IL-36 在炎性疾病中的研究进展

白介素36(IL-36)是IL-1 家族成员,由3 个生物学功能相似的分子IL-36α、IL-36β和IL-36酌组成。IL-36 在体内需通过与特异性受体IL-36R 结合而发挥促炎症作用,而IL-36Ra 是其受体拮抗剂。IL-36 在体内犹如一个辅助者,参与树突状细胞与T 细胞的激活、成熟、极化、抗原提呈和刺激促炎因子产生等功能。它作为一种新发现的促炎因子,在银屑病、炎性肠病、关节炎、系统性红斑狼疮、肺部疾病等多种炎性疾病中发挥着重要作用。     

Emerging role of IL-35 in inflammatory autoimmune diseases

Interleukin 35 (IL-35) is the recently identified member of the IL-12 family of cytokines and provides the possibility to be a target for new therapies for autoimmune, inflammatory diseases. It is composed of an α chain (p35) and a β chain (EBI3). IL-35 mediates signaling by binding to its receptors, activates subsequent signaling pathways, and therefore, regulates the differentiation, function of T, B cells, macrophages, dendritic cells. Recent findings have shown abnormal expression of IL-35 in inflammatory autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes, psoriasis, multiple sclerosis, autoimmune hepatitis, experimental autoimmune uveitis. In addition, functional analysis suggested that IL-35 is critical in the onset and development of these diseases. Therefore, the present study will systematically review what had been occurred regarding IL-35 in inflammatory autoimmune disease. The information collected will help to understand the biologic role of IL-35 in immune cells, and give information about the therapeutic potential of IL-35 in these diseases.     

IL-22——炎症性疾病关键因子

白细胞介素-22(IL-22)是IL-10细胞因子家族的成员,它参与抗微生物防御,保护和修复组织损伤以及急性期反应。它的信号机制涉及到IL-22与白介素-22受体1(IL-22R1)的结合,以及这个二元复合物和白介素-10受体2(IL-10R2)的胞外域的结合。IL-22不仅可以由辅助T淋巴细胞17(Th17细胞)分泌,而且也可以由Th22,自然杀伤细胞22(NK22)等细胞产生。IL-22的高表达出现在银屑病、异位性皮炎以及溃疡性结肠炎等患者中;而在急性呼吸窘迫综合症和系统性红斑狼疮患者的血清中,IL-22的表达水平下降;这说明了IL-22的表达量与这些疾病的发病情况有着紧密的联系。目前的研究表明IL-22靶向于消化道、皮肤与呼吸器官的非造血细胞,在黏膜固有免疫中起重要作用。本文主要对IL-22的结构、功能、信号通路以及在各种炎症性疾病和自身免疫病中起的作用展开介绍。     

IL-17 signaling in host defense and inflammatory diseases

Interleukin (IL)-17, the signature cytokine secreted by T helper (Th) 17 cells, plays important roles in host defense against extracellular bacterial infection and fungal infection and contributes to the pathogenesis of various autoimmune inflammatory diseases. Here we review the recent advances in IL-17-mediated functions with emphasis on the studies of IL-17-mediated signal transduction, providing perspective on potential drug targets for the treatment of autoimmune inflammatory diseases.     

Inhibition of IL-1, IL-6, and TNF-alpha in immune-mediated inflammatory diseases

Blockade of cytokines, particularly of tumour necrosis factor alpha (TNF-α), in immuno-inflammatory diseases, has led to the greatest advances in medicine of recent years. We did a thorough review of the literature with a focus on inflammation models in rodents on modified gene expression or bioactivity for IL-1, IL-6, and TNF-α, and we summarized the results of randomized controlled clinical trials in human disease. What we have learned herewith is that important information can be achieved by the use of animal models in complex, immune-mediated diseases. However, a clear ranking for putative therapeutic targets appears difficult to obtain from an experimental approach alone. This is primarily due to the fact that none of the disease models has proven to cover more than one crucial pathogenetic aspect of the complex cascade of events leading to characteristic clinical disease signs and symptoms. This supports the notion that the addressed human immune-mediated diseases are polygenic and the summation of genetic, perhaps epigenetic, and environmental factors. Nevertheless, it has become apparent, so far, that TNF-α is of crucial importance in the development of antigen-dependent and antigen-independent models of inflammation, and that these results correlate well with clinical success. With some delay, clinical trials in conditions having some relationship with rheumatoid arthritis (RA) indicate new opportunities for blocking IL-1 or IL-6 therapeutically. It appears, therefore, that a translational approach with critical, mutual reflection of simultaneously performed experiments and clinical trials is important for rapid identification of new targets and development of novel treatment options in complex, immune-mediated, inflammatory diseases.     

IL-17 in inflammatory skin diseases psoriasis and hidradenitis suppurativa

The skin is one of the most important organs in the body, providing integrity and acting as a barrier to exclude microbes, allergens and chemicals. However, chronic skin inflammation can result when barrier function is defective and immune responses are dysregulated or misdirected against harmless or self-antigens. During the last 15 years interleukin (IL)-17 cytokines have emerged as key players in multiple inflammatory disorders, and they appear to be especially prominent in skin inflammation. IL-17 cytokines produced by T cells and other cell types potently activate keratinocytes to promote inflammation in a feed-forward loop. Given this key pathogenic role of the IL-17 pathway in autoimmune and inflammatory disease, it has been the focus of intense efforts to target therapeutically. The inflammatory effects of IL-17 can be targeted directly by blocking the cytokine or its receptor, or indirectly by blocking cytokines upstream of IL-17-producing cells. Psoriasis has been the major success story for anti-IL-17 drugs, where they have proven more effective than in other indications. Hidradenitis suppurativa (HS) is another inflammatory skin disease which, despite carrying a higher burden than psoriasis, is poorly recognized and under-diagnosed, and current treatment options are inadequate. Recently, a key role for the IL-17 pathway in the pathogenesis of HS has emerged, prompting clinical trials with a variety of IL-17 inhibitors. In this review, we discuss the roles of IL-17A, IL-17F and IL-17C in psoriasis and HS and the strategies taken to target the IL-17 pathway therapeutically.     

Inhibition of IL-1, IL-6, and TNF-α in immune-mediated inflammatory diseases

Blockade of cytokines, particularly of tumour necrosis factor alpha (TNF-α), in immuno-inflammatory diseases, has led to the greatest advances in medicine of recent years. We did a thorough review of the literature with a focus on inflammation models in rodents on modified gene expression or bioactivity for IL-1, IL-6, and TNF-α, and we summarized the results of randomized controlled clinical trials in human disease. What we have learned herewith is that important information can be achieved by the use of animal models in complex, immune-mediated diseases. However, a clear ranking for putative therapeutic targets appears difficult to obtain from an experimental approach alone. This is primarily due to the fact that none of the disease models has proven to cover more than one crucial pathogenetic aspect of the complex cascade of events leading to characteristic clinical disease signs and symptoms. This supports the notion that the addressed human immune-mediated diseases are polygenic and the summation of genetic, perhaps epigenetic, and environmental factors. Nevertheless, it has become apparent, so far, that TNF-α is of crucial importance in the development of antigen-dependent and antigen-independent models of inflammation, and that these results correlate well with clinical success. With some delay, clinical trials in conditions having some relationship with rheumatoid arthritis (RA) indicate new opportunities for blocking IL-1 or IL-6 therapeutically. It appears, therefore, that a translational approach with critical, mutual reflection of simultaneously performed experiments and clinical trials is important for rapid identification of new targets and development of novel treatment options in complex, immune-mediated, inflammatory diseases.     

转录因子激活蛋白-1与慢性支气管肺炎性疾病

转录因子激活蛋白-1是由亮氨酸拉链类蛋白构成的同源/异源二聚体,是诸多信号转导途径在细胞核内的交汇点,在慢性阻塞性肺疾病、支气管哮喘和肺间质纤维化等慢性炎症性疾病的发生、发展过程中有重要作用。其作用机制包括调控转录、磷酸化及蛋白质的相互作用,涉及炎性细胞因子、黏附分子、谷胱甘肽、蛋白酶等的表达调控及炎性细胞的活化,还参与哮喘对糖皮质激素抵抗的发生。     

Expression of IL-27 in human Th1-associated granulomatous diseases

Interleukin (IL)‐27 is a newly described member of the IL‐12 family. It is a heterodimeric cytokine composed of two subunits, p28 and Epstein–Barr virus‐induced gene 3 (EBI3). In vitro studies have shown that IL‐27 is mainly produced by activated monocytes and dendritic cells. It induces the proliferation of naïve CD4‐positive T cells and synergizes with IL‐12 for interferon‐γ (IFN‐γ) production. Knock‐out mice for the IL‐27 receptor (WSX‐1/TCCR) have impaired Th1 responses and form abnormal granulomas when injected with bacillus Calmette‐Guérin. However, the expression profile of IL‐27 in vivo is currently unknown. To investigate the potential role of IL‐27 in the development of a Th1 response in humans in vivo, this study has analysed the in situ expression of IL‐27 subunits in three types of granulomatous disease (tuberculosis, sarcoidosis, and Crohn's disease), each characterized by a Th1 response. Tissue sections from patients with tuberculosis (n = 9), sarcoidosis (n = 8), or Crohn's disease (n = 7) were analysed by immunohistochemistry with anti‐EBI3 and anti‐p28 antibodies, in parallel with control tissues (control reactive lymph nodes, n = 14, and control intestinal tissues, n = 11). In granulomatous tissues, EBI3 and p28 co‐expression was detected in epithelioid and multinucleate giant cells in granulomas. In addition, sinus or tissue macrophages, endothelial cells, and plasma cells were found to co‐express EBI3 and p28. These data support a possible role for IL‐27 in human Th1 responses. Copyright © 2004 John Wiley & Sons, Ltd.     

IL-37 抑制IL-18 在大鼠肺纤维化模型中的表达及意义的探讨

目的:初步研究博来霉素致肺纤维化大鼠肺组织中IL-37、IL-18 的表达水平,探讨其在PF 发生、发展中的表达及意义。方法:将45 只清洁级Wistar 大鼠按随机数字表法分为健康对照组(N 组)、博来霉素组(B 组)、地塞米松治疗组(D组),每组大鼠各15 只,B 组及D 组大鼠给予气管内注射博来霉素4 mg/ kg 制作肺纤维化模型,N 组给予相同体积生理盐水作为对照,D 组大鼠于肺纤维化造模基础上第2 天每日腹腔注射地塞米3 mg/ kg,N、B 组大鼠腹腔注射生理盐水作为对照。各组大鼠分别于造模后第7、14、28 天处死,HE 染色评价肺组织病理形态学变化,碱水解法及酶联免疫吸附法分别测定肺组织匀浆中羟脯氨酸(HYP)、IL-37 含量,RT-PCR 法测定肺组织中IL-18mRNA 表达量。结果: HE 染色显示B、D 组大鼠肺组织病理学改变由肺泡炎症逐渐发展为纤维化,B、D 组HYP 含量随时间推移逐渐升高,以第28 天为著(P<0.05);于B、D 组IL-37、IL-18mRNA 表达于第7 天升高至最高点,后逐渐降低,至第28 天均高于N 组,差异有统计学意义(P<0.05); D 组IL-37、IL-18mRNA 表达在同一时间均低于B 组(P<0.05)。结论:IL-37、IL-18 在大鼠肺纤维化发病早期起重要作用,可能参与了肺纤维化发生与发展。     

Th17细胞及白细胞介素17A在慢性气道炎症性疾病中的作用

长期以来,人们对于T淋巴细胞的研究集中在辅助性T细胞1型、2型(Th1、Th2)、调节性T细胞(Treg)以及细胞毒性T细胞(Tc)等亚群上。传统理论认为,Th1细胞介导细胞免疫,在抗胞内菌感染的过程中发挥作用;而Th2细胞介导体液免疫,与过敏性疾病以及抗寄生虫感染的过程紧密相关。Th1/Th2失衡被认为是许多疾病产生和发展的重要因素。     

白细胞介素1β和白细胞介素17在根尖周病组织肥大细胞上的表达

 目的：观察不同类型慢性根尖周病组织中肥大细胞（mast cells, MCs）的分布情况,并分析白细胞介素1β（interleukin-1β,IL-1β）和白细胞介素17（interleukin-17,IL-17）在MCs上的表达情况,探讨MCs IL-1β和IL-17在根尖周病发病机制中的作用。方法：本实验共收集102例样本,分为3组：（1）根尖肉芽肿组32例;（2）根尖囊肿组35例;（3）正常对照组35例。组织标本经4%中性甲醛缓冲液固定48 h以上;石蜡包埋,组织连续切片,HE染色,在光学显微镜下观察其组织学改变;采用免疫荧光双染色法,在荧光显微镜下观察各组标本组织表达IL-1β和IL-17的MCs数目。结果：两组慢性根尖周病的炎症反应程度明显高于正常对照组（P<0.01）;根尖囊肿组与根尖肉芽肿组之间炎症反应程度无显著差异（P>0.05）。与正常对照组相比,两组慢性根尖周病组织中IL-1β和IL-17阳性MCs数目均显著增多（P<0.01）;根尖囊肿组与根尖肉芽肿组IL-1β和IL-17阳性MCs密度无显著性差异（P>0.05）。经Pearson相关分析,3组标本组织中IL-1β和IL-17阳性MCs密度与组织炎症反应程度存在直线的正相关关系（P<0.01）。结论：慢性根尖周病组织中MCs数目明显增多,同时IL-1β和IL-17阳性的MCs密度显著增高。IL-1β和IL-17阳性MCs密度与根尖周病的炎症程度趋势相一致。这提示IL-1β和IL-17阳性MCs可能在慢性根尖周病的致病机制中发挥重要作用。     

Expression and functions of very late antigen 1 in inflammatory joint diseases

In the human immune system, very late antigen 1 (VLA-1), a putative collagen receptor, is expressed on the surface of T lymphocytes that have undergone mitogenic or antigenic stimulation. A new VLA-1-specific monoclonal antibody, 1B3.1, was used to probe the expression and function of VLA-1 on T lymphocytes in patients with arthritis. Synovial mononuclear cells from the joints of patients with rheumatoid arthritis or other joint diseases contained 32.9±13.8% 1B3.1-positive cells (42.8±10.4% in patients with rheumatoid arthritis and 28 ± 12.6% in non rheumatoid patients). In the peripheral blood, patients with active rheumatoid arthritis expressed VLA-1 on 11.7±6.0% of their mononuclear cells, compared to 1.9±1.5% in controls (P<0.001). Using dual fluorescence analysis, virtually all the 1B3.1-positive synovial cells were CD3+ T lymphocytes and included both CD4+ and CD8+ T cells. When 1B3.1-expressing synovial mononuclear cells orin vitro activated T lymphocytes were triggered with anti-CD3 antibodies, marked augmentation of their proliferation occurred if they were simultaneously cross-linked with mab 1B3.1. Collagen type IV, a putative ligand of VLA-1, also augmented T-cell proliferation to anti-CD3. The data suggest that the VLA-1 molecule could play an important role in the pathophysiology of arthritis by modulating T-cell activation in these diseases.     

Expression of lysosome-associated membrane proteins in human colorectal neoplasms and inflammatory diseases

The lysosome-associated membrane proteins (LAMPs)-1 and -2 are major constituents of the lysosomal membrane. These molecules are known to be among the most glycosylated proteins of several types of cells and cancer cells, and their expression in cancer cells is marked by a distinct difference in the structures of the oligosaccharides as compared to nonmalignant cells. We analyzed by immunohistochemistry the intensity and distribution of LAMP-1 and LAMP-2 in 9 human colorectal cancer cases and in 16 control cases, including inflammatory diseases (diverticulitis, ulcerative colitis, and Crohn's disease). LAMP proteins were expressed more intensely in the epithelium of colorectal neoplasms than in normal mucosa (P < 0.05), and no significant differences were found between adenoma and cancer cells (P > 0.05) in the same tissue section. Further, in sites of inactive inflammatory diseases and nonneoplastic areas in cancer specimens, no significant increases in epithelial LAMP proteins were observed, even in the proliferative zone of the lower crypt epithelium. Northern blot analysis showed increased expression of LAMP-1 and LAMP-2A in two of three colorectal cancers examined and increased LAMP-2B in all three cancers. Our findings suggest that LAMPs are related to neoplastic progression, but there is no direct association between the expression of LAMP molecules and cell proliferation.     

Cytogenetic variants of dysregenerative and precancerous epithelial changes in chronic inflammatory pulmonary diseases

Surgical material of the lungs and their parts from 31 patients and open biopsies were studied. Proliferative activity (Ki-67, PCNA) and oncomarkers expression (bcl-2, p-53, c-myc, b-TGF, chromogranin-A) were studied immunohistochemically in the foci of various epithelial changes. It is established that a wide spectrum of alterations in pulmonary tissue is associated with variability of precursor cells and may have nosological features.     

The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases

Chemokines are small proteins that control several tissue functions, including cell recruitment and activation under homeostatic and inflammatory conditions. CXCL8 (interleukin-8) is a member of the chemokine family that acts on CXCR1 and CXCR2 receptors. CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, and CXCL7 are also ELR+ chemokine members that bind to these receptors, especially CXCR2. The majority of studies on the biology of CXCL8 and their receptors have been performed in polymorphonuclear leukocytes. However, many other cells express CXCR1/CXCR2, including epithelial, endothelial, fibroblasts and neurons, contributing to the biological effects of CXCL8. There is substantial amount of experimental data suggesting that CXCL8 and receptors contribute to elimination of pathogens, but may also contribute significantly to disease-associated processes, including tissue injury, fibrosis, angiogenesis and tumorigenesis. Here, we discuss the biology of CXCL8 family and the potential therapeutic use of antagonists or blockers of these molecules in the context of organ-specific diseases.     

Characterization of interleukin-15 (IL-15) and the IL-15 receptor complex

IL-15 interacts with a heterotrimeric receptor that consists of the and subunits of the IL-2 receptor (IL-2R) as well as a specific, high-affinity IL-15-binding subunit, which is designated IL-15R. Since both the and the subunits of the IL-2R are required for signaling by either IL-2 or IL-15, it is not surprising that these cytokines share many activitiesin vitro. However, the differential expression of these cytokines and the chains of their receptors within various tissues and cell types suggests that IL-2 and IL-15 may perform at least partially distinct physiological functions. The production of IL-15 by macrophages, and possibly other cell types, in response to environmental stimuli and infectious agents suggests that IL-15 may play a role in protective immune responses, allograft rejection, and the pathogenesis of autoimmune diseases.     

Not-so-sweet sixteen: the role of IL-16 in infectious and immune-mediated inflammatory diseases.

Over the past two decades, our understanding of interleukin-16 (IL-16) has increased substantially. Initial studies characterizing IL-16 as a chemotactic cytokine (but not a chemokine) just scratched the surface of the unique properties of this cytokine. Since then, scientists have determined that IL-16 has a wide range of effects on cells, including upregulation of CD25, induction of cells to progress to the G(1) phase, inhibition of antigen- specific proliferation yet with retained antigen nonspecific proliferative properties, and discovery of a novel neuronal form with unique properties. Recently, a plethora of studies have implicated IL-16 in exacerbation of infectious, immune-mediated, and autoimmune inflammatory disorders, including atopic dermatitis, irritable bowel syndrome, systemic lupus erythematosus, neurodegenerative disorders, and viral infections. Herein, we review the body of evidence supporting a role for IL-16 in infectious and immune-mediated inflammatory disorders and explore the known and possible mechanism of actions in the numerous diseases.