The Interleukin-23 / Interleukin-17 axis in intestinal inflammation

Although the precise aetiology of inflammatory bowel disease (IBD) remains unclear, recent discoveries have led to an improved understanding of disease pathogenesis. Whilst these findings have underscored the central role of innate and adaptive immune responses in intestinal inflammation, they have also precipitated a paradigm shift in the key cytokine pathways that drive disease. The prevailing dogma that IBD was mediated by interleukin (IL)-12-driven T-helper (Th)1 CD4 T cell responses towards the bacterial flora has been largely dispelled by findings that the closely related cytokine IL-23 appears to be the key mediator of intestinal inflammation. IL-23 is associated with a novel subset of IL-17-secreting CD4 T cells termed Th17 cells and rodent studies have implicated the IL-23/IL-17 axis in autoimmune inflammation. Genome-wide association studies in IBD patients have confirmed the predominant role of the IL-23 pathway, indicating that this could represent an important future therapeutic target.     

Th17细胞及IL-23在炎症性肠病中的研究进展

炎症性肠病(IBD)是一种病因和发病机制尚不清楚的发生在胃肠道的慢性非特异性炎症性疾病。大量证据表明先天性和获得性免疫系统的异常均对该疾病起着关键性作用。传统观点认为炎症性肠病与Th1细胞和Th2细胞所介导的免疫应答有关;但最新研究指出,体内Th17细胞以及白细胞介素IL-23的存在,与炎症性肠病的发生息息相关。本文对炎症性肠病中Th17细胞及IL-23的研究进展作一综述。     

Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease

Inflammatory bowel diseases(IBDs) are chronic disorders of modern society, requiring management strategies aimed at prolonging an active life and establishing the exact etiology and pathogenesis.These idiopathic diseases have environmental, genetic,immunologic, inflammatory, and oxidative stress components. On the one hand, recent advances have shown that abnormal immune reactions against the microorganisms of the intestinal flora are responsible for the inflammation in genetically susceptible individuals. On the other hand, in addition to T helper cell-type(Th) 1 and Th2 immune responses,other subsets of T cells, namely regulatory T cells and Th17 maintained by IL-23 are likely to develop IBD. IL-23 acts on innate immune system members and also facilitates the expansion and maintenance of Th17 cells. The IL-17/IL-23 axis is relevant in IBD pathogenesis both in human and experimental studies. Novel biomarkers of IBD could be calprotectin,microRNAs, and serum proinflammatory cytokines.An efficient strategy for IBD therapy is represented by the combination of IL-17 A and IL-17 F in acute IL-17 A knockout TNBS-induced colitis, and also definite decrease of the inflammatory process in IL-17 F knockout, DSS-induced colitis have been observed.Studying the correlation between innate and adaptive immune systems, we hope to obtain a focused reviewin order to facilitate future approaches aimed at elucidating the immunological mechanisms that control gut inflammation.     

Th17/Treg失衡与炎症性肠病的关系

炎症性肠病(inflammatory bowel disease.IBD)的病因和发病机制尚未完全明确,肠道黏膜免疫系统异常反应所导致的炎症过程在发病中起重要作用.辅助性T细胞17(T helper 17 cells,Th17)可介导慢性炎症和自身免疫性疾病的发生,调节性T细胞(regulatory T cell,Treg)有抑制自身免疫的功能,二者存在相互转化的关系.有研究表明Th17/Treg转化平衡是维持肠道免疫稳态的重要因素,这可能是导致人类IBD的原因之一.最近研究表明TGF-β,IL-6和维甲酸(retinoic acid,RA)可能是调控二者平衡关系的重要因素.肠道菌群(intestinal flora)与IBD的发生发展关系密切,益生菌(probiotics)对IBD的治疗作用成为研究的热点.深化对Th17/Treg转化调控关系的研究是当前重要的研究课题.     

IL-17A plays an important role in induction of type 2 diabetes and its complications

Type 2 diabetes (T2D) is the most prevalent metabolic disease worldwide. Previous studies revealed that immune responses, genetic factors, and inflammatory processes played important roles in the pathogenesis and complications of T2D. It has been documented that some people who have T2D are suffering from serious organ-specific pathophysiological conditions including nephropathy and retinopathy. The mechanisms responsible for progression of the disease and its long-term complications are yet to be clarified. IL-17A as a pro-inflammatory cytokine has a dual function, inducing early immune responses against infections and participating in autoimmunity and destructive inflammatory conditions. Therefore, the aim of this review was to address the recent information regarding the status and association of IL-17A with T2D and its related disorders.     

Th17细胞及肠道内共生菌群在炎症性肠病中的作用

炎症性肠病(inflammatory bowe ldisease,IBD)是一种以慢性肠道炎症性疾病,病因未明,肠道黏膜异常的免疫反应在发病中有着重要作用.最近发现一类辅助T淋巴细胞Th17细胞,能在肠黏膜中大量分泌IL-17A和IL-17F.减少肠道Th17细胞数量和其相关的细胞因子的表达能够缓解肠道炎症反应,预示Th17细胞在IBD发病中起到一定作用.肠道共生菌与IBD的发病也有着密切关系,肠道共生菌群的变化可能导致Th17细胞的数量发生改变引起炎症,或者通过其他机制和途径诱发免疫紊乱,从而使得炎症得以发生.本文就Th17细胞的分化与其在IBD中的作用,以及共生菌群和Th17细胞之间的相互联系作一综述.     

Stepwise regulation of TH1 responses in autoimmunity: IL-12-related cytokines and their receptors

Interleukin (IL)-12 is a key cytokine of cell-mediated immune responses. Until recently, IL-12 was believed to be unique in its ability to induce the differentiation of naive T cells toward the TH1 phenotype and in its pathogenic activity, as shown in various disease models including inflammatory bowel disease. However, recently, 2 additional cytokines closely related to IL-12, IL-23 and IL-27, were discovered. Until then, the role of IL-12 was overestimated because it was believed that the p40 subunit was unique to IL-12. The discovery that IL-12 shares p40 with IL-23 and that IL-23 but not IL-12 is essential in models of chronic inflammation and autoimmunity led to a model in which IL-12 is essential to induce interferon-gamma-producing TH1 cells, whereas IL-23 mediates effector functions. The latest cytokine added to this cytokine family is IL-27. IL-27 has the unique feature to act on naive T cells, rendering them susceptible to IL-12 signaling. Thus, IL-27 may be essential for the early events of a cell-mediated immune response. This review focuses on these novel cytokines and their role in cell-mediated immune responses and discusses differences and common features within the family of IL-12-related cytokines.     

Functional relevance of T helper 17 (Th17) cells and the IL-17 cytokine family in inflammatory bowel disease

The recent discovery and characterization of T helper 17 cells (Th17) and their signature cytokines (IL-17) represents a hallmark in T-cell immunobiology by providing a new distinctive pathway for the communication between adaptive and innate immunity. From the six members of the IL-17 cytokine family presently known, at least two have evident proinflammatory qualities and are involved in several chronic inflammatory disorders, including inflammatory bowel disease (IBD). IL-17A and IL-17F are abundantly found in inflamed IBD mucosa, suggesting their pivotal role in IBD. However, the precise implication of IL-17 cytokine family members in IBD pathogenesis and the mechanisms regulating their secretion are incompletely understood. Importantly, recent findings suggest that beyond IL-17 production-Th17 cells may secret a plethora of other effector cytokines such as IL-21, IL-22, and IL-9- which is in part induced by its own IL-9 production. However, the use of anti-IL-17 therapeutic strategies in experimental models of chronic inflammation results in disease-ameliorating effects suggesting their potential use in IBD patients. In this review article we discuss the latest findings on the role of Th17 cells and IL-17 family members in IBD immunopathology, as well as research perspectives.     

Roles of the novel interleukin-12-associated cytokine, interleukin-23, in the regulation of T-cell-mediated immunity

Interleukin (IL)-12 is a heterodimeric proinflammatory cytokine formed by a 35-kDa light chain (p35) and a 40-kDa heavy chain (p40). This cytokine is a key regulator of cell-mediated immunity, and therefore should have therapeutic potential in infectious diseases and tumors. Recently, a novel IL-12-associated cytokine, IL-23 has been discovered. IL-23 is also a heterodimer that consists of the p40 subunit of IL-12 and a novel subunit, p19. Several studies have shown that IL-23 possesses immunoadjuvant activity against tumor and infectious diseases as well as IL-12. On the other hand, there is increasing evidence that IL-12 and IL-23 have discrete roles in the regulation of T-cell-mediated immunity despite their structural similarities. IL-12 leads to the development ofinterferon-γ-producing T-helper type 1 (Th1) cells, whereas IL-23 amplifies and stabilizes a new CD4⁺ T-cell subset, Th17 producing IL-17. The IL-23/Th17 axis rather than the IL-12/Th1 axis contributes to several immune-mediated inflammatory autoimmune diseases. Furthermore, IL-23/IL-17 promotes tumor incidence and growth. Therefore, IL-23 and Th17 are attracting considerable attention at present. Taken together, these findings suggest that IL-23 may be an immunoadjuvant against infectious diseases and tumors, and a viable target for the treatment of inflammatory diseases.     

Research progress of P2X7 receptor in inflammatory bowel disease

Inflammatory bowel disease is a chronic nonspecific inflammatory disease of the intestine. Its pathogenesis is not yet fully understood. It may be related to heredity, environmental triggers, infection, immune dysfunction and other factors. Purinergic receptor (P2X7R) ligand-gated ion channel is closely related to inflammation and widely expressed in intestinal cells. Previous studies have shown that ATP/P2X7R signal is involved in the pathogenesis of intestinal inflammation, but its specific mechanism needs further study. This article reviews the research progress of P2X7 receptor in inflammatory bowel disease.     

The Regulation of Thymic Stromal Lymphopoietin in Gut Immune Homeostasis

Thymic stromal lymphopoietin is a novel IL-7-like cytokine that exerts immunomodulatory effects and is constitutively expressed by intestinal epithelial cells in response to commensal bacteria colonization. Thymic stromal lymphopoietin can directly or indirectly promote Th2 and Treg responses, and is believed to inhibit Th1 and Th17 responses and limit the expression of proinflammatory cytokines such as IL-17 and IFN-γ. In response to infection by enteric pathogens, intestinal epithelial cells upregulate thymic stromal lymphopoietin expression in order to generate balance between inflammation and immune clearance. Recently, however, aberrant expression of thymic stromal lymphopoietin has been associated with inflammatory bowel disease. Thus, we sought to examine the relationship between the TLSP-TSLPR pathway and inflammation in hopes of contributing to the search for a novel therapeutic target to treat a variety of inflammatory diseases, including inflammatory bowel disease.     

Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease

The etiopathology of inflammatory bowel disease (IBD) remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflammation. IBD including Crohn's disease (CD) and ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Th1mediated inflammatory disorder while UC is regarded as a Th2like disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Th1 or Th2 cells, and several cytokines [e.g. interleukin (IL)-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Th1/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.     

Emerging role of IL-23/IL-17 axis in H pylori-associated pathology

Colonization of stomach by H pylori is followed by a marked infiltration of the mucosa with polymorphonuclear leukocytes, macrophages, and lymphocytes that very often remains asymptomatic, but in some circumstances can lead to the development of gastroduodenal ulceration, gastric carcinoma, and mucosa-associated lymphoid tissue lymphoma. The molecular mechanisms by which Hpylori triggers and maintains the local immune response are complex, but there is evidence that cytokines produced by both immune and non-immune cells contribute to amplify the ongoing inflammation. H pylori infection is associated with a marked mucosal induction of T helper （Th） type 1 and Th17-type cytokines that is governed by specific antigen-presenting cell-derived molecules, such as interleukin （IL）-12 and IL-23. In this paper, we will review the available data on the expression and role of IL-23 and IL-17 in H pylori-related gastritis.     

IL-17在炎性肠病中的表达及其与LPS协同诱导肠上皮细胞表达IL-8的作用机制

目的:探讨IL-17细胞因子在TNBS诱导的炎性肠病动物模型中的表达变化,明确IL-17和脂多糖(LPS)在诱导HT-29肠上皮细胞IL-8表达中的协同作用及细胞内信号机制.方法:探讨IL-17及其受体在TNBS炎性肠病模型中的表达变化,利用细胞培养、FASC、Real-time PCR、酶联免疫吸附(ELISA)、Western blot等技术,观察IL-17及不同剂量LPS干预人肠上皮细胞(HT-29细胞)后细胞因子IL-8在蛋白水平的表达,以及IL-17受体(IL-17Ra)在mRNA水平的表达变化及引起上述效应的细胞内信号传导机制.结果:TNBS诱导的炎性肠病动物模型中IL-17以及IL-17Ra显著升高(P<0.03);炎症介质IL-17能与一定浓度范围内的LPS协同促进IL-8的表达(2187.61±132.42vs2634.27±134.63,P=0.01),增强NF-κB信号通路的活化,促进炎症反应.但随着LPS剂量升高,LPS本身诱导IL-8表达的活性降低,且与IL-17的协同作用消失(1841.43±50.38vs1685.67±71.47,P=0.03).结论:IL-17与低浓度的LPS可协同促进HT-29细胞炎症介质的表达,但与高浓度LPS联合时,两者无协同效应.     

Expression of IL-23 and IL-17 and effect of IL-23 on IL-17 production in ankylosing spondylitis

The objective of this study was to investigate the expression of IL-23 and IL-17 and the influence of IL-23 on IL-17 production in ankylosing spondylitis (AS) patients. IL-23 and IL-17 levels in the serum and supernatants of cultured peripheral blood mononuclear cells (PBMCs) were determined by ELISA. IL-23p19 mRNA expression in PBMCs were analyzed using RT-PCR. The patients with AS at active stage showed elevated levels of IL-23 and IL-17 in the serum and supernatants of cultured PBMCs. A higher expression of IL-23p19 mRNA in PBMCs of AS patients was also observed. A significantly enhanced production of IL-17 in the supernatants of cultured PBMCs was found in the presence of recombinant IL-23 and this effect was more significant in patients with AS. The results suggest that IL-23 and IL-17 may play critical roles in the pathogenesis of AS and IL-23-stimulated production of IL-17 by PBMCs may be responsible for the development of AS.     

Changes and significance of IL-25 in chicken collagen II-induced experimental arthritis (CIA)

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease. It is a systemic inflammatory disease, characterized by chronic, symmetrical, multi-articular synovial arthritis. IL-25 (IL-17E) is a member of the recently emerged cytokine family (IL-17s), which is expressed in Th2 cells and bone marrow-derived mast cells. Unlike the other members of this family, IL-25 is capable of inducing Th2-associated cytokines (IL-4, IL-5, and IL-13) and also promotes the release of some pro-immune factors (IL-6 and IL-8). IL-25 is also a pleiotropic factor, which constitutes a tissue-specific pathological injury and chronic inflammation. In this study, we used chicken collagen II-induced experimental arthritis (CIA) model in DBA/1 mice to investigate the relationship between IL-25 and other inflammatory factors, revealing the possible mechanism in CIA. Our results showed that the expression level of IL-25 was enhanced in the late stage of CIA, and IL-17 was increased in the early stage of the disease. It is well known that IL-17 has a crucial role in the development of RA pathogenesis, and IL-25 plays a significant role in humoral immune. For reasons given above, we suggested that the IL-25 inhibited IL-17 expression to some extent, while enhancing the production of IL-4. It was confirmed that IL-25 not only regulated the cellular immune, but also involved the humoral immune in rheumatoid arthritis.     

Th17 immune response in IBD: A new pathogenic mechanism

Although traditionally associated with exaggerated Th1 or Th2 cell response, the gut inflammation occurring in patients with IBD is also characterized by production of cytokines made by a distinct lineage of T helper cells, termed Th17 cells. The discovery that this new inflammatory T-cell subset drives immune-mediated pathology and that the antigen-presenting cell-derived IL-23 is necessary for amplifying Th17 cell-associated inflammation has contributed to elucidate new pathways of intestinal tissue damage as well as to open new avenues for development of therapeutic strategies in IBD.In this review, we discuss the available data regarding the involvement of Th17 cells and their interplay with other mucosal cell types in the modulation of intestinal tissue inflammation.