The IL-23/IL-17 pathway in inflammatory bowel disease

The etiology of inflammatory bowel disease is unknown but available evidence suggests that a deregulated immune response towards the commensal bacterial flora is responsible for intestinal inflammation in genetically predisposed individuals. IL-23 promotes expansion and maintenance of Th17 cells, which secrete the proinflammatory cytokine IL-17 and have been implicated in the pathogenesis of many chronic inflammatory disorders. Recent studies have shown that IL-23 also acts on cells of the innate immune system that can contribute to inflammatory cytokine production and tissue inflammation. A role for the IL-23/IL-17 pathway in the pathogenesis of chronic intestinal inflammation in inflammatory bowel disease has emerged from both animal and human studies. Here we aim to review the recent advances in this rapidly moving field.     

Interleukin-18 and Crohn's disease

The etiology and pathogenesis of inflammatory bowel disease remains an area under intense investigation. Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4+ T cells and macrophages in inflamed intestinal mucosa. IL-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4+ T cells by inducing interferon-gamma. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes in human CD and murine CD model.     

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.     

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.     

Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases

The cytokine responses characterizing the inflammatory bowel diseases are the key pathophysiologic elements that govern the initiation, evolution, and, ultimately, the resolution of these forms of inflammation. Studies during the last 2 decades now provide a detailed (but not yet complete) picture of the nature of these responses. The first tier of cytokine responses are governed by the T-cell differentiation patterns dominating the disease. In Crohn's disease, the major cytokines arise from T-helper cell (Th) 1 and Th17 CD4(+) T-cell differentiation and consist of interferon-γ and interleukin (IL)-17/IL-22 generated by these types of differentiation. The relative importance of these cytokines to Crohn's inflammation is still unclear, although evidence is mounting that interferon-γ is primus inter pare (first among equals). In contrast, in ulcerative colitis, a Th2-like differentiation process is paramount, which results in expansion of natural killer T cells producing IL-13 (and perhaps IL-5). These disease-specific cytokine patterns give rise to a second tier of cytokines that span the Th1/Th17-Th2 divide and act as upstream facilitators and downstream mediators of inflammation. These cytokines include the well-known tumor necrosis factor-α, IL-1β, IL-6 triumphirate, as well as a more recently studied cytokine known as TL1A (tumor necrosis factor-like ligand). In this review, we will explore this cytokine landscape with the view of providing an understanding of how recent and future anticytokine therapies actually function.     

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 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.     

Interleukin-27 Suppresses T Helper-17 Inflammation in Allergic Rhinitis

Background: T helper 17 (Th17) cells and the related cytokines, interleukin (IL)- 17 and IL-23, were proved to play pivotal roles during the development of allergic rhinitis (AR). IL-27, an anti-inflammatory cytokine, has been reported to promote the production of IL-12R and induce Th1 cell responses. However, its effect on Th17 responses was not fully understood. Objective: We conducted the present research to explore the role of IL-27 in the regulation of Th17 responses in AR. Methods: Thirty confirmed AR patients and 20 controls were recruited for the study. The mRNA expression and protein levels of IL-27 were analyzed employing quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively, and their correlations with Th17 cytokines were analyzed. We utilized ELISA and qPCR to analyze the effect of IL-27 on the differentiation of Th17 cells and the production of IL-17 and IL-23 from peripheral blood mononuclear cells (PBMCs). Results: We found that the IL-27 levels in AR were downregulated and negatively related to IL-17 and IL-23 levels. The recombinant IL-27 inhibited the mRNA expression of RORγt and the protein expression of IL-17 and IL-23 in PBMCs through MEK, NF-κB, and JNK pathways. Conclusion: Our data demonstrated that IL-27 suppressed Th17 responses through MEK, NF-κB, and JNK pathways.     

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.     

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.     

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.     

白细胞介素-23在炎症性肠病的表达升高并诱导促炎细胞因子分泌

目的 通过分析白细胞介素(IL)-23p19及其受体(IL-23R)在炎症性肠病(IBD)患者中的表达,研究IL-23对IBD患者外周血T细胞激活和效应应答的影响,探讨其在疾病发生过程中的免疫病理作用.方法 收集12例克罗恩病(CD)患者、25例溃疡性结肠炎(UC)患者和20名健康者外周血和肠黏膜组织活检标本,使用免疫组化染色和逆转录(RT)-PCR分析IL-23p19表达,分离外周血单个核细胞(PBMC)和肠黏膜固有层内单个核细胞(LPMC),利用流式细胞仪检测IL-23R在CD4+、CD8+T细胞和自然杀伤(NK)细胞表面表达.体外培养PBMC,使用IL-23和抗CD3单抗体外刺激,使用酶联免疫吸附试验检测肿瘤坏死因子(TNF)-α、干扰素(IFN)-γ和白细胞介素(IL)-2分泌.结果 IBD患者炎症肠黏膜组织内IL-23p19蛋白和mRNA表达水平比健康对照者显著升高(P<0.05).IL-23R在IBD患者外周血和肠黏膜固有层组织内CD4+、CD8+T细胞和NK细胞表达水平也比健康者显著升高(P<0.05).体外培养PBMC,使用IL-23刺激,发现IL-23可显著诱导IBD患者,尤其是CD患者PBMC激活,分泌高水平TNF-α、IFN-γ和IL-2(P<0.05).结论 IL-23及其受体在IBD患者炎症肠黏膜组织中表达升高,IL-23可诱导IBD患者淋巴细胞分泌高水平的炎性介质,提示IL-23参与了肠黏膜炎症损伤,阻断IL-23生物学效应可能治疗IBD.     

CD40–CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells

IL-17-producing CD4⁺ T cells have been recognized as key players in organ-related autoimmune disease; however, the parameters that govern their development are yet to be elucidated fully. By using both in vivo and in vitro systems, we have investigated the role of antigen dose, pathogen-associated molecular patterns, and CD40–CD40 ligand (CD40L) cross-talk in Th17 differentiation. We found that the strength of antigenic stimulation critically influenced the extent of Th17 differentiation, because high, but not low or intermediate, antigen concentrations led to IL-17 production. Strong antigenic stimulation of T cells up-regulated CD40L expression, which in concert with certain microbial stimuli (i.e., cytosine phosphate guanine, curdlan, and zymosan) synergistically increased dendritic cell (DC) IL-6 production and Th17 polarization. CD40-deficient DCs exhibited reduced cytokine release and failed to drive Th17 development in vitro. These results were confirmed in vivo where the absence of CD40–CD40L cross-talk was found to prevent the expansion of IL-17-producing cells and accordingly the development of experimental autoimmune encephalitis. Our data demonstrate that CD40–CD40L cross-talk is important for Th17 development by translating strong T cell receptor and microbial stimuli into IL-6 production.     

Critical role of IL-17 receptor signaling in acute TNBS-induced colitis

BACKGROUND: Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are characterized by recurrent inflammation in the gastrointestinal tract. Infiltration of CD4 lymphocytes and neutrophils is one of the predominant features of IBD. MATERIALS AND METHODS: Recently, interleukin (IL)-23 and the downstream T cell-derived cytokine IL-17 have been found to be elevated in intestinal tissue and serum of IBD patients. However, the role of IL-17 and IL-17R signaling in gut inflammation is unknown. To examine this role, we investigated gut inflammation in wild-type or IL-17R knockout mice. RESULTS: Using a model of acute trinitrobenzenesulfonic acid (TNBS)-induced colitis, we found that IL-17 was produced in colon tissue at 24 and 48 hours and that IL-17R knockout mice were significantly protected against TNBS-induced weight loss, IL-6 production, colonic inflammation, and local macrophage inflammatory protein-2 induction. This protection occurred in the presence of equivalent induction of local IL-23 and higher levels of IL-12p70 and interferon-gamma in IL-17R knockout mice compared with wild-type mice. Moreover, IL-17R knockout mice showed reduced tissue myeloperoxidase activity. Furthermore, overexpression of an IL-17R IgG1 fusion protein significantly attenuated colonic inflammation after acute TNBS. CONCLUSIONS: These results demonstrate that IL-17R signaling plays a critical role in the development of TNBS-induced colitis and may represent a target for therapeutic intervention for IBD.     

Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage

BACKGROUND AND AIMS: Persistent inflammation observed in inflammatory bowel disease may be the consequence of an increased or aberrant immune response to normal gut constituents or an overall immune dysregulation and imbalance. Cytokines play an important role in immune regulation and interleukin 18 (IL-18) is one such cytokine that has emerged as being instrumental in driving CD4+ T cell responses towards a Th1-type. IL-18 can also directly mediate inflammation, moderate interleukin 1 activity, and can act on cell types other than T cells. It has been reported recently that IL-18 mRNA and protein are upregulated in gut tissue from IBD patients. The aim of this study was to understand more about the role of IL-18 in contributing to the pathology of IBD and to assess whether blocking IL-18 activity may be of therapeutic benefit as a treatment regimen for IBD. METHODS: Mice with dextran sulphate sodium (DSS) induced colitis were treated with recombinant IL-18 binding protein (IL-18bp.Fc), a soluble protein that blocks IL-18 bioactivity. Histopathological analysis was performed and RNA from the large intestine was analysed using the RNase protection assay and gene arrays. RESULTS: IL-18 RNA levels increased very early in the colon during DSS colitis. Treatment of mice with IL-18bp.Fc inhibited IBD associated weight loss and significantly inhibited the intestinal inflammation induced by DSS. IL-18bp.Fc treatment also attenuated mRNA upregulation of multiple proinflammatory cytokine genes, chemokine genes, and matrix metalloprotease genes in the large intestine that are commonly elevated during IBD. CONCLUSIONS: IL-18bp treatment attenuated inflammation during DSS induced colitis in mice. Neutralising IL-18 activity may therefore be of benefit for ameliorating the inflammation associated with human intestinal diseases.     

Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease

BACKGROUND & AIMS: Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4(+) T cells and macrophages in inflamed intestinal mucosa. Interleukin (IL)-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4(+) T cells by inducing interferon gamma. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes. METHODS: Serum IL-18 concentration was measured by enzyme-linked immunosorbent assay. Expression of IL-18 and IL-18 receptor in human intestinal mucosa was determined using immunohistochemistry and flow cytometry. The functional activity of IL-18 was assessed by the use of recombinant IL-18 to stimulate both the growth of intestinal mucosal lymphocytes and IL-2 receptor induction activity. RESULTS: The serum IL-18 concentration was significantly higher in patients with CD than normal controls. In the inflamed colonic mucosa of CD, many IL-18(+)CD68(+) macrophages had infiltrated the lamina propria. Intestinal mucosal lymphocytes from CD expressed functional IL-18 receptors. Recombinant IL-18 induced significant proliferative responses in freshly isolated mucosal lymphocytes from CD patients, but not from normal controls. IL-18 up-regulated IL-2 receptor expression in mucosal lymphocytes from patients with CD, but not from normal controls. CONCLUSIONS: These findings suggest that infiltrated macrophages in the inflamed intestinal mucosa in CD produce IL-18, and that macrophage-derived IL-18 may serve as a potent regulatory factor for intestinal mucosal lymphocytes, thereby contributing to chronic intestinal inflammation in CD.     

Distinct roles of helper T-cell subsets in a systemic autoimmune disease

Imbalance of T-helper cell (Th) differentiation and subsequent cytokine dysregulation is implicated in inflammatory and autoimmune diseases. In particular, 2 cytokines produced by different Th cell populations, interferon-gamma (IFN-gamma) and interleukin-17 (IL-17), have been shown to play a critical role in autoimmunity. We have examined the roles of these cytokines in a mouse model of systemic autoimmunity resulting from the deletion of IL-2 in which autoimmune hemolytic anemia (AIHA) is a prominent feature. We demonstrate that, in IL-2-knockout (KO) BALB/c mice, elimination of the Th1 cytokine, IFN-gamma, delays the development of AIHA. Further, CD4(+) T cells from IL-2/IFN-gamma-KO mice produce elevated levels of IL-17 compared with wild-type (WT) and IL-2-KO, and these mice eventually develop intestinal inflammation. In contrast, elimination of the Th17 cytokine, IL-17, from IL-2-KO mice fails to suppress early acute AIHA development. These results suggest that in a systemic autoimmune disease with multiple manifestations, Th1 cells drive the early autoantibody response and IL-17-producing cells may be responsible for the more chronic tissue inflammation.