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.     

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.     

Healing of intestinal inflammation by IL-22

An interleukin (IL)-10 family cytokine, IL-22 is characterized by several unique biological properties, including 1) the target restricted to innate cells; 2) the distinct expression pattern between large and small intestines; 3) alteration of the cellular source depending on several factors; 4) the dual abilities to serve as protective versus proinflammatory mediators in inflammatory responses; and 5) the close association with some major inflammatory bowel disease (IBD) susceptibility genes. The major functions of IL-22 in the intestine are the stimulation of epithelial cells to produce a wide variety of antibacterial proteins, the reinforcement of mucus barrier through stimulation of mucin 1 production under intestinal inflammatory conditions, and the enhancement of epithelial regeneration with goblet cell restitution. Through these beneficial functions, IL-22 contributes to the improvement of some types of experimental chronic colitis, which are mediated by T helper (Th)1 or Th2 responses. Most important, studies using both loss-of-function and gain-of-function approaches have clearly demonstrated the ability of IL-22 to promote intestinal wound healing from acute intestinal injury. These findings highlight IL-22 as an attractive and promising target for future IBD therapy. Alternatively, the enormous progress in the field of IL-22 biology has also suggested more complicated mechanisms with the IL-22 pathway than previously predicted. This review article briefly summarizes previous and current knowledge on IL-22 particularly associated with intestinal inflammation.     

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.     

Immunopathology of inflammatory bowel disease

Inflammatory bowel disease(IBD)results from a complex series of interactions between susceptibility genes,the environment,and the immune system.The host microbiome,as well as viruses and fungi,play important roles in the development of IBD either by causing inflammation directly or indirectly through an altered immune system.New technologies have allowed researchers to be able to quantify the various components of the microbiome,which will allow for future developments in the etiology of IBD.Various components of the mucosal immune system are implicated in the pathogenesis of IBD and include intestinal epithelial cells,innate lymphoid cells,cells of the innate(macrophages/monocytes,neutrophils,and dendritic cells)and adaptive(T-cells and B-cells)immune system,and their secreted mediators(cytokines and chemokines).Either a mucosal susceptibility or defect in sampling of gut luminal antigen,possibly through the process of autophagy,leads to activation of innate immune response that may be mediated by enhanced toll-like receptor activity.The antigen presenting cells then mediate the differentiation of na?ve T-cells into effector T helper(Th)cells,including Th1,Th2,and Th17,which alter gut homeostasis and lead to IBD.In this review,the effects of these components in the immunopathogenesis of IBD will be discussed.     

Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease

Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.     

New insights into the cellular immunology of the intestine in relation to the pathophysiology of inflammatory bowel diseases

The authors review advances about altered immunological cellular mechanisms in inflammatory bowel diseases (IBD). The innate immune response might play a role in the inductive phase : epithelial barrier defect, production of inflammatory cytokines and defective neutrophil function. Dendritic cells have a pivotal role, since they sense the nature of the micro-organisms in the intestine in order to drive either adaptive immune responses through IL-12 or IL-4 and co-stimulatory molecules, or immunotolerance through regulatory T cells (Tr). T helper(Th)1 cytokines (IFNgamma, TNF-alpha, IL-12) are secreted in excess in Crohn's disease (CD) whereas in ulcerative colitis an atypical Th2 immune response (IL-4, TGFbeta) has been reported. However, activation of Th can only lead to effective immune response if co-stimulatory molecules expressed on activated T cells bind to their specific ligands on the antigen-presenting-cells, mesenchymal and endothe-, lial cells. This binding is necessary to generate an effective immune response, to enhance expression of adhesion molecules and T cell recruitment, promoting chronic inflammation in IBD. A defective function of Tr might contribute to excessive T cell response. Innate CD4 + CD25 + Tr derived from the thymus represent 5-10% of T cells in peripheral lymphoid organs. Acquired peripheral Tr downregulate the immune response through IL-10 and TGF-beta production. In IBD effector T cells might downregulate the development of Tr cells in the thymus. Another defective mechanism in CD is T cell resistance to apoptosis, leading to inappropriate immune homeostasis and accumulation of T cells in the tissues. New therapeutic agents have been proposed for correcting deficiencies of innate immunity or reducing excessive immune responses, with promising results confirmed by randomized controlled trials.     

Interactions between the host innate immune system and microbes in inflammatory bowel disease

The intestinal immune system defends against pathogens and entry of excessive intestinal microbes; simultaneously, a state of immune tolerance to resident intestinal microbes must be maintained. Perturbation of this balance is associated with intestinal inflammation in various mouse models and is thought to predispose humans to inflammatory bowel disease (IBD). The innate immune system senses microbes; dendritic cells, macrophages, and epithelial cells produce an initial, rapid response. The immune system continuously monitors resident microbiota and utilizes constitutive antimicrobial mechanisms to maintain immune homeostasis. associations between IBD and genes that regulate microbial recognition and innate immune pathways, such as nucleotide oligomerization domain 2 (Nod2), genes that control autophagy (eg, ATG16L1, IRGM), and genes in the interleukin-23-T helper cell 17 pathway indicate the important roles of host-microbe interactions in regulating intestinal immune homeostasis. There is increasing evidence that intestinal microbes influence host immune development, immune responses, and susceptibility to human diseases such as IBD, diabetes mellitus, and obesity. Conversely, host factors can affect microbes, which in turn modulate disease susceptibility. We review the cell populations and mechanisms that mediate interactions between host defense and tolerance and how the dysregulation of host-microbe interactions leads to intestinal inflammation and IBD.     

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.     

Role of mucosal dendritic cells in inflammatory bowel disease

The gastrointestinal innate and adaptive immune system continuously faces the challenge of potent stimuli from the commensal microflora and food constituents. These local immune responses require a tight control, the outcome of which is in most cases the induction of tolerance. Local T cell immunity is an important compartment of the specif ic intestinal immune system. T cell reactivity is programmed during the initial stage of its activation by professional presenting cells. Mucosal dendritic cells （DCs） are assumed to play key roles in regulating immune responses in the antigenrich gastrointestinal environment. Mucosal DCs are a heterogeneous population that can either initiate （innate and adaptive） immune responses, or control intestinal inflammation and maintain tolerance. Defects in this regulation are supposed to lead to the two major forms of inflammatory bowel disease （IBD）, Crohn＇s disease （CD） and ulcerative colitis （UC）. This review will discuss the emerging role of mucosal DCs in regulating intestinal inflammation and immune responses.     

Roles of IL-18 in basophils and mast cells.

Basophils and mast cells are effecter cells in allergen/IgE-mediated immune responses. They induce type 1 immediate immune response in airway or other organ, resulting in bronchial asthma and other allergic diseases. However, they also play a critical role in host defense against infection with helminthes. Upon linkage of FcepsilonRI with a complex of allergen and IgE, basophils and mast cells release a large amount of Th2 cytokines and chemical mediators. Therefore these responses are "acquired allergic responses" and induce allergic diseases, such as bronchial asthma. However, basophils and mast cells derived from cultured bone marrow cells with IL-3 for 10 days express IL-18Ralpha chain and produce Th2 cytokines in response to the stimulation with IL-3 and IL-18 without FcepsilonRI cross-linkage. Furthermore, they produce Th2 cytokines upon stimulation with several TLR ligands, such as LPS. This finding may suggest the presence of allergen/IgE-independent allergic responses, which we would like to designate as "innate allergic response". However, in vivo treatment with IL-18 and IL-2 protects against gastrointestinal nematode infection by activating intestinal mucosal mast cells in STAT6-independent manner, suggesting the importance of innate allergic response against helminth infection. Here we discuss the functional role of IL-18-induced "innate allergic response" in disease and host defense.     

Interleukin (IL)-13 and IL-4 Are Potent Inhibitors of IL-8 Secretion by Human Intestinal Epithelial Cells

Intestinal epithelial cells are able to producesoluble mediators that initiate or amplify inflammatoryevents in the intestinal mucosa. Interleukin (IL)-8 issuggested to be a cytokine playing a major role during the acute and chronic processes ininflammatory bowel disease (IBD). TH-2 cytokines havebeen described as down-regulating the inflammatoryresponse. We analyzed the effects of IL-10, IL-13, and IL-4 on IL-8 secretion in intestinalepithelial cells. The human colonic epithelial cell lineCaco-2 and freshly isolated intestinal epithelial cellswere used. Cells were stimulated with IL-1beta after treatment with TH-2 cytokines. Levels of IL-8were determined by employing enzyme-linked immunosorbentassay (ELISA). Stimulation with IL-1beta results in atime-dependent IL-8 secretion. The addition of IL-4 and IL-13, but not IL-10, to activatedepithelial cells resulted in a strong decrease in IL-8secretion. Maximal inhibition required that TH-2cytokines be added up to 60 min before or simultaneous with stimulatory agents. We present novelfindings that IL-4 and IL-13 strongly down-regulate IL-8secretion from intestinal epithelial cells. Amicroenvironment containing high concentrations of IL-4and IL-13 may alter the recruitment of immune cellsto enterocytes at least partly by inhibiting IL-8production. This inhibition might diminish the severityof the intestinal inflammatory response and, thus reduce clinical disease activity.     

Role of NLRP3 inflammasome in inflammatory bowel diseases

Inflammasomes are multiprotein intracellular complexes which are responsible for the activation of inflammatory responses. Among various subtypes of inflammasomes, NLRP3 has been a subject of intensive investigation. NLRP3 is considered to be a sensor of microbial and other danger signals and plays a crucial role in mucosal immune responses, promoting the maturation of proinflammatory cytokines interleukin 1β(IL-1β) and IL-18. NLRP3 inflammasome has been associated with a variety of inflammatory and autoimmune conditions, including inflammatory bowel diseases(IBD). The role of NLRP3 in IBD is not yet fully elucidated as it seems to demonstrate both pathogenic and protective effects. Studies have shown a relationship between genetic variants and mutations in NLRP3 gene with IBD pathogenesis. A complex interaction between the NLRP3 inflammasome and the mucosal immune response has been reported. Activation of the inflammasome is a key function mediated by the innate immune response and in parallel the signaling through IL-1β and IL-18 is implicated in adaptive immunity. Further research is needed to delineate the precise mechanisms of NLRP3 function in regulating immune responses. Targeting NLRP3 inflammasome and its downstream signaling will provide new insights into the development of future therapeutic strategies.     

Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease

Inflammatory bowel disease(IBD)includes Crohn’s disease and ulcerative colitis.The exact etiology and pathology of IBD remain unknown.Available evidence suggests that an abnormal immune response against the microorganisms in the intestine is responsible for the disease in genetically susceptible individuals.Dysregulation of immune response in the intestine plays a critical role in the pathogenesis of IBD,involving a wide range of molecules including cytokines.On the other hand,besides T helper(Th)1 and Th2 cell immune responses,other subsets of T cells,namely Th17 and regulatory T cells,are likely associated with disease progression.Studying the interactions between various constituents of the innate and adaptive immune systems will certainly open new horizons of the knowledge about the immunologic mechanisms in IBD.     

Ⅱ型固有淋巴细胞与支气管哮喘的最新研究进展

Ⅱ型固有淋巴细胞(group 2 innate lymphoid cells,ILC2s)是最近才被发现的一类固有淋巴细胞群,并被认为是Th2型细胞因子的主要来源.目前,ILC2s在哮喘中的作用已引起广泛关注.当致敏原刺激气道上皮细胞后,上皮细胞来源的细胞因子IL-33、IL-25、TSLP激活ILC2s,诱导ILC2s产生大量的Th2型细胞因子以及某些生长因子如双调蛋白,这与哮喘的发生以及上皮细胞的修复密切相关.ILC2s不仅能与其他固有免疫细胞相互作用,还可以调控适应性免疫应答,在过敏性炎症反应中起着连接固有免疫与适应性免疫的桥梁作用.本文主要综述ILC2s的调控与功能以及ILC2s在哮喘发病中的最新研究进展.     

Role of cytokines in inflammatory bowel disease

Inflammatory bowel disease （IBD）, which includes Crohn’s disease （CD） and ulcerative colitis （UC）, rep- resents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal mac- rophages play an important role in the mucosal im- mune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major con- tributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD. Therefore, several cyto- kine therapies have been developed and tested for the treatment of IBD patients.     

Current view of the immunopathogenesis in inflammatory bowel disease and its implications for therapy

Although the aetiology of inflammatory bowel disease （IBD） remains unknown, the pathogenesis is gradually being unravelled, seeming to be the result of a combination of environmental, genetic, and immunological factors in which an uncontrolled immune response within the intestinal lumen leads to inflammation in genetically predisposed individuals. Multifactorial evidence suggests that a defect of innate immune response to microbial agents is involved in IBD. This editorial outlines the immunopathogenesis of IBD and their current and future therapy. We present IBD as a result of dysregulated mucosal response in the intestinal wall facilitated by defects in epithelial barrier function and the mucosal immune system with excessive production of cytokines growth factors, adhesion molecules, and reactive oxygen metabolites, resulting in tissue injury. Established and evolving therapies are discussed in the second part of this editorial and at the end of this section we review new therapies to modulate the immune system in patients with IBD.     

IL-10 and its related cytokines for treatment of inflammatory bowel disease

Inflammatory bowel diseases (IBDs), including Crohn‘s disease and ulcerative colitis are chronic inflammatory disorders of gastrointestinal tract. Although the etiology is incompletely understood, initiation and aggravation of the inflammatory process seem to be due to a massive local mucosal immune response.Interleukin-10 (IL-10) is a regulatory cytokine which inhibits both antigen presentation and subsequent pro-inflammatory cytokine release, and it is proposed as a potent anti-inflammatory biological therapy in chronic IBD. Many methods of IL-10 as a treatment for IBD have been published. The new strategies of IL-10 treatment, including recombinant IL-i0, the use of genetically modified bacteria, gelatine microsphere containing IL-10,adenoviral vectors encoding IL-i0 and combining regulatory T cells are discussed in this review. The advantages and disadvantages of these IL-10 therapies are summarized.Although most results of recombinant IL-10 therapies are disappointing in clinical testing because of lacking efficacy or side effects, therapeutic strategies utilizing gene therapy may enhance mucosal delivery and increase therapeutic response. Novel IL-10-related cytokines, including IL-19,IL-20, IL-22, IL-24, IL-26, IL-28 and IL-29, are involved in regulation of inflammatory and immune responses. The use of IL-10 and IL-10-related cytokines will provide new insights into cell-based and gene-based treatment against IBD in near future.