IL-23: changing the verdict on IL-12 function in inflammation and autoimmunity

IL-12 and IL-23 are molecules mainly produced by activated accessory and antigen-presenting cells. The tools for studying the biology of IL-12 in man and laboratory rodents have greatly advanced our appreciation of the central role of this molecule in cell-mediated immunity and inflammation. In particular, IL-12 is thought to be the prime-regulator of TH1 development. Targeting what was thought to be IL-12 function in vivo, resulted in drastic amelioration of inflammation and autoimmunity firmly linking TH1 polarisation to autoimmune development. Upon discovery of IL-23 and the fact that the large subunit of IL-23 is shared by IL-12, the research community only begins to grasp that the features attributed to IL-12 and TH1 development in inflammation are, in fact, dependent on IL-23 and not on IL-12. Hence, the perception of IL-12 biology is, to a large extent, based on a mistaken identity. In this review, the authors provide an overview of their current understanding of IL-12 and IL-23 biology in inflammation and autoimmunity, and how this viewpoint has been readjusted over the past 15 years.     

Retinoid-related orphan receptor γt is a potential therapeutic target for controlling inflammatory autoimmunity

Retinoid-related orphan receptor gamma t (RORγt) is a member of the nuclear receptor family that is specifically expressed in T cell compartments. RORγt regulates the development of T cells in the thymus and the differentiation of effector T cells in the periphery. During T cell development, RORγt enhances CD4⁺CD8⁺ double positive thymocyte survival by upregulating Bcl-x_L. In the periphery, RORγt regulates IL-17 production and dictates the differentiation of pro-inflammatory T helper 17 (T_H17) cells that play a critical role in inflammatory conditions and autoimmunity. RORγt-deficient T cells fail to differentiate into T_H17 cells, whereas forced expression of RORγt is sufficient to induce naive T cells to produce IL-17. T_H17 cells are believed to be the major inflammatory cells in autoimmune diseases. Therefore, inhibition of RORγt activity could potentially alleviate the symptoms associated with the T_H17-dependent inflammatory autoimmune diseases. RORγt is thus potentially an excellent therapeutic target for the intervention of inflammatory autoimmunity.     

Aptamers against interleukin-12-related cytokines as novel therapeutics in autoimmune diseases

Endogenous interleukin (IL)-12 plays a pivotal role in promoting cell-mediated immunity against intracellular pathogens. Uncontrolled cell-mediated immune responses, however, may lead to chronic inflammation and autoimmune disease. Unfortunately, treatment of either infection or autoimmunity with immunomodulating drugs always incur the danger of favouring the other form of disease. The recent discovery of the dimeric IL-12-related cytokine IL-23 adds to our understanding of the fine tuning of cellular immunity. Only recently, studies revealed IL-23, and not IL-12, to be the decisive factor in this immune deviation and a variety of autoimmune disorders have now been shown to be strikingly dependent on IL-23. Therefore, targeting of IL-23-mediated, rather than IL-12-dependent, mechanisms represent a promising therapeutic approach for autoimmune diseases. The invention of aptamers that are capable of neutralising IL-23 and/or IL-12 and their potential use as autoimmune disease therapeutics will be discussed.     

IL-23 in Infections,Inflammation, Autoimmunity and Cancer: Possible Role in HIV-1 and AIDS

The growing family of interleukin (IL)-12-like cytokines produced by activated macrophages and dendritic cells became the important players in the control of infections, development of inflammation, autoimmunity and cancer. However, the role of one of them—heterodimer IL-23, which consists of IL12p40 and the unique p19 subunit in HIV-1 infection pathogenesis and progression to AIDS, represent special interest. We overviewed findings of IL-23 involvement in control of peripheral bacterial pathogens and opportunistic infection, central nervous system (CNS) viral infections and autoimmune disorders, and tumorogenesis, which potentially could be applicable to HIV-1 and AIDS.     

Targeting IL-1 in Sjögren's syndrome

Introduction: IL-1 plays key roles in the biological functions of various cells. In particular, many roles of IL-1 in the immune system have been discovered by numerous studies. This review focuses on the association of IL-1 with the pathogenesis of autoimmunity.

Areas covered: An overview of the biological functions of the IL-1 family and the IL-1 receptors (IL-1Rs), including the maintenance of systemic or local homeostasis, and the signaling pathway through IL-1/IL-1R in various immune systems are described. Several functions of IL-1 in the pathogenesis of Sjögren's syndrome (SS) have been demonstrated with a focus on the immune responses and target tissues in SS. In addition to the role of IL-1 in the immune responses in SS, the function of IL-1 in ocular mucosa lesions in SS has been described. Lastly, there is an overview of possible therapeutic strategies for IL-1 inhibition in SS.

Expert opinion: IL-1 plays critical roles in the onset and development of SS by controlling systemic or local immune responses and maintaining the survival and mucosal defense of target epithelial cells. The inhibition of the pathogenic functions of IL-1 may be beneficial for treating SS.     

Anti-IL-4/-13 based therapy in asthma

It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches have identified new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach resulted in the development of biologics targeted at inhibition of IL-4, IL-5 and IL-13. However, early clinical trials with these biologics in patients with asthma were for the most part disappointing even though they were highly effective in animal models of asthma. It is becoming apparent that significant clinical effects with anti-cytokine-based biologic therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of discriminatory biomarkers and genetic profiling may aid identification of such patients with asthma. This review is an update of the evidence demonstrating the effectiveness or otherwise of the targeting of the T_H2 cytokines IL-4 and IL-13 with biologics in patients with asthma.     

Therapeutic potential of IL-27 in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by a diverse array of autoantibody production, complement activation and immune complex deposition, causing tissue and organ damage. Effective medical treatment for SLE is lacking because the etiology and pathogenesis of SLE are incompletely understood. It has been confirmed that cytokine-mediated immunity plays a crucial role in the pathogenesis of various autoimmune diseases including SLE. Recently, IL-27 was identified, which belongs to the IL-12 cytokine family. IL-27 exerts profound anti-inflammatory effects in several experimental autoimmune models. In particular, suppressive effects on T_H17 cells, which are implicated in the pathogenesis of SLE. Moreover, administration of IL-27 or augmentation of IL-27 signaling suppresses some autoimmune diseases, including autoimmune diabetes and murine lupus, suggesting that IL-27 may be therapeutically relevant in SLE. In this article, we discuss the biological features of IL-27 and summarize recent advances on the role of IL-27 in the pathogenesis and treatment of SLE. Even though IL-27 has shown therapeutic potential in SLE, further research, particularly in humans, is needed in order to establish the precise role of IL-27 in SLE.     

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.     

Stimulation of natural killer activity in peripheral blood lymphocytes of healthy donors and melanoma patients in vitro: synergism between interleukin (IL)-12 and IL-15 or IL-12 and IL-2

Interleukin-2 (IL-2) and IL-12 modify the functional status of T- and natural killer (NK) cells by regulating proliferation, cytolytic activity, cytokine induction, and T-cell subset differentiation. These effects are exploited in immunotherapy of cancer patients with IL-2 or IL-12, which, however, is limited by potentially life-threatening side effects. IL-15 shares many of the biological activities of IL-2 and may therefore represent a therapeutic alternative. Here we have compared the ability of these interleukins to stimulate NK activity in peripheral blood lymphocytes (PBLs) isolated from healthy donors (n = 12) as well as from patients (n = 12) suffering from metastatic disease (melanoma). Target (K562) cell lysis was assessed by determining the release of ⁵¹Cr and lactate dehydrogenase (LDH) which gave equivalent results. The NK-resistant DAUDI cell line served as control target. Unstimulated NK activity was significantly lower in PBLs purified from melanoma patients. However, cytolytic activity was readily stimulated by preincubation of PBLs (18 h) with cytokines such that the maximum target cell lysis was comparable to that seen in PBL of healthy donors. Similarly, the potency of IL-2 (EC₅₀ = 20.2±1.3 and 22.0±1.3 u/ml in healthy donors and patients, respectively), IL-12 (EC₅₀ = 11.0±1.1 and 4.3±1.6 u/ml) and IL-15 (EC₅₀ = 0.3±0.1 and 0.2±0.1 u/ml) was comparable. Importantly, if the preincubation was carried out with cytokine concentrations in the EC₅₀ range, the effects of two cytokines (tested in all combinations) were additive. A synergism was evident in PBLs obtained both from healthy donors and melanoma patients if concentration-response curves for IL-12 were determined in the presence of increasing concentrations of IL-2 (enhanced efficacy) or IL-15 (enhanced efficacy and potency). Our observations suggest possible alternatives to the monotherapy with IL-2 (or IL-12) in cancer treatment. Provided that the present findings can be extrapolated to the situation in vivo, the combined administration of IL-12 and IL-15 may be as efficacious as the immunotherapy with IL-2; this approach ought to allow for a marked reduction in cytokine dose and thereby improve the therapeutic index. Received: 9 February 1998 / Accepted: 12 June 1998     

Therapeutic potential of IL-10 and its viral homologues: an update

IL-10, initially identified as a cytokine synthesis inhibiting factor released by Type 2 T-helper (T_H2) cells, is now known to be produced by many cell populations and to play a central role in the regulation of immune and inflammatory responses. Although its principal function is to limit, and ultimately terminate, inflammatory responses by suppressing the activation and effector function of T cells, monocytes and macrophages, IL-10 also affects the growth and/or differentiation of B cells, natural killer cells, cytotoxic and T_H2 cells, mast cells and dendritic cells. Importantly, IL-10 appears to be essential for the development and function of a subset of regulatory T cells prominently involved in the maintenance of peripheral tolerance and the control of immune homeostasis. IL-10 exerts these various effects by binding to a cellular receptor (IL10R) composed of at least two subunits. Furthermore, several viral IL-10 homologues that signal through the same receptor complex display immunosuppressive activities similar to those of the mammalian cytokine. Preclinical studies have suggested that the immunosuppressive activities of IL-10 hold potential for the treatment of inflammatory and autoimmune disorders. Recombinant human IL-10 (ilodecakin, Tenovil^TM, Schering-Plough) has therefore been developed and evaluated by systemic administration in a number of such diseases, including Crohn’s disease, rheumatoid arthritis, psoriasis, chronic hepatitis C and acute pancreatitis. Although the results of these clinical trials have been heterogeneous and disappointing overall, they have provided further insight into the immunobiology of IL-10 and have suggested possible approaches to improve its therapeutic utility. Here, the patent literature associated with IL-10 and its viral homologues is discussed in the light of these recent advances, taking into perspective the experimental evidence that supports future prospects for the therapeutic use of this important class of immunoregulatory cytokines.     

Antagonists of IL-1R: a patent evaluation (WO2012122985)

IL-1 is a master cytokine that plays a pivotal role in local and systemic inflammation and is involved in the host response to both physiological and pathological stimuli. The recent development of biological compounds targeting IL-1 activity in vivo has revealed the contribution of this cytokine to a large number of human inflammatory and autoimmune diseases. Nevertheless, these currently used drugs display some disadvantages that limit their use in several IL-1-driven diseases, urging for the identification of more powerful agents. The present article describes the identification of new small peptides displaying IL-1 inhibitory activity and covered by the patent WO2012122985. The experimental work in support of the patent's claims is also discussed. Specific attention is paid to the comparison with the original compound from which the peptides were originated: the IL-1 receptor antagonist (IL-1RA) protein. The potential advantages brought about by the present invention as well as the limits documented by the experimental results shown in the patent are also discussed.     

Targeting IL-17 in autoimmunity and inflammation

The discovery of two distinct subsets of helper T cells, IFN-γ-producing Th1 cells and IL-4-producing Th2 cells, about three decades ago enabled us to understand the immunopathology of cell-mediated and allergic inflammatory diseases in humans. The observation that T cell-mediated experimental autoimmune diseases can be induced in mice lacking Th1 and Th2 cell responses prompted many immunologists to hypothesize that there might be additional subsets in helper T cell population which mediate autoimmunity in the absence of Th1 and Th2 cells. Consequently, multiple independent research groups identified IL-17-expressing RORγt⁺CD4⁺ T cell population as a distinct subset of helper T cells which promotes autoimmune tissue inflammation. Subsequent studies have revealed that innate immune cells, including γδ T cells, NKT cells and innate lymphoid cells, also produce type 17 cytokines and contribute to tissue inflammation. In this review, we discuss our current understanding on the biology of IL-17 and the therapeutic potential of targeting IL-17 for the treatment of immune disorders in humans.     

Targeting cytokines of the interleukin-12 family in autoimmunity

In the past, autoimmunity was thought to be mediated by antibodies and immune complexes. It has now become clear that many autoimmune diseases, especially tissue specific, are T cell-mediated, or at least T cell-dependent. The pathogenesis of cell-mediated autoimmune diseases, including multiple sclerosis, uveitis, diabetes, arthritis, and others, is now thought to be, in a large measure, driven by interferon-gamma-producing, antigen-specific T cells, which are polarized toward the T helper type 1 (Th1) phenotype. Interleukin (IL)-12 and the more recently discovered IL-23 and IL-27 constitute a unique family of structurally-related, heterodimeric cytokines, which regulate cell-mediated immune responses and Th1-type inflammatory reactions. Thus, these cytokines may have a central role in the development and progression of cell-mediated autoimmune diseases. Therefore, pharmacologically targeting cytokines of the IL-12 family would be useful in the modulation of several autoimmune diseases. This review summarizes the recent findings concerning IL-12 family cytokine-mediated autoreactive inflammatory responses, and also describes some possible therapeutic interventions, including medicinal compounds at mitigating autoimmune inflammation.     

The multikinase inhibitor Sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE2 in murine macrophages

Classical activating stimuli like LPS drive macrophages to secrete a battery of inflammatory cytokines, including interleukin (IL)-12/23, through Toll-like receptor (TLR) signaling. TLR activation in the presence of some factors, including prostaglandin E₂ (PGE₂), promotes an anti-inflammatory cytokine profile, with production of IL-10 and suppression of IL-12/23 secretion. Extracellular signal-regulated kinase (ERK) is a key regulator of macrophage IL-10 production. Since it inhibits ERK, we investigated the impact of Sorafenib on the cytokine profile of macrophages. In the presence of PGE₂, Sorafenib restored the secretion of IL-12 and suppressed IL-10 production. Moreover, IL-12 secretion was enhanced by Sorafenib under conditions of TLR ligation alone. Furthermore, the impact of tumor culture supernatants, cholera toxin, and cAMP analogs (which suppress IL-12 secretion), was reversed by Sorafenib. Sorafenib inhibited the activation of the MAP kinase p38 and its downstream target mitogen and stress activated protein kinase (MSK), and partially inhibited protein kinase B (AKT) and its subsequent inactivation of the downstream target glycogen synthase kinase 3-β (GSK3-β). Interference with these pathways, which are pivotal in determining the balance of inflammatory versus anti-inflammatory cytokines, provides a potential mechanism by which Sorafenib can modulate the macrophage cytokine phenotype. These data raise the possibility that the use of Sorafenib as cancer therapy could potentially reverse the immunosuppressive cytokine profile of tumor-associated macrophages, rendering the tumor microenvironment more conducive to an anti-tumor immune response.     

CCR6 as a possible therapeutic target in psoriasis

Importance of the field: Psoriasis is a common, chronic autoimmune disease of the skin. Despite a number of effective treatments, new therapies are needed with enhanced efficacy, safety and convenience. Chemokine receptors are GPCRs that control leukocyte trafficking, and like other GPCRs, are good potential drug targets. The chemokine receptor CCR6 is expressed on the T_H17 subset of CD4⁺ T cells, which produces IL-17A/F, IL-22, TNF-α and other cytokines, and which has been implicated in the pathogenesis of psoriasis. CCR6 and its ligand, CCL20/MIP-3α, are highly expressed in psoriatic skin and CCR6 is necessary for the pathology induced in a mouse model of psoriasis-like inflammation.

Areas covered in this review: This review summarizes the evidence for the importance of the IL-23/T_H17 axis, and in particular CCR6 and CCL20 in psoriasis, dating from 2000 to the present, and discusses the possibility of inhibiting CCR6 as a treatment for the disease.

What the reader will gain: The review informs the reader of the current thinking on the mechanisms of inflammation in psoriasis and the possible roles for CCR6 (and CCL20) in disease pathogenesis.

Take home message: We conclude that CCR6 should be investigated as a potential therapeutic target in psoriasis.     

Targeting IL-6 in the treatment of inflammatory and autoimmune diseases

Background: IL-6, a glycoprotein composed of 212 amino acids in human, has a wide range of biological activity, including regulation of immune response, support of hematopoiesis, generation of acute-phase reactions and induction of inflammation and oncogenesis. Several approaches including inhibition of IL-6 production, blockage of IL-6 binding to IL-6 receptor, blockage of IL-6/IL-6R complex binding to gp 130 and blockage of the intracytoplasmic signal through gp 130 can be used to block IL-6 functions. Objective: To summarize pre-clinical development and efficacy and safety of anti-IL-6 therapies in the treatment of inflammatory and autoimmune diseases. Methods: Journal articles found within a PubMed search and data presented in abstract form from international conferences up to May 2009 are described in this review. Results/conclusions: Tocilizumab, which blocks IL-6 binding to IL-6 receptor, used as monotherapy or in combination with methotrexate for RA therapy leads to significant clinical response and amelioration of joint damage, which is superior to methotrexate. Some adverse events such as liver function disorders, hyperlipidemia, neutropenia, diarrhea and infection are observed in clinical trials. IL-6 blockers targeting directly IL-6 rather than the IL-6 receptor and fully human monoclonal antibody targeting the IL-6 receptor are currently under development. Overall, targeting IL-6 has provided a promising approach in the management of some inflammatory and autoimmune diseases.     

IL-23／IL-17炎症轴在实验性自身免疫性肝炎中的作用

目的通过建立实验性自身免疫性肝炎小鼠模型,观察外源性IL-23对实验性自身免疫性肝炎模型小鼠中IL-17的影响,探讨其可能的作用机制。方法以肝抗原S-100免疫C57BL／6小鼠制作自身免疫性肝炎动物模型,提取出脾淋巴细胞,将IL-23加入到抗CD,抗体活化后的脾淋巴细胞中进行培养,免疫组化观察IL-17在肝细胞中的分布及表达水平,RT-PCR和ELISA检测IL-17在脾淋巴细胞中的表达。结果与对照组相比,模型组肝细胞中IL-17表达升高;IL-23作用于模型组活化的脾淋巴细胞后IL-17的表达水平明显高于对照组。结论IL-23／IL-17炎症轴在EAH的病理机制中发挥着重要的作用,IL-23可能通过上调IL-17的表迭使AIH模型小鼠症状加重,并为AIH的治疗提供了新的靶点。     

Targeting IL-23 in human diseases

Importance of the field: IL-23 is one of the most intriguing cytokine for its many immunological functions, which are the basis of its important role in host defense but also of its possible contribution to the pathogenesis of several diseases.

Areas covered in this review: The literature and patents about IL-23 pathway and their targeting in therapeutic potential applications. Findings published within the last 5 years receive particular attention.

What the reader will gain: An overview of the emerging role of IL-23 in physiological and pathological conditions and a review of the different approaches (IL-23 pathway-based) currently used for autoimmune diseases and cancer therapies and the results obtained both in preclinical models and in clinical trials.

Take home message: Inhibition/targeting of IL-23 may be a good and novel therapeutic strategy, especially in the treatment of diseases like psoriasis, for which current treatments show more pronounced side effects than those of IL-23-blocking and employed as part of specific patient-tailored therapies in inflammatory bowel diseases.     

Targeting IL-23 in autoimmunity

Dysregulated cell-mediated immune responses may lead to chronic inflammation and autoimmune disorders. The recent discovery of the dimeric interleukin (IL)-12-related cytokine IL-23 now adds to our understanding of the fine-tuning of cellular immunity. The critical implication of the role that IL-12p40 plays in autoimmune inflammation has long been misinterpreted and only recently have studies revealed that it is IL-23, and not IL-12, that is the decisive factor in this immune deviation. Therefore, targeting of IL-23 or the IL-23 receptor is a promising therapeutic approach for autoimmune diseases. This review summarizes recent findings regarding IL-23-mediated autoreactive inflammatory responses, and introduces possible therapeutic interventions that are aimed at mitigating autoimmune inflammation.