The IL-6/sIL-6R complex as a novel target for therapeutic approaches

IL-6 plays a pivotal role in immune responses and certain oncologic conditions. The intense investigation of its biological activity and function led to the discovery of two different IL-6-driven signalling pathways. Binding to the membrane-bound IL-6 receptor (mIL-6R, CD126) causes the recruitment of two gp130 co-receptor molecules (CD130) and the activation of intracellular signalling cascades via gp130. Although this classical pathway is mainly limited to hepatocytes, neutrophils, monocytes/macrophages and certain other leukocyte populations, which express IL-6R on their surface, an alternative mechanism has also been described. Proteolytic cleavage of the mIL-6R protein or translation from alternatively spliced mRNA leads to the generation of a soluble form of the IL-6R (sIL-6R), which is likewise able to bind to IL-6. The resulting IL-6/sIL-6R complex is also capable of binding to gp130 and inducing intracellular signalling. Through this so-called ‘trans-signalling’ mechanism, IL-6 is able to stimulate cells that lack an endogenous mIL-6R. High levels of IL-6 and sIL-6R have been reported in several chronic inflammatory and autoimmune diseases as well as in cancer. Preclinical animal disease models have provided strong evidence that specific blockade of IL-6-regulated signalling pathways represents a promising approach for the therapy of these diseases. An optimised variant of the recently described fusion protein sgp30Fc is now heading towards its clinical evaluation.     

IL-13 as a therapeutic target for respiratory disease

Interleukin-13 (IL-13) is a critical mediator of asthma pathology. On B cells, monocytes, epithelial cells, and smooth muscle cells, IL-13 acts through the IL-13Ralpha1/IL-4Ralpha complex to directly induce activation responses that contribute to atopic disease. In human populations, genetic polymorphisms in IL-13, its receptor components, or the essential signaling element STAT6, have all been associated with increased risk of atopy and asthma. Animal studies using IL-13 deficient mice, IL-13 transgenic animals, and IL-13 neutralization strategies have confirmed an essential role for this cytokine in driving major correlates of asthma pathology, including airway hyperresponsiveness (AHR), lung eosinophilia, mucus generation, and fibrosis. Ongoing studies continue to define both overlapping and distinct roles for IL-13 and the related cytokine, IL-4, in promoting asthmatic changes. Furthermore, new evidence concerning the role of the "decoy" receptor, IL-13Ralpha2, has prompted re-evaluation of the receptor forms that underlie the numerous activities of IL-13. In this review, we summarize the essential role of IL-13 in asthma, compare the relative contributions of IL-13 and IL-4 to key aspects of the asthmatic phenotype, and outline novel therapeutic strategies to target this critical cytokine.     

The immunological synapse as a novel therapeutic target

The onset of adaptive immune responses includes the presentation of foreign antigenic peptides to T-cells, and the formation of a T-cell-antigen-presenting cell interface termed the immunological synapse (IS). Although the generation of a mature IS is thought to be the hallmark of T-cell activation, new evidence suggests that microclusters ofat signaling molecules at the periphery of the IS are responsible for initiating and maintaining T-cell activation while the core of the IS provides a platform for signal downregulation. In this context, costimulatory molecules and self-peptides contribute to sustain the signaling required for T-lymphocyte differentiation into effector cells. This review discusses these aspects in the identification of novel candidates for therapeutic modulation of immune responses.     

The IL-33/ST2 pathway: therapeutic target and novel biomarker

For many years, the interleukin-1 receptor family member ST2 was an orphan receptor that was studied in the context of inflammatory and autoimmune disease. However, in 2005, a new cytokine--interleukin-33 (IL-33)--was identified as a functional ligand for ST2. IL-33/ST2 signalling is involved in T-cell mediated immune responses, but more recently, an unanticipated role in cardiovascular disease has been demonstrated. IL-33/ST2 not only represents a promising cardiovascular biomarker but also a novel mechanism of intramyocardial fibroblast-cardiomyocyte communication that may prove to be a therapeutic target for the prevention of heart failure.     

FXR as a novel therapeutic target for vascular disease

Diseases such as atherosclerosis involve large blood vessel narrowing and hardening, an increase in activated and inflammatory cells, and an accumulation of lipids such as cholesterol. The farnesoid X receptor (FXR) is a recently identified steroid-like receptor. Bile acids are FXR ligands, which use FXR feedback to limit their own biosynthesis in the liver from cholesterol. FXR ligands have been proposed as novel targets in cardiovascular disease, as they affect lipid metabolism in the liver and gastrointestinal tract and lower circulating triglycerides and cholesterol. Recent evidence also suggests that FXR is expressed in the vasculature, implicating FXR as a novel potential 'direct' target for cardiovascular diseases. This review aims to introduce the FXR literature and discuss the mechanisms by which FXR may both directly and indirectly affect the progression of cardiovascular disease.     

PSGL-1 as a novel therapeutic target

The first events of leukocyte recruitment into the tissues are leukocyte tethering (capture) and rolling along the vessel wall, which are mediated primarily by selectins. P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-type glycoprotein ligand expressed by all leukocytes and is a ligand for E-, P- and L-selectin. Quantitative and qualitative differences in the expression, affinity binding to the selectins and glycosylation of PSGL-1 between leukocyte subtypes suggest that potential PSGL-1 blockade should not have broad negative consequences in physiology and host defense. PSGL-1 has a well-documented role in organ targeting during inflammation in animal models, and inhibition of PSGL-1, though challenging, represents an attractive basis for antiinflammatory strategies. The consistent number of studies accumulated in the last 10 years since PSGL-1 was first characterized should induce us to ask whether we should put more effort into developing new drugs aimed to target more effectively PSGL-1 function in human diseases.     

Leptin as a novel therapeutic target for immune intervention

The recent cloning of the leptin (obese, ob) gene has determined fundamental insight into the understanding of the regulation of food intake, basal metabolism and reproductive function. Leptin, mainly secreted by adipocytes, belongs to the helical cytokine family and its plasma concentrations correlate with fat mass and respond to changes in energy balance. Initially, leptin was considered as an anti-obesity hormone, but experimental evidence has also shown pleiotropic effects of this molecule on hematopoiesis, angiogenesis, lymphoid organ homeostasis and T lymphocyte functions. More specifically, leptin links the pro-inflammatory T helper (Th)-1 immune response to the nutritional status and the energy balance. Indeed, decreased leptin concentrations during conditions of food deprivation lead to impaired immune capabilities. This review focuses on the potential therapeutic utilities for agents that manipulate the leptin-adipocyte axis and discusses novel strategies for an immune intervention in pathologic conditions.     

Mitochondrial complex I as a therapeutic target for Alzheimer's disease

Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.     

Oligopeptide antagonist of IL-6: a novel approach to target IL-6 activities

IL-6 exerts multiple effects on different systems. Increased levels of IL-6 are present in several inflammatory diseases as well as in cancer patients. The successful use of IL-6 antagonists in experimental models of inflammatory diseases as well as in human diseases, such as rheumatoid arthritis, clearly demonstrates that IL-6 is involved in the pathophysiology of inflammatory diseases. This patent describes a novel oligopeptide that interferes with the binding of IL-6 to its receptor, thus acting as a receptor antagonist. This peptide inhibits the biological activities of IL-6 in vitro and in vivo. This approach is an interesting development among other strategies aimed at targeting IL-6 in inflammatory diseases and cancer.     

NOTCH signaling as a novel cancer therapeutic target

NOTCH-ligand interaction is a highly conserved mechanism that regulates specific cell fate decision during development. In addition to its functions in developmental and cell maturation processes, studies indicate that NOTCH activation plays a role in the onset and progression of many human malignancies. The prevailing new strategy for rationally targeted cancer treatment is aimed at the development of target-selective "smart" drugs on the basis of characterized mechanisms of action. The connection between NOTCH signaling and tumorigenesis suggests that NOTCH may be such a target candidate. Gamma-secretase is a large membrane-integral multisubunit protease complex, which is essential for NOTCH receptor activation. Inhibitors of this enzyme are being developed for Alzheimer's disease, due to its role in cleaving beta-amyloid precursor in the brain. Recently, Gamma-secretase inhibitors (GSIs), as well as various biopharmaceutical or genetic NOTCH signaling inhibitors have been suggested as potential novel cancer therapeutic strategies. This review summarizes the evidence linking NOTCH signaling to several types of cancer, as well as the possible therapeutic indications of NOTCH inhibitors and the challenges facing their clinical development.     

Cytokines as a therapeutic target for allergic diseases: a complex picture

Production of IgE antibodies promotes the development of allergic disorders such as asthma, rhinitis and atopic eczema. Though Th2 cytokines play a pivotal role in the allergic inflammatory cascade, therapeutic strategies which target these factors have not been curative in clinical trials. In humans, the allergic phenotype encompasses a broad spectrum of diverse clinical entities, which are dictated by genetics as well as the nature of the allergen and the time in life at which allergen is encountered. The disparate findings in animal and human systems highlight the complexity of cytokine-mediated events in allergic responses in man. Different allergic phenotypes cannot be distinguished strictly on the basis of Th1 and Th2 cytokines. These observations coupled with an emerging role for regulatory T cells in modulation of the allergic response warrant re-examination of the cytokine network in allergic disease. This article highlights the challenges of dissecting the role of individual cytokines in the development of allergic responses and manifestation of allergic symptoms. Regulatory T cells have been implicated in modulation of the activity of allergen-specific Th1 and Th2 effector cells and immune outcome; however, the characteristics of these regulatory T cells remain largely undefined. The effects of existing and emerging therapies which target Th1, Th2 and regulatory cytokines on established allergic responses are examined in the context of this new paradigm. Taken together, existing data suggest that a multi-faceted approach, which is tailored to each patient, will be required in order to attain clinical benefit.     

Identification of MFG-E8 as a novel therapeutic target for diseases

Introduction: Milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a peripheral membrane glycoprotein has been widely studied in recent years due to its omnipresent locations, express and multiple functions. Traditionally, MFG-E8 was identified as an outstanding factor for phagocytosis of apoptotic cells and a significant factor in immune systems. Recent studies with some new findings have shed an interesting light on the old peripheral membrane glycoprotein in various diseases.

Areas covered: In inflammatory and the systemic lupus erythematosus-type autoimmune disease, age-related diseases and tumors, MFG-E8 plays a multifunctional role in attenuating inflammation and improving prognosis, healing wound and remodeling arterial and enhancing tumorigenicity and cancer metastasis. This review provides a comprehensive view on the latest advances in the field. The summarized knowledge will help to explore the potential therapeutic roles of MFG-E8 and to design MFG-E8-based strategies for the treatment of these diseases.

Expert opinion: Though the exact roles of MFG-E8 have not been fully elucidated in diseases. MFG-E8 may serve as a promising therapeutic strategy.     

TANK-binding kinase 1 as a novel therapeutic target for viral diseases

Introduction: TANK-binding kinase 1 (TBK1) is vital for the induction of antiviral innate immune responses. Both RNA and DNA viral infection induces TBK1 activation, triggers phosphorylation of interferon regulatory factor (IRF) 3 and subsequent expression of type I interferons (IFNs; IFN-α/β). Type I IFNs can induce the expression of numerous antiviral genes called interferon-stimulated genes (ISGs) to build a remarkable antiviral state and limit viral replication. Thus, optimal TBK1 activity is crucial for IRF3-induced type I IFNs expression and ISGs-mediated viral elimination.

Areas covered: This review provides an overview of the diverse roles of TBK1 in antiviral innate immune responses, the regulatory mechanisms of TBK1 activity and the implication in antiviral development.

Expert opinion: TBK1 is a key kinase against antiviral infection via inducing type I IFNs expression. Multiple types of post-translational modifications of TBK1 tightly regulate TBK1 activity and subsequent TBK1-dependent antiviral responses. The identified regulators of TBK1 unveil regulatory mechanisms of host antiviral innate immunity and immuno-escape mechanism of virus provide strategies to control viral diseases by modulating TBK1 activity.     

sIL-2R、IL-6在重症肌无力胸腺瘤中的表达及意义

目的探讨可溶性白细胞介素2受体(sIL-2R)、白细胞介素6(IL-6)在胸腺瘤合并MG发病机制中的作用。方法搜集胸腺切除手术的27例胸腺瘤患者的相关资料,对切除的胸腺瘤组织用免疫组化的方法,确定SIL-2R、IL-6在胸腺瘤组织中的表达情况。结果 SIL-2R细胞因子、IL-6在胸腺瘤合并MG的胸腺瘤组织呈高表达。结论可溶性白细胞介素2受体(SIL-2R)、IL-6在胸腺瘤合并MG的表达呈正相关。     

Validating the GTP-cyclohydrolase 1-feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches

Background and Purpose

6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH₄) is an essential cofactor for nitric oxide biosynthesis. Substantial clinical evidence indicates that intravenous BH₄ restores vascular function in patients. Unfortunately, oral BH₄ has limited efficacy. Therefore, orally bioavailable pharmacological activators of endogenous BH₄ biosynthesis hold significant therapeutic potential. GTP-cyclohydrolase 1 (GCH1), the rate limiting enzyme in BH₄ synthesis, forms a protein complex with GCH1 feedback regulatory protein (GFRP). This complex is subject to allosteric feed-forward activation by L-phenylalanine (L-phe). We investigated the effects of L-phe on the biophysical interactions of GCH1 and GFRP and its potential to alter BH₄ levels in vivo.

Experimental Approach

Detailed characterization of GCH1–GFRP protein–protein interactions were performed using surface plasmon resonance (SPR) with or without L-phe. Effects on systemic and vascular BH₄ biosynthesis in vivo were investigated following L-phe treatment (100 mg·kg⁻¹, p.o.).

Key Results

GCH1 and GFRP proteins interacted in the absence of known ligands or substrate but the presence of L-phe doubled maximal binding and enhanced binding affinity eightfold. Furthermore, the complex displayed very slow association and dissociation rates. In vivo, L-phe challenge induced a sustained elevation of aortic BH₄, an effect absent in GCH1(fl/fl)-Tie2Cre mice.

Conclusions and Implications

Biophysical data indicate that GCH1 and GFRP are constitutively bound. In vivo, data demonstrated that L-phe elevated vascular BH₄ in an endothelial GCH1 dependent manner. Pharmacological agents which mimic the allosteric effects of L-phe on the GCH1–GFRP complex have the potential to elevate endothelial BH₄ biosynthesis for numerous cardiovascular disorders.     

HDAC6 as a potential therapeutic target for peripheral nerve disorders

ABSTRACT

Introduction: Peripheral neuropathies are a heterogeneous group of diseases that are characterized by a progressive, ascending loss of nerve function arising from the peripheral regions of the limbs. The phenotypic overlap between different types of hereditary and acquired peripheral neuropathies indicates that similar pathophysiological processes are at play. Many downstream pathways in peripheral neurons, such as axonal transport, protein degradation, and interactions with Schwann cells, organelle damage, channelopathies, and neuroinflammatory signaling, have been proposed and each affects peripheral nerves in a negative way. Histone deacetylase 6 (HDAC6) plays an important role at the intersection of these converging pathogenic pathways. The enzymatic deacetylase activity of HDAC6 is upregulated in neurodegenerative disorders and typically results in downstream neuronal stress.

Areas covered: The role of HDAC6 in the common pathogenic mechanisms of peripheral neuropathies. In addition, we discuss the current preclinical and clinical HDAC6 inhibitors (HDAC6i), their chemical structure, development, and limitations.

Expert opinion: The development and testing of non-hydroxamic acid-based, should be the focus of the future research. Moreover, HDAC6i should be further investigated as a preventative measure and therapeutic strategy for inherited and acquired peripheral neuropathies.     

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.