IL-17 cytokine/receptor families: emerging targets for the modulation of inflammatory responses

IL-17 was identified a decade ago as a pro-inflammatory cytokine produced by activated T cells that stimulates the secretion of other cytokines from various non-lymphoid cells by acting through a unique cell surface receptor, IL17R. Evidence that IL-17 may contribute to several immune-mediated diseases, such as rheumatoid arthritis and airway inflammation, prompted much interest in this cytokine. Recently, the large-scale analysis of expressed sequence tags (EST) led to the discovery of novel genes dispersed in the human genome that encode at least five additional cytokines structurally related to IL-17. Screening of EST databases also uncovered at least four novel genes encoding Type I transmembrane proteins with significant homology to IL-17R, thereby forming a family of receptors whose cognate ligands are likely to belong to the IL-17 cytokine family. Initial characterisation of some of these cytokines and one IL-17R homologue demonstrated their involvement in regulating inflammatory responses in a manner similar to, albeit distinct from, that of prototypic IL-17. The IL-17 cytokine/receptor families appear therefore to represent unique signalling systems within the cytokine network that might offer innovative approaches to manipulate immune and inflammatory responses. The prospect of targeting these molecules for therapeutic purposes has generated a substantial volume of patent literature that will be reviewed here.     

IL-19, IL-20 and IL-24: potential therapeutic targets for autoimmune diseases

IL-19, IL-20 and IL-24 are members of the IL-10 family of cytokines, the human IL-19, IL-20 and IL-24 genes are all located on the q32 region of chromosome 1, and the three cytokines also share a common receptor IL-20R1/IL-20R2 heterodimer. These cytokines due to the similarity and shared receptor usage, are quite overlapping in function. Recently, the available evidence has indicated that interaction of these cytokines with their receptors might exhibit pro-inflammatory effects on autoimmune diseases, particularly psoriasis and rheumatoid arthritis. Since an imbalance between anti- and pro-inflammatory cytokines contribute to the development of autoimune diseases, these cytokines may be implicated in the pathogenesis of autoimmunity. In this paper, we concisely discuss the biological features of IL-19, IL-20 and IL-24, and focus on their potential roles in autoimmune diseases. Hopefully the information obtained will lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for autoimmune diseases.     

Interleukin-2 family cytokines: potential for therapeutic immmunoregulation

IL-2 is a four-helix bundle cytokine that was initially identified as a T cell growth factor more than two decades ago. Since then, extensive investigations have led to the discovery of additional cytokines, including IL-4, IL-7, IL-9, IL-15 and IL-21, which display many similarities with IL-2 and have been grouped, together with the latter, as a distinct IL-2 cytokine family. These cytokines are all globular proteins that contain two sets of short-chain α-helical domains. They all play major roles in promoting and maintaining T lymphocyte populations, albeit in non-redundant and often complementary manners, whilst acting on other cell lineages as well. Most remarkably, their cell surface receptor complexes, which consist of two or three subunits, including a cytokine-specific private subunit, all use a shared subunit called the common γ chain (γc). This common subunit was shown to be mutated in X-linked severe combined immunodeficiency and to uniquely recruit the Janus kinase, Jak3. Accordingly, IL-2 family cytokines all utilise Jak3 in their mechanisms of intracellular signalling, together with more ubiquitous kinases. Owing to their prominent roles in lymphocyte development and homeostasis, IL-2 family cytokines have been the focus of much interest for the purpose of therapeutic applications. They may provide tools to bolster immune responses for the treatment of neoplastic diseases, viral infections and immunodeficiencies. Conversely, their blockade may help achieve immunosuppression for the treatment of transplant rejection, as well as inflammatory, autoimmune and allergic disorders. Here, the patent literature of the past four years pertaining to these important cytokines will be reviewed in the context of the current understanding of their biological significance.     

The role of cytokines in rheumatoid arthritis: inhibition of cytokines in therapeutic trials

Although the precise role(s) of cytokines in rheumatoid arthritis (RA) is still being investigated, increasing evidence implicates interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha as contributing importantly to the inflammatory, and perhaps destructive manifestations of the disease. Several natural endogenous inhibitors of IL-1 and TNF-alpha have been identified; these include interleukin-1 receptor antagonist (IL-1RA), soluble IL-1 receptors (sIL-1R), and soluble TNF-alpha receptors (sTNFR). Although increased levels of these natural inhibitors occur in sera and at sites of inflammation in patients with RA, there is an excess of IL-1 and TNF-alpha in comparison with their respective natural inhibitors that favors the proinflammatory actions of these cytokines. Therefore, a potential therapeutic maneuver for treating RA is to neutralize these implicated cytokines. Biologic agents aimed at inhibiting the proinflammatory activities of these cytokines thus far have included cytokine receptor antagonists, anticytokine monoclonal antibodies (MAbs), fusion molecules consisting of soluble cytokine receptors combined with human fusion protein (Fc) constructs or polyethylene glycol (PEG), and counterregulatory cytokines which oppose actions of the target cytokine (e.g., IL-10, IL-4 and IL-11). Inhibitors of the processing and synthesis of IL-1 and TNF-alpha are also under development. The encouraging clinical results observed in short-term trials of TNF-alpha and IL-1 inhibitors using sTNFR:Fc fusion proteins, anti-TNF MAbs and recombinant human IL-1 receptor antagonist (rhuIL-1RA) clearly warrant further studies not only to determine whether these agents are capable of modifying the destructive component of the disease, but also whether they can be administered safely for long periods. Pivotal trials with these agents have potential therapeutic applicability to other autoimmune and inflammatory disorders.     

IL-19, IL-20 and IL-24: potential therapeutic targets for autoimmune diseases

IL-19, IL-20 and IL-24 are members of the IL-10 family of cytokines, the human IL-19, IL-20 and IL-24 genes are all located on the q32 region of chromosome 1, and the three cytokines also share a common receptor IL-20R1/IL-20R2 heterodimer. These cytokines due to the similarity and shared receptor usage, are quite overlapping in function. Recently, the available evidence has indicated that interaction of these cytokines with their receptors might exhibit pro-inflammatory effects on autoimmune diseases, particularly psoriasis and rheumatoid arthritis. Since an imbalance between anti- and pro-inflammatory cytokines contribute to the development of autoimune diseases, these cytokines may be implicated in the pathogenesis of autoimmunity. In this paper, we concisely discuss the biological features of IL-19, IL-20 and IL-24, and focus on their potential roles in autoimmune diseases. Hopefully the information obtained will lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for autoimmune diseases.     

Glycoprotein 130 cytokine signal as a therapeutic target against cardiovascular diseases

Postnatal cardiomyocytes have only limited capacity of proliferation. Therefore, the myocardium is intrinsically equipped with cardioprotective machineries and protects itself from pathological stresses. One of the most important cardioprotective systems is the signal network of autocrine/paracrine factors, including neurohumoral factors, growth factors, and cytokines. In this review, we focus on the roles of interleukin-6 (IL-6) family cytokines, also known as glycoprotein 130 (gp130) cytokines, in cardioprotection. These cytokines make a complex with their specific cytokine receptor α-subunits. The cytokine-receptor α-subunit complex binds to gp130, a common receptor of the IL-6 family, followed by the activation of JAK/STAT, ERK, and PI3 kinase/Akt pathways. In cardiomyocytes, signals through gp130 promote cell survival and angiogenesis through the JAK/STAT pathway. Activation of gp130 in cardiac stem cells induces their endothelial transdifferentiation, leading to neovascularization. Recently, accumulating evidence has revealed that altered JAK/STAT activity is associated with heart failure, suggesting that the JAK/STAT pathway is a therapeutic target against cardiovascular diseases. Interestingly, activation of the JAK/STAT pathway with interleukin-11 (IL-11) exhibits preconditioning effects in ischemia/reperfusion model. Moreover, IL-11 treatment after coronary ligation prevents cardiac remodeling through the JAK/STAT pathway. Since IL-11 is used for patients with thrombocytopenia, we propose that IL-11 is a candidate cytokine clinically available for cardioprotection therapy.     

Full house: 12 receptors for 27 cytokines

With the sequencing of the human genome nearing completion, it appears that all members of the class II cytokine receptor family (CRF2) have been identified and partially characterized. The entire family is composed of exactly one dozen members. Eleven of them combine as various heterodimers to transduce signals across the cellular membrane for 27 cytokines divided into four structurally related groups: 6 cytokines of the IL-10 family, 17 type I IFNs, 1 type II IFN and 3 IFN-lambdas. The last CRF2 member is the soluble receptor which can neutralize the action of one of the cytokines of the IL-10 family, IL-22. Although the extracellular domains of all CRF2 proteins reveal primary and structural homology, their intracellular domains are very dissimilar. Nevertheless, signaling events induced through various combinations of CRF2 subunits partially overlap, leading to the induction of overlapping but cytokine-specific biological activities.     

ICE/Caspase-1 inhibitors as novel anti-inflammatory drugs

In recent years, several strategies that selectively inhibit pro-inflammatory cytokines, have yielded effective protein-based therapies for inflammatory disorders, validating the therapeutic hypothesis that intervention in cytokine signalling can provide clinical benefit. However, these protein-based products must be administered by injection, a constraint associated with inconvenience, adverse effects and expense for patients, caregivers and insurers. Besides interfering with the effects of cytokines such as TNF-α or IL-1β that have already been produced, inhibition of pro-inflammatory cytokine production or signalling with low-molecular weight orally-active drugs would combine the convenience of conventional pharmaceuticals with the focused efficacy of the protein therapies. Reducing IL-1β and IL-18 production by inhibition of IL-1β converting enzyme (ICE, caspase-1) is one promising strategy because of the key roles of these cytokines in many inflammatory diseases. Pralnacasan, the first orally available, potent and selective ICE inhibitor to enter clinical trials, is currently under investigation in rheumatoid arthritis.     

Effects of montelukast, a cysteinyl-leukotriene type 1 receptor antagonist, on the pathogenesis of bleomycin-induced pulmonary fibrosis in mice

Cysteinyl-leukotrienes are potent mediators involved in various inflammatory diseases and lung disorders such as asthma. However, their precise role in the pathogenesis of pulmonary fibrosis is unknown. In the present study, we investigated the effect of montelukast, a cysteinyl-leukotriene type 1 receptor antagonist, on bleomycin-induced pulmonary fibrosis in mice. Montelukast (10 mg/kg/day) was orally administered to the bleomycin-induced pulmonary fibrosis mice for 3 days before and 14 days after intratracheal instillation of bleomycin. We evaluated the effects of montelukast on the development of pulmonary fibrosis in these mice and investigated the expression of various cytokines and two cysteinyl-leukotriene receptors. Treatment with montelukast significantly attenuated the increased fibrotic area and hydroxyproline content in the fibrotic lungs of bleomycin-instilled mice. Montelukast treatment also decreased mRNA levels of IL-6, IL-10, IL-13, and TGF-β1, all of which were elevated in fibrotic lungs. In fibrotic lungs, TNF-α and IL-1β mRNA levels were increased and IFN-γ mRNA levels were decreased, but montelukast did not affect these mRNA levels. Furthermore, cysteinyl-leukotriene type 1 receptor mRNA levels were increased, whereas cysteinyl-leukotriene type 2 receptor mRNA levels were decreased in fibrotic lungs. Montelukast treatment induced the recovery of cysteinyl-leukotriene type 2 receptor mRNA levels to normal control levels but did not change cysteinyl-leukotriene type 1 receptor mRNA levels. These results suggest that montelukast exhibits its beneficial effects by inhibiting the overexpression of IL-6, IL-10, IL-13, and TGF-β1 and by modulating the homeostatic balance between the cysteinyl-leukotriene type 1 and type 2 receptors.     

The role of IL-17 and family members in the pathogenesis of arthritis

Interleukin (IL)-17 is a T-cell-derived cytokine that is expressed in the synovium of patients with arthritis. IL-17 contributes to the pathogenesis of arthritis, and demonstrates additive or even synergistic effects with IL-1 and tumor necrosis factor (TNF) in inducing joint pathology. It is a potent inducer of receptor activator of nuclear factor-kappa B. IL-17 also has the capacity to induce joint destruction in an IL-1-independent manner. The discovery of IL-17 family members may further elucidate the role of this cytokine family in arthritis pathology, with IL-17F a promising candidate. Anti-IL-17 cytokine therapy may be an interesting new antirheumatic approach to the prevention of joint destruction, in addition to anti-TNF and anti-IL-1 therapy.     

Why chemokines are cytokines while their receptors are not cytokine ones?

Chemotactic cytokines, or chemokines, are a large family of small proteins, which are distinguished from other cytokines in that they are the only members of the cytokine family that act on G-protein coupled receptor superfamily. This minireview tries to answer the title question by structure/function analysis of chemokines, cytokines, and their receptors. We also consider secretion of chemokines/cytokines in health and disease as well as expression of their receptors both in immune system and brain. Our analysis suggests that cytokine and chemokine receptors may share similar architecture with Toll-like receptors. Such similarity hints a similar way of their functioning as molecular switches controlled by protein-protein interactions. Hence, we pay attention to the related receptor-receptor associations and evolutionary conserved leucine-rich motifs.     

Interleukin-18: a pro-inflammatory cytokine that plays an important role in acute pancreatitis

A large body of clinical and experimental evidence suggests that cytokines play a key role in the pathogenesis of local and systemic complications of acute pancreatitis. IL-18 is a pro-inflammatory cytokine that plays a key role in many human diseases, including acute pancreatitis. This review focuses on the present understanding in IL-18 and its potential role in acute pancreatitis. IL-18 levels reflect the severity of acute pancreatitis and display a significant negative correlation with the concentrations of antioxidative damage factors, serum selenium and glutathione peroxidases (GPx). The relationship between IL-18 and other pro-inflammatory cytokines shows that IL-18 is one of the key mediators of inflammation in the pathogenesis of acute pancreatitis. Elevation of serum IL-18 levels may mediate acute pancreatitis associated liver injury. The use of IL-18 antagonists as direct routes to block IL-18 activity and P2X₇ receptor antagonists and interleukin-1β-converting enzyme (ICE) inhibitors as indirect routes to block IL-18 activity suggest that specific therapeutic inhibition of IL-18 is a promising therapeutic approach for acute pancreatitis.     

炎性细胞因子抑制剂高通量筛选方法的研究

目的　建立能够同时作用于炎症相关细胞因子的药物筛选模型 ,探讨多指标综合筛选方法 ,为发现新的抗炎先导化合物提供快速有效的方法。方法　采用人血白细胞为研究对象 ,以脂多糖 (LPS)刺激诱发炎性因子生成 ,探讨最佳刺激条件 ,建立多指标检测方法和综合评价药物作用的分析方法。观察不同浓度脂多糖 (0 5～ 5 0mg·L-1)及不同作用时间 (0～ 4h)炎性因子IL 1、IL 8、TNF α生成水平的变化。同时观察 5 LO抑制剂NDGA (nordihydroguaiareticacid)和COX 2抑制剂Diclofenac在多种细胞因子筛选模型上的应用。结果　脂多糖可浓度依赖性 (0 5～ 5 0mg·L-1)和时间依赖性 (0～ 4h)地刺激人血白细胞释放IL 1、IL 8和TNF α。脂多糖 (终浓度 5mg·L-1)刺激人血白细胞 4h有较高释放 ,与对照组比差异明显。NDGA和Diclofenac在脂多糖刺激 4h对炎性因子释放有显著抑制作用。结论　这种脂多糖体外刺激人血白细胞释放多种炎性因子的筛选模型可用于高通量大规模筛选具有抗炎作用的先导化合物 ,提高了筛选效率     

Vascular effects of glycoprotein130 ligands--part II: biomarkers and therapeutic targets

Glycoprotein130 (gp130) ligands are defined by the use of the common receptor subunit gp130 and comprise interleukin (IL)-6, oncostatin M (OSM), IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF), IL-27 and neuropoietin (NP). In part I of this review we addressed the pathophysiological functions of gp130 ligands with respect to the vascular wall. In part II of this review on the vascular effects of gp130 ligands we will discuss data about possible use of these molecules as biomarkers to predict development or progression of cardiovascular diseases. Furthermore, the possibility to modulate circulating levels of gp130 ligands or their tissue expression by specific antibodies, soluble gp130 protein, renin-angiotensin-aldosterone system (RASS) inhibitors, statins, agonists of peroxisome proliferator-activated receptors (PPAR), hormone replacement therapy, nonsteroidal anti-inflammatory drugs (NSAID) or lifestyle modulating strategies are presented. Recent knowledge about the application of recombinant cytokines from the gp130 cytokine family as therapeutic agents in obesity or atherosclerosis is also summarized. Thus the purpose of this review is to cover a possible usefulness of gp130 ligands as biomarkers and targets for therapy in cardiovascular pathologies.     

Interleukin-2 as immunotherapeutic in the autoimmune diseases

Interleukins, also called cytokines are secretory proteins that bind to specific receptors and play a critical role in the intercellular communication between cells of the immune system. Cytokines are mainly produced by T lymphocytes, macrophages and eosinophils. Among its functions are the activation and suppression of immune system responses, induction of cell division and regulation of memory cells. Interleukin 2 (IL-2) is a secretory monomeric glycoprotein composed of 149 amino acids containing a signal peptide of 20 amino acids. It is classified as a member of the type I cytokines family. IL-2 binds to its receptor (IL-2R receptor) with high affinity and its signaling function promotes the activation of various subtypes of lymphocytes during the process of cell differentiation to generate an immune or homeostatic response. The specificity of IL-2 depends on its binding to low, medium or high-affinity receptors. Interleukin 2 acts as a regulator of the proliferation of CD4+ and CD8+ T cells. There is a relationship between IL-2 and autoimmune diseases due to its influence in the differentiation of T helper cells, which in turn directly influence immunological response processes. Therefore, IL-2 is a key element in the control and treatment of those diseases. In recent years, many therapeutic agents based on biomolecules and recombinant chimeric proteins have been developed to treat different autoimmune diseases. In this review, we focus on the use of interleukin 2 as a versatile therapeutic agent, alone or associated with other molecules to increase the efficiency of autoimmune disease treatment.     

Chemokines,chemokine receptors and small-molecule antagonists: recent developments

The physiological roles of chemokine receptors have expanded beyond host defense and now represent important targets for intervention in several disease indications. Chemokine receptors have joined the ranks of other members of the G-protein-coupled receptor (GPCR) family in therapeutic potential as small-molecule chemokine receptor antagonists move from discovery to the clinic. Chemokine receptors belong to the rhodopsin family of GPCRs and, as such, are expected to be closely related in structure to other Class A members. In this review, we summarize information that is pertinent to chemokine receptors as therapeutic targets, the status of low molecular weight antagonists in clinical development, molecular modeling of receptor-small-molecule interactions, and the challenges that face drug discovery and development programs.     

Targeting the IL-1 family members in skin inflammation

The IL-1 family of cytokines comprises 11 proteins with pro- and anti-inflammatory functions that are mediated through an equally large group of receptors and coreceptors. Dysregulation of the IL-1 system may lead to diseases such as psoriasis, atopic dermatitis, contact dermatitis and cutaneous lupus erythematosus. These inflammatory skin conditions greatly affect quality of life and life expectancy, and their frequencies are increasing. However, treatment options for these diseases are unsatisfactory. This review briefly summarizes new findings, reported in the past 2 years, implicating IL-1 family members in skin inflammation. Furthermore, how the biological activities of the IL-1 family members may be inhibited is discussed.