IL-33及其与相关疾病关系的研究进展

IL-33是最近发现的一种新IL-1家族细胞因子,可发挥双重作用,作为细胞因子参与调节Th2型机体免疫和炎症反应;同时作为核因子定位于细胞核内,起转录调控作用.IL-33被认为是Th2型免疫反应的关键活化因子,例如在线虫和变态反应疾病中促进Th2细胞、肥大细胞、嗜碱粒细胞、嗜酸性细胞活化释放IL-5、IL-13等Th2...     

Th17细胞与气道变应性疾病

气道变应性疾病传统上认为是以Th2型免疫应答占优势的Th1/Th2细胞功能失衡所致.近年来,大量研究证实Th17细胞在气道变应性炎症中发挥重要作用,使人们对气道变应性疾病有了崭新的认识.IL-17A能促进中性粒细胞的募集、活化,促进炎症反应;IL-23-Th1轴不仅能诱导中性粒细胞性气道炎症,还能正调节嗜酸性粒细胞性气...     

Regulation of immune responses by interleukin-27

Summary: Cytokine-mediated immunity plays a crucial role in the pathogenesis of various diseases including autoimmunity. Recently, interleukin-27 (IL-27) was identified, which, along with IL-12, IL-23, and IL-35, belongs to the IL-12 cytokine family. These family members play roles in the regulation of T helper (Th) cell differentiation. IL-27 is unique in that while it induces Th1 differentiation, the same cytokine suppresses immune responses. In the absence of IL-27-mediated immunosuppression, hyper-production of various pro-inflammatory cytokines concomitant with severe inflammation in affected organs was observed in IL-27 receptor α chain (WSX-1)-deficient mice infected with Trypanosoma cruzi. Experimental allergic or inflammatory responses were also enhanced in WSX-1-deficient mice. The immunosuppressive effects of IL-27 depend on inhibition of the development of Th17 cells (a newly identified inflammatory T-helper population) and induction of IL-10 production. Moreover, administration of IL-27 or augmentation of IL-27 signaling suppresses some diseases of autoimmune or allergic origin, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines. In this review, we discuss recent studies on the role of IL-27 in immunity to parasitic and bacterial infections as well as in allergy and autoimmunity in view of its pro- and anti-inflammatory properties.     

Functional specialization of interleukin-17 family members

Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F). Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal?infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses. The functions of IL-17B, IL-17C, and IL-17D remain largely elusive. In this review, we describe the identified functions of each IL-17 family member and discuss the potential of these molecules as therapeutic targets.     

TH17 and TH22 cells: a confusion of antimicrobial response with tissue inflammation versus protection

Substantial progress in understanding mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumors, organ transplantation, chronic infections, and pregnancy is in an exciting developmental phase that might lead to a variety of targeted therapeutic approaches. Recent progress in the interaction between immune/inflammatory cell subsets through cytokines, particularly the extension of the knowledge on reciprocal regulation and counterbalance between subsets of T(H)1, T(H)2, T(H)9, T(H)17, T(H)22, T follicular helper cells and different subsets of regulatory T cells, as well as corresponding and co-orchestrating B-cell, natural killer cell, dendritic cell, and innate lymphoid cell subsets, offers new possibilities for immune intervention. Studies on new subsets confirm the important role of T cells in the instruction of tissue cells and also demonstrate the important role of feedback regulation for the polarization toward distinct T-cell subsets. T(H)17 and T(H)22 cells are 2 emerging T(H) cell subsets that link the immune response to tissue inflammation; IL-17A and IL-17F and IL-22 are their respective prototype cytokines. Although both cytokines play roles in immune defense to extracellular bacteria, IL-17 augments inflammation, whereas IL-22 plays a tissue-protective role. This review focuses on current knowledge on T(H)17 and T(H)22 cells and their role in inflammation, with special focus on the mechanisms of their generation and driving and effector cytokines, as well as their role in host defense, autoimmunity, and allergic diseases.     

Interleukin-17 and its expanding biological functions

Interleukin-17 (IL-17) and IL-17-producing cells have been shown to play important roles in inflammation and the immune response. IL-17 is believed to be mainly produced by T helper 17 (Th17) cells, a unique helper T-cell subset different from Th1 and Th2 cells. Other subsets of T cells such as γδT and natural killer T (NKT) cells have also been found to produce IL-17 in response to innate stimuli. IL-17 acts as a proinflammatory cytokine that can induce the release of certain chemokines, cytokines, matrix metalloproteinases (MMPs) and antimicrobial peptides from mesenchymal and myeloid cells. This leads to the expansion and accumulation of neutrophils in the innate immune system and links innate and adaptive immunity in vivo. Furthermore, increasing evidence indicates that IL-17 and IL-17-producing cells are involved in the pathogenesis of various diseases such as allergies, autoimmune diseases, allograft transplantation and even malignancy. They may also play protective roles in host defense against infectious diseases and promote induction of cytotoxic T lymphocyte (CTL) responses against cancer. Targeting of the IL-17 axis is under investigation for the treatment of inflammatory disorders.     

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。     

Th17 cells and their associated cytokines in liver diseases

T helper 17 (Th17) cells are a newly identified subset of T helper cells that play important roles in host defense against extracellular bacteria as well as in the pathogenesis of autoimmune disease. The functions of Th17 cells are mediated via the production of several cytokines including interleukin (IL)-17 and IL-22. Recent studies show that the frequency of IL-17⁺ cells is significantly elevated in a variety of chronic liver diseases including alcoholic liver disease, viral hepatitis and hepatocellular carcinoma. IL-17 receptor is expressed virtually on all types of liver cells, while IL-22 receptor expression is restricted to epithelial cells including hepatocytes in the liver. IL-17 seems to play an important role in inducing liver inflammation via stimulating multiple types of liver nonparenchymal cells to produce proinflammatory cytokines and chemokines, while IL-22 appears to be an important factor in promoting hepatocyte survival and proliferation.     

Th17 Cytokines in Inflammatory Bowel Diseases: Discerning the Good from the Bad

T helper (Th) 17 cells are a branch of the CD4+ T cell compartment involved in host protection against bacterial and fungal infections as well as in orchestration of chronic inflammation and autoimmunity in many organs. Th17 cells produce interleukin (IL)-17A and variable amounts of IL-17F, IL-21, IL-22 and IL-26, under the regulation of retinoic-acid-related orphan receptors (ROR)-γt and ROR-α. Accumulating evidence supports the involvement of Th17 cells in the tissue-damaging immune response occurring in patients with Crohn's disease and patients with ulcerative colitis, the two major forms of inflammatory bowel disease (IBD) in human beings. However in the gut, Th17 cells can also have tissue-protective effects, mostly depending on their ability to enhance epithelial barrier function and counter-regulatory mechanisms. In this article, we summarize the available data on the dual role of Th17 cells in gut homeostasis and inflammation and discuss whether and how Th17 cytokine blockers can enter into the therapeutic armamentarium of IBD.     

Th22细胞在炎症免疫性疾病中作用的研究进展

Th22细胞是最近发现的CD4+T细胞功能亚群,表达CCR6、CCR4和CCR10,且分泌IL-22和TNF-α,不分泌IFN-γ、IL-4、IL-17,是独立于Th1、Th2和Th17的细胞亚群。Th22细胞主要参与皮肤的自稳调节和病理状态,可以调控皮肤的固有免疫反应、防御功能及表皮损伤后的修复功能,在炎症性皮肤病的病理生理机制中发挥重要作用。此外,Th22细胞也参与了炎症性肠病、类风湿关节炎、肝炎、试验性自身免疫性心肌炎等炎症免疫性疾病的病理过程。本文对Th22细胞其细胞因子IL-22在炎症免疫性疾病中作用的研究进展做一综述。     

Regulation and pro-inflammatory function of interleukin-17 family cytokines

Summary: The interleukin-17 (IL-17) family consists of six cytokines in mammals. Among them, IL-17 and IL-17F are expressed by a novel subset of CD4⁺ helper T cells and play critical function in inflammation and autoimmunity. IL-17E, also called IL-25, has been associated with allergic responses. Here, I summarize recent work by my laboratory as well as other investigators in understanding the regulation and function of these three cytokines. From these studies, IL-17 family cytokines may serve as novel targets for pharmaceutical intervention of immune and inflammatory diseases.     

Th17 cytokines and mucosal immunity

Summary: The T-helper 17 (Th17) lineage is a recently described subset of memory T cells that is characterized by its CD4⁺ status and its ability to make a constellation of cytokines including interleukin-17A (IL-17A), IL-17F, IL-22, and, in humans, IL-26. Although most extensively described in the autoimmunity literature, there is growing evidence that the Th17 lineage plays a significant role in mediating host mucosal immunity to a number of pulmonary pathogens. This review highlights our current understanding of the role of the Th17 lineage and Th17 cytokines in mediating mucosal immunity to both pulmonary and gastrointestinal pathogens. While we have the strongest evidence that the Th17 lineage is centrally involved in mediating the host response to Gram-negative extracellular pulmonary pathogens, this literature is rapidly evolving and demonstrates a central role for Th17 cytokines both in primary infection and in recall responses seen in vaccine studies. In this review, we summarize the current state of this literature and present possible applications of Th17-targeted immunotherapy in the treatment and prevention of infection.     

IL-33: biological properties,functions, and roles in airway disease

Interleukin (IL)-33 is a key cytokine involved in type 2 immunity and allergic airway diseases. Abundantly expressed in lung epithelial cells, IL-33 plays critical roles in both innate and adaptive immune responses in mucosal organs. In innate immunity, IL-33 and group 2 innate lymphoid cells (ILC2s) provide an essential axis for rapid immune responses and tissue homeostasis. In adaptive immunity, IL-33 interacts with dendritic cells, Th2 cells, follicular T cells, and regulatory T cells, where IL-33 influences the development of chronic airway inflammation and tissue remodeling. The clinical findings that both the IL-33 and ILC2 levels are elevated in patients with allergic airway diseases suggest that IL-33 plays an important role in the pathogenesis of these diseases. IL-33 and ILC2 may also serve as biomarkers for disease classification and to monitor the progression of diseases. In this article, we reviewed the current knowledge of the biology of IL-33 and discussed the roles of the IL-33 in regulating airway immune responses and allergic airway diseases.     

The biological functions of T helper 17 cell effector cytokines in inflammation

T helper 17 (Th17) cells belong to a recently identified T helper subset, in addition to the traditional Th1 and Th2 subsets. These cells are characterized as preferential producers of interleukin-17A (IL-17A), IL-17F, IL-21, and IL-22. Th17 cells and their effector cytokines mediate host defensive mechanisms to various infections, especially extracellular bacteria infections, and are involved in the pathogenesis of many autoimmune diseases. The receptors for IL-17 and IL-22 are broadly expressed on various epithelial tissues. The effector cytokines of Th17 cells, therefore, mediate the crucial crosstalk between immune system and tissues, and play indispensable roles in tissue immunity.     

The link between IL-23 and Th17 cell-mediated immune pathologies

IL-23--produced by dendritic cells--and Th17 cells have both been identified as major factors involved in autoimmune inflammation, yet their relationship with each other remains controversial. This review aims to describe the initial discovery of Th17 cells, their subsequent characterization as a unique T helper subset in mouse and man, as well as the mechanisms involved in regulating these cells. Finally, the roles of IL-23 in inflammatory diseases in relation to Th17 function will be discussed.     

Activation of Peripheral Th17 Lymphocytes in Patients with Asthma

A recently identified interleukin (IL)-17-producing T-helper (Th) lymphocyte subset, which comprises Th17 cells producing hallmark cytokines IL-17A, IL-17F and IL-22, is involved in chronic inflammatory diseases. Elevated gene and protein expressions of IL-17 are manifested in allergic asthma. We further characterized the activation of Th17 cells in asthmatic patients. Peripheral blood mononuclear cells (PBMC) were purified from 31 asthmatic patients and 20 sex- and age-matched control subjects. The number of IL-17A secreting cells in peripheral blood was enumerated by enzyme-linked immunosorbent spot assay. Cell surface expression of Th17-related chemokine receptor CCR6, and plasma level of IL-17A, IL-17F and IL-22, and ex vivo production of IL-17A and IL-22 were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. The number of peripheral Th17 lymphocytes, expression of CCR6 on Th cells, and ex vivo IL-23, anti-CD3 and anti-CD28 induced production of IL-22 by PBMC were significantly elevated in asthmatic patients compared with control subjects (all p < 0.01). This clinical study further confirmed increased number of peripheral Th17 lymphocytes and cell surface expression of CCR6 receptors on Th cells in asthmatic patients. Pro-inflammatory cytokine IL-23 can exacerbate disease severity by activating pathogenic Th17 lymphocytes to release downstream inflammatory cytokine IL-22 in asthma.     

IL-23/IL-17轴在银屑病免疫发病机制中的作用

银屑病是一种以T淋巴细胞异常活化和浸润为主要特征的慢性炎性反应皮肤病。Th17细胞及IL-23/IL-17轴在银屑病的发病机制中可能处于关键地位,并成为新的治疗靶标。IL-23诱导Th17细胞分化增殖,分化成熟的Th17可以分泌IL-17、IL-21、IL-22等多种细胞因子,Th17类细胞因子在银屑病等多种自身免疫疾病和炎性疾病中起重要作用。     

IL-21在Th17细胞炎症反应中的作用

Th17细胞是新近发现的T淋巴细胞亚群.作为不同于Th1、Th2的细胞亚群,已经被证实在自身免疫病、感染、炎症等疾病中发挥重要作用.IL-21作为Th17细胞的自分泌调节因子,在Th17细胞功能的维持、抑制Th1、调节性T细胞(Treg)分化等方面发挥关键作用.Th17细胞能够自分泌产生IL-21,从而促进自身分化过程...     

Interleukin-23: as a drug target for autoimmune inflammatory diseases

Interleukin-23 (IL-23) is a member of the IL-12 family of cytokines with pro-inflammatory properties. Its ability to potently enhance the expansion of T helper type 17 (Th17) cells indicates the responsibility for many of the inflammatory autoimmune responses. Emerging data demonstrate that IL-23 is a key participant in central regulation of the cellular mechanisms involved in inflammation. Both IL-23 and IL-17 form a new axis through Th17 cells, which has evolved in response to human diseases associated with immunoactivation and immunopathogeny, including bacterial or viral infections and chronic inflammation. Targeting of IL-23 or the IL-23 receptor or IL-23 axis is a potential therapeutic approach for autoimmune diseases including psoriasis, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. The current review focuses on the immunobiology of IL-23 and summarizes the most recent findings on the role of IL-23 in the pre-clinical and ongoing clinical studies.