Interleukin 17 sustains rather than induces inflammation

Interleukin (IL)17 is a novel cytokine that has been suggested to play a key role in sustaining chronic inflammation in autoimmune diseases. Since its discovery, much attention has been given to mediators and factors responsible for the development of IL-17-producing cells while very few studies have investigated the inflammatory properties of this cytokine. Here we aimed to characterize the inflammatory properties of IL-17 and to establish if this cytokine per se can initiate an inflammatory reaction or if its main role is to contribute to the exacerbation of ongoing inflammation. To this aim we used two different mouse models of inflammation: the paw oedema and the airpouch. Interestingly, injection of IL-17 in the hind paw did not cause oedema while administration in the pre-inflamed tissues of 6-day-old air pouches induced a long lasting inflammatory reaction that was sustained between 4 and 24 h post-injection. Phenotypic analysis of cellular infiltrates demonstrated selective PMN recruitment in exudates and pouch lining tissues. This event was accompanied by induction of a distinct set of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α and chemokines KC and MCP-1. Co-administration of a neutralizing anti-KC antibody with IL-17 significantly reduced its inflammatory response suggesting a key role for this chemokine in mediating the inflammatory effects of IL-17. In conclusion these results demonstrate that IL-17 does not initiate an inflammatory reaction while, if injected in pre-inflamed tissues, is able to further amplify biochemical and cellular events characteristic of the early stages of the inflammatory reaction.     

IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases

IL-19 and IL-20 are two cytokines that were discovered in 2000 and 2001, respectively. Based on the structure and location of their genes, their primary and secondary protein structures and the used receptor complexes, they were classified with IL-10, IL-22, IL-24, IL-26, IL-28 and IL-29 in the IL-10 family of cytokines, and form a subgroup with IL-24 within this family. IL-19 and IL-20 are produced by monocytes as well as non-immune tissue cells under inflammatory conditions. IL-19 and IL-20 act via a receptor complex that consists of the IL-20R1 and IL-20R2 chains. IL-20 is additionally able to signal via a second receptor complex (IL-22R1/IL-20R2). It is controversial whether or not IL-19 and IL-20 regulate the function of immune cells. However, the expression of their receptors aliments the perception that the cells of the skin, lungs and reproductive organs as well as various glands are major targets of these mediators. Results from animal experiments and massively increased expression of these mediators in human inflamed tissues support the assumption that they play an important role in the pathogenesis of a few inflammatory diseases. For this reason, the authors have reviewed the facts known at present regarding these cytokines and postulate that IL-19 and IL-20 are pharmacologically interesting distal elements of an inflammatory cascade.     

IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases

IL-19 and IL-20 are two cytokines that were discovered in 2000 and 2001, respectively. Based on the structure and location of their genes, their primary and secondary protein structures and the used receptor complexes, they were classified with IL-10, IL-22, IL-24, IL-26, IL-28 and IL-29 in the IL-10 family of cytokines, and form a subgroup with IL-24 within this family. IL-19 and IL-20 are produced by monocytes as well as non-immune tissue cells under inflammatory conditions. IL-19 and IL-20 act via a receptor complex that consists of the IL-20R1 and IL-20R2 chains. IL-20 is additionally able to signal via a second receptor complex (IL-22R1/IL-20R2). It is controversial whether or not IL-19 and IL-20 regulate the function of immune cells. However, the expression of their receptors aliments the perception that the cells of the skin, lungs and reproductive organs as well as various glands are major targets of these mediators. Results from animal experiments and massively increased expression of these mediators in human inflamed tissues support the assumption that they play an important role in the pathogenesis of a few inflammatory diseases. For this reason, the authors have reviewed the facts known at present regarding these cytokines and postulate that IL-19 and IL-20 are pharmacologically interesting distal elements of an inflammatory cascade.     

After interleukin-12p40, are interleukin-23 and interleukin-17 the next therapeutic targets for inflammatory bowel disease?

Inflammatory bowel disease (IBD), typified by Crohn's disease and ulcerative colitis, is a common disorder characterized by recurrent and serious inflammation of the gastrointestinal tract. Recent immunologic advances have established that T cells and inflammatory cytokines play a pivotal role in the gastrointestinal inflammation of IBD. However, many cytokines not only elicit inflammation but also protect host against microbial invasion. Hence, suppression of these dual-purpose cytokines often exposes the patients to significant risk of infection. Recent research on Interleukin (IL)-23, IL-17, and IL-17 producing T cells has become the vanguard of further understanding the contribution of cytokines to autoimmune and inflammatory diseases. IL-23 is a newly discovered member of the IL-12-related cytokine family, and is primarily involved in the differentiation of pathogenic T cells characterized by their production of IL-17. IL-17 is a potent inflammatory mediator implicated in a number of autoimmune diseases. The discovery of this IL-23/IL-17-mediated inflammatory axis is having a profound impact on the elucidation of T cell-mediated pathogenesis as well as development of novel therapeutic targets. In this review, we discuss the current literature and present our recent studies on the role of IL-23 and IL-17 in the pathogenesis of IBD. Controlling the expression/production of IL-23 and IL-17 is an approach that would allow the development of a novel treatment strategy with more anti-inflammatory efficacy and potentially with less suppressive effects on host defenses.     

Humanized antihuman IL-6 receptor antibody, tocilizumab

Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune responses and inflammatory reactions. Overproduction of IL-6 has been shown to play a role in inflammatory autoimmune diseases such as rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA) and, therefore, an agent blocking IL-6 actions can be a therapy of these diseases. IL-6 belongs to a cytokine family, which shares the cytokine receptor subunit glycoprotein (gp) 130. This family also includes IL-11, oncostatin-M, and leukemia inhibitory factor (LIF). In the IL-6 receptor (IL-6R) system, both a membrane-bound IL-6R and a soluble form of IL-6R are able to mediate IL-6 signals into the cells through the interaction of gp130. Tocilizumab is a humanized antihuman IL-6 receptor antibody designed using genetic engineering technology. Tocilizumab recognizes both the membrane-bound and the soluble form IL-6R and specifically blocks IL-6 actions. Tocilizumab is expected to ameliorate the autoimmune inflammatory diseases with IL-6 overproduction and has been clinically developed as a therapeutic agent for RA, systemic-onset and articular types of JIA, Crohn's disease, etc. Tocilizumab has been shown to be effective not only for improving signs and symptoms but also for preventing joint destruction of RA. Immunopharmacology and clinical benefit of tocilizumab in RA is addressed.     

IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues

IL-22, also termed IL-TIF, is a member of the IL-10 family of cytokines. Its principal source appears to be memory CD4 T cells with a Th1 polarized phenotype. IL-22 induces its signals through a two-component receptor comprised of IL-22R1 and CRF2-4/IL10Rb. Both of these receptor components also participate in separate receptor complexes specific for other IL-10 family cytokines. Because CRF2-4 exhibits ubiquitous expression, the tropism of IL-22 action appears to be dictated by the expression of IL-22R1. IL-22R1 has a highly restricted expression pattern. Its highest expression, by far, is in the acinar cell population of the pancreas. Lower, but still functional, levels of expression are also observed in skin, colon, liver, and kidney. The responses that have been observed to date for IL-22 resemble the "acute phase" type responses elicited by IL-6, suggesting that IL-22 might be appropriately considered as a T cell-derived IL-6-like activity having distinct target cell specificity. The functional role of this system remains unclear, but it is likely that the responses elicited by this cytokine serve to contribute both to acute host defense against pathogens and to safeguard vulnerable target tissues under conditions of stress.     

IL-27 and autoimmune rheumatologic diseases: The good,the bad,and the ugly

The footprint of cytokines is evident in almost every biological process, such as development, as well as the pathogenesis of the different diseases, immune responses to pathogens, etc. These small proteins are categorized into different functional classes; for instance, they can play a pro-inflammatory or anti-inflammatory role in different situations, or they can confer a polarization to the immune system. Interleukin (IL)-27 is a member of the IL-12 family. Antigen-presenting cells are the primary source of IL-27 production, which exerts its effects by bindings to the IL-27 receptor expressed on the surface of target cells. Interaction of IL-27 and IL-27 receptor leads to activation of the JAK-STAT and p38 MAPK signaling pathways. Most studies focused on the inflammatory effects of this cytokine, but gradually anti-inflammatory effects were also revealed for this cytokine, which changed the traditional perception of the function of this cytokine. The functionality of IL-27 in the pathogenesis of rheumatic diseases has been attributed to a double-blade sword. Hence, novel therapeutic approaches have been devised targeting IL-12 family that has been accompanied with promising results. In this review, we focused on the inflammatory and anti-inflammatory properties of IL-27 in different autoimmune rheumatologic diseases and its plausible therapeutic potentials.     

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.     

人白细胞介素-21及其受体的研究进展

 人白细胞介素(interleukin, IL)21（IL-21）是一种由CD4⁺ T细胞、自然杀伤细胞、17型辅助性T细胞等分泌的I型细胞因子。IL-21受体是一种典型的I型细胞因子受体,在大部分骨髓细胞、淋巴细胞等表面都有表达。IL-21与IL-21受体结合可对机体免疫应答产生广泛的影响。IL-21具有抗肿瘤作用,IL-21与其他细胞因子、抗体、疫苗联用是一种有效的肿瘤治疗方法。     

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.     

IL-17-expressing cells as a potential therapeutic target for treatment of immunological disorders

IL-17 is a multifunctional cytokine produced by activated CD4+ and CD8+ lymphocytes as well as stimulated unconventional Tγδ and natural killer T cells. IL-17 induces expression of chemokines, proinflammatory cytokines and metalloproteinases, thereby stimulating the inflammation and chemotaxis of neutrophils. Elevation of proinflammatory cytokines is associated with asthma and autoimmune disorders, such as multiple sclerosis, rheumatoid arthritis and psoriasis. Although the role of IL-17 in these disorders is not always easy to define, extensive research has demonstrated an aggravating influence of IL-17 in some animal models. Thus, the development of therapeutics to reduce IL-17 levels is a promising strategy for ameliorating inflammatory diseases. This review briefly summarizes recent knowledge about stimulants and intracellular signaling pathways that induce development and maturation of IL-17-expressing cells. Its positive and negative roles on disease progression and its importance in vaccine-induced memory are also discussed. Finally, recent literature describing potential therapeutic approaches for targeting IL-17 is presented.     

Ciglitazone,a Peroxisome Proliferator-Activated Receptor Gamma Ligand,Inhibits Proliferation and Differentiation of Th17 Cells

Peroxisome proliferator-activated receptor gamma (PPARγ) was identified as a cell-intrinsic regulator of Th17 cell differentiation. Th17 cells have been associated with several autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), inflammatory bowel disease (IBD), and collagen-induced arthritis. In this study, we confirmed PPARγ-mediated inhibition of Th17 cell differentiation and cytokine production at an early stage. Treatment with ciglitazone, a PPARγ ligand, reduced both IL-1β-mediated enhancement of Th17 differentiation and activation of Th17 cells after polarization. For Th17 cell differentiation, we found that ciglitazone-treated cells had a relatively low proliferative activity and produced a lower amount of cytokines, regardless of the presence of IL-1β. The inhibitory activity of ciglitazone might be due to decrease of CCNB1 expression, which regulates the cell cycle in T cells. Hence, we postulate that a pharmaceutical PPARγ activator might be a potent candidate for treatment of Th17-mediated autoimmune disease patients.     

Proinflammatory cytokine responses in skin and epidermal cells following epicutaneous administration of anticoagulant rodenticide warfarin in rats

Context: Dermal toxicity of coumarin anticoagulant rodenticides, such as warfarin, represents potential risk for workers handling these agents and for individuals applying easily available rodenticides in their households as well.

Objective: In this study, proinflammatory effects of repeated epicutaneous administration of warfarin in rats were explored by examining inflammatory cytokine skin responses.

Materials and methods: Ex vivo production of IL-1β, IL-6, TNF-α and IL-17 by skin explants and by epidermal cells isolated by enzyme (dispase/trypsin) digestion from skin repeatedly (once a day, three consecutive days) exposed to 10?µg of warfarin was measured 24?h and 72?h following the last warfarin application by ELISAs for respective rat cytokines.

Results: Warfarin treatment resulted in histological changes, but skin or epidermal cell viability were not compromised, judging by MTT reduction assay. Both skin and epidermal cells responded to administration of this agent by production of all examined inflammatory cytokines (skin explants by TNF-α and IL-17; epidermal cells by IL-1β and TNF-α) except IL-6.

Discussion: Along with histomorphological changes, cytokines indicate functional consequences in treated skin. IL-1β production, that precede production of TNF-α, might be responsible for production of the latter cytokine. Sustained production of IL-1β suggests persistence of epidermal cell stimulation or existence of some amplification mechanisms. Requirements for T cells seem to exist concerning epidermal cell IL-17 production.

Conclusion: Presented data provide additional new information concerning proinflammatory effects of warfarin.     

Effects of sustained stimulation with multi-wall carbon nanotubes on immune and inflammatory responses in mice

Possible effects of multi-wall carbon nanotubes (MWCNTs) on immune and inflammatory responses were examined in mice. Female ICR mice were given a single intraperitoneal administration (2 mg/kg body weight) of either MWCNTs, carbon black (CB), or crocidolite (blue asbestos) and controls received a vehicle of 2% sodium carboxymethyl cellulose (CMC Na). In the peritoneal cavity of MWCNT-administered mice, the liver had changed to a rounded shape and fibrous adhesions were seen on internal organs. Peritoneal cells overexpressed mRNA for genes of T helper (Th)2 cytokines (interleukin [IL]-4, IL-5, and IL-13), Th17 cytokine (IL-17), pro-inflammatory cytokines/chemokines (IL-1β, IL-33, tumor necrosis factor α, and monocyte chemotactic protein-1), and myeloid differentiation factor 88 for at least 2 weeks after the administration of MWCNTs, while those of Th1 cytokine genes (IL-2 and interferon γ) were overexpressed several weeks later and expression levels remained high up to 20 weeks. In MWCNT-treated mice, the numbers of leukocytes, monocytes, and granulocytes in the peripheral blood and the expression of the leukocyte adhesion molecules, cluster of differentiation (CD)49d and CD54, on granulocytes were increased 1 week after administration and remained high up to week 20. Production of ovalbumin-specific IgM and IgG(1) was enhanced by MWCNTs. These changes were not observed after CB or crocidolite administration. Thus, this study showed that MWCNTs exhibited sustained stimulating effects on immune and inflammatory responses, unlike the other mineral fibers with structural similarities.     

Interleukin-7: a key mediator in T cell-driven autoimmunity, inflammation, and tissue destruction

IL-7, expressed by stromal cells in primary lymphoid organs, is known for its critical role in the development and homeostatic expansion of T cells in humans and mice. IL-7 is equally important for B cell development in human and mice, but only in mice seems critical for B cell development and expansion. Recent studies demonstrate that this potent immunostimulatory cytokine is overexpressed in inflamed tissues of patients with (rheumatic) autoimmune diseases and that expression levels correlate with clinical parameters of disease. In inflamed tissues several cell types, including macrophages, dendritic cells, and fibroblasts produce IL-7. IL-7 primarily acts on T cells that abundantly express the IL-7 receptor and that are increased at the inflammatory sites, and predominantly induces Th1 and Th17-associated cytokine secretion. IL-7-mediated T cell-dependent activation of macrophages, dendritic cells and B cells is accompanied by up regulation of T cell differentiating factors, chemokines, adhesion/co-stimulatory molecules and catabolic cytokines and enzymes. Moreover, overexpression of IL-7 is associated with ectopic lymphoid aggregate formation, corresponding with the capacity of IL-7 to induce LTβ and TNFα and to activate innate lymphoid tissue inducer cells. Additionally, IL-7 promotes T cell-driven osteoclastogenesis and fibroblast activation, processes involved in tissue destruction in chronic inflammation. Altogether this suggests that IL-7 is an important proinflammatory mediator in several chronic (rheumatic) inflammatory autoimmune diseases. The substantial amelioration of inflammation and immunopathology in experimental animal models for these diseases by blocking IL-7(receptor) supports this role of IL-7 and demonstrates that IL-7 and its receptor represent novel targets for immunotherapy.     

IL-37 (IL-1F7) the newest anti-inflammatory cytokine which suppresses immune responses and inflammation

Cytokines such as interleukins, chemokines and interferons are immunomodulating and inflammatory agents, characterized by considerable redundancy, in that many cytokines appear to share similar functions. Virtually all nucleated cells, but especially epithelial cells and macrophages, are potent producers of cytokines. The objective of this study is to review the detailed mechanism of action and the biological profiles of IL-37, the newest anti-inflammatory cytokine. This review focuses on IL-37, a key cytokine in regulating inflammatory responses, mainly by inhibiting the expression, production and function of proinflammatory cytokines: IL-1 family pro-inflammatory effects are markedly suppressed by IL-37.     

Are Th17 cells and their cytokines a therapeutic target in Guillain–Barré syndrome?

Introduction: Guillain–Barré syndrome (GBS) is an immune-mediated inflammatory disorder of the peripheral nervous system (PNS). Experimental autoimmune neuritis (EAN) is a useful animal model for studying GBS. Currently, GBS remains a life-threatening disorder and more effective therapeutic strategies are in urgent need.

Areas covered: Accumulating evidence has revealed that T helper (Th) 17 cells and their cytokines are pathogenic in GBS/EAN. Drugs attenuated clinical signs of GBS/EAN, in part, by decreasing Th17 cells or IL-17A. Th17 cells and their cytokines might be potential therapeutic targets. Approaches targeting Th17 cells or their cytokines are in development in treating Th17 cells-involved disorders. In this review, we summarize the up-to-date knowledge on roles of Th17 cells and their cytokines in GBS/EAN, as well potential approaches targeting Th17 cells and their cytokines as clinical applications.

Expert opinion: As Th17 cells produce different sets of pro-inflammatory cytokines and Th17-related cytokines are not exclusively produced by Th17 cells, targeting Th17 cell development may be superior to blocking a single Th17 cytokine to treat Th17 cells-involved disorders. Considering the essential role of retinoic acid-related orphan receptor γT (RORγT) and IL-23 in Th17 cell development, RORγT inhibitors or IL-23 antagonists may provide better clinical efficacy in treating GBS/EAN.     

Expression profiles of genes involved in the mouse nuclear factor-kappa B signal transduction pathway are modulated by mangiferin

The polyphenol mangiferin (MA) has been shown to have various effects on macrophage function, including inhibition of phagocytic activity and of free radical production. To further characterize the immunomodulatory activity of MA, this study investigated its effects on expression by activated mouse macrophages of diverse genes related to the NF-kappaB signaling pathway, using a DNA hybridization array containing 96 NF-kappaB-related genes and on cytokine levels using a cytokine protein array. MA at 10 microM significantly inhibited the expression of (a) two genes of the Rel/NF-kappaB/IkappaB family, RelA and RelB (=I-rel), indicating an inhibitory effect on NF-kappaB-mediated signal transduction; (b) TNF receptor-associated factor 6 (Traf6), indicating probable blockage of activation of the NF-kappaB pathway by lipopolysaccharide (LPS), tumor necrosis factor (TNF), and interleukin 1 (IL-1); (c) other proteins involved in responses to TNF and in apoptotic pathways triggered by DNA damage, including the TNF receptor (TNF-R), the TNF-receptor-associated death domain (TRADD), and the receptor interacting protein (RIP); (d) the extracellular ligand IL-1alpha, again indicating likely interference with responses to IL-1; (e) the pro-inflammatory cytokines IL-1, IL-6, IL-12, TNF-alpha and RANTES (CCL5), and cytokines produced by monocytes and macrophages, including granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF); (f) other toll-like receptor proteins (in addition to Traf6), including JNK1, JNK2 and Tab1; (g) Scya2 (small inducible cytokine A2=monocyte chemoattractant protein 1); and (h) various intracellular adhesion molecules (ICAMs), and the vascular cell adhesion molecule VCAM-1, which is locally increased in atheromas. The inhibition of JNK1, together with stimulation of c-JUN (i.e. the Jun oncogene) and the previously reported superoxide-scavenging activity of MA, suggests that MA may protect cells against oxidative damage and mutagenesis. Taken together, these results indicate that MA modulates the expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumorogenesis, inflammation and various autoimmune diseases, and raise the possibility that it may be of value in the treatment of inflammatory diseases and/or cancer.