoantibodies against IL-17A, IL-17F and/or IL-22 and present CMC as their only infectious disease. Finally, CMC is the main clinical phenotype observed in patients with inborn errors specifically affecting IL-17 immunity. Indeed, patients with AD IL-17F deficiency or AR IL-17RA or ACT1 deficiency display CMC and, to a lesser extent, superficial staphylococcal diseases. Candida infection was recently reported in psoriasis patients treated with anti-IL-17A antibodies. Careful monitoring for CMC is thus important during anti-IL-17 treatment.     

白鲜皮提取液对湿疹模型小鼠血清IL-10、IL-17和IL-22含量的影响

目的:研究白鲜皮对湿疹模型小鼠血清IL-10、IL-17和IL-22的作用效果和机制。方法:将60只BALB/C小鼠随机分为6组,每组10只,除空白组外,其余5组均给予2,4-二硝基氯苯诱导和激发造成小鼠湿疹模型。造模成功后分别给予0.025%地塞米松洗剂和不同浓度(0、1%、3%、5%)白鲜皮提取液进行干预处理,测量激发前后耳中部厚度差、左右耳重量差及测定血清IL-10、IL-17和IL-22值变化,进行干预后评估。结果:不同浓度白鲜皮提取液均可明显降低小鼠的耳厚度和重量差,同时升高小鼠血清IL-10含量,但仅中高浓度组可显著降低IL-17和IL-22含量,差异有统计学意义(P0.05)。此外,高浓度白鲜皮提取液组与0.025%地塞米松洗剂组在小鼠的耳厚度差和重量差及IL-10、IL-17和IL-22含量上均无明显差异(P0.05);中低浓度白鲜皮提取液组在耳厚度差和重量差及IL-17和IL-22含量值明显高于0.025%地塞米松洗剂组,血清IL-10含量明显低于0.025%地塞米松洗剂组,差异均有统计学意义(P0.05)。结论:不同浓度白鲜皮提取液均可改善湿疹模型小鼠的皮肤损害,而高浓度的白鲜皮提取液与0.025%地塞米松洗剂效果相当;其机制可能与下调炎症因子IL-17和IL-22、上调IL-10的表达相关。