Soluble cytokine receptors: their role in immunoregulation

A number of cytokine receptors exist in soluble form in the biological fluids of both animals and humans, a phenomenon that might have immunoregulatory implications in vivo. Although these soluble receptors specifically inhibit binding and activity of their respective cytokines in vitro, their actual function in vivo as cytokine inhibitors or as carrier proteins is unclear. Abnormalities in the production of these substances might contribute to the pathophysiology of immune and neoplastic diseases. Besides their role in regulating cytokine activity in vivo, soluble cytokine receptors hold significant potential for therapeutic use as very specific anticytokine agents and as indicators in diagnosis and assessment of immune parameters, prognosis, disease progression, response to treatment, etc., in a variety of autoimmune and malignant diseases.     

RNAi Screen Reveals Potentially Novel Roles of Cytokines in Myoblast Differentiation

Cytokines are cell-secreted signaling molecules that modulate various cellular functions, with the best-characterized roles in immune responses. The expression of numerous cytokines in skeletal muscle tissues and muscle cells has been reported, but their function in skeletal myogenesis, the formation of skeletal muscle, has been largely underexplored. To systematically examine the potential roles of cytokines in skeletal myogenesis, we undertook an RNAi screen of 134 mouse cytokine genes for their involvement in the differentiation of C2C12 myoblasts. Our results have uncovered 29 cytokines as strong candidates for novel myogenic regulators, potentially conferring positive and negative regulation at distinct stages of myogenesis. These candidates represent a diverse collection of cytokine families, including interleukins, TNF-related factors, and chemokines. Our findings suggest the fundamental importance of cytokines in the cell-autonomous regulation of myoblast differentiation, and may facilitate future identification of novel therapeutic targets for improving muscle regeneration and growth in health and diseases.     

Receptor fusion proteins for the inhibition of cytokines

Cells are exposed to a large variety of cytokines that signal through corresponding cytokine receptors. In healthy tissues or tissues that respond properly to disturbed homeostasis, the cross-talk of a few conserved core signaling pathways downstream of the cytokine receptors is translated into an adequate cellular response. In chronic inflammatory diseases but also in cancer associated inflammation cytokine expression and the downstream signaling networks are dysregulated. Targeted therapies are aimed at the specific interference with dysregulated cytokine signaling. In this article some concepts of pharmacological intervention with cytokine signaling will be reviewed including biologics that target cytokines and cytokine receptors. Receptor fusion proteins consisting of the ligand-binding domains of cytokine receptors are highly specific and potent cytokine inhibitors and will be discussed in more detail.     

Poxviruses: Capturing Cytokines and Chemokines

Cytokines play a critical role in the regulation of immune responses and constitute important targets for virus immune evasion mechanisms. One strategy used by large DNA viruses is to encode proteins that mimic cytokines or cytokine receptors, which modulate the activity of cytokines during infection. Poxviruses encode a unique set of proteins that are secreted from the infected cell and function as soluble cytokine receptors or binding proteins and sequester tumor necrosis factor, interleukin-1β, or chemokines. Characterization of these poxvirus proteins is providing information on virus pathogenesis, the function of cytokines, and new strategies for immune modulation and therapeutic intervention.     

Th细胞亚群在自身免疫病的发病及治疗中作用的实验研究进展

本文回顾了Ｔｈ细胞亚群的功能、交互调节、影响其分化的因素以及Ｔｈ细胞亚群在自身免疫病发病中的可能作用;概括了通过调节Ｔｈ细胞亚群来治疗自身免疫病的方法,包括：上调ＣＤ１ｄ治疗、给予相关细胞因子治疗、佐剂治疗、用抗细胞因子、细胞因子受体、ＣＤ４０配体和Ｂ７分子的单克隆抗体治疗以及ＣＴＬＡ和ＣＴＬＡＩｇ治疗。这些方法为自身免疫病的治疗提供了新的思路。     

CytReD: A database collecting human cytokinome information

The cytokines/related receptors system represents a complex regulatory network that is involved in those chronic inflammatory processes which lead to many diseases as cancers. We developed a Cytokine Receptor Database (CytReD) to collect information on cytokine receptors related to their biological activity, gene data, protein structures and diseases in which these and their ligands are implicated. This large set of information may be used by researchers as well as by physicians or clinicians to identify which cytokines, reported in the literature, are important in a given disease and, therefore, useful for purposes of diagnosis or prognostic. AVAILABILITY: The database is available for free at http://www.cro-m.eu/CytReD/     

Therapeutic relevance of altered cytokine expression

Cytokines and their receptors have numerous physiological functions. Altered concentrations of these mediators are associated with various afflictions. For example, over-expression of cytokines has been associated with altered drug concentrations and activity. Greater concentrations of cardiovascular drugs have been observed in humans and laboratory animals with various types of inflammatory disorders compared to healthy controls. Interestingly, the observed higher concentrations of drugs such as propranolol and verapamil have not been associated with increased effects. Indeed, reduced response to these cardiovascular drugs is observed, suggestive of cytokine-mediated downregulation of receptors. Increased cytokine concentrations have also been associated with decreased response to drugs used in treatment of other disorders such as AIDS, asthma and psychiatric diseases. This reduced response to drug in the presence of altered cytokine concentrations is especially relevant to the elderly population which has a greater incidence of multiple diseases and elevated concentrations of various cytokines compared to younger individuals. Furthermore, inflammatory conditions and their accompanied increased over-expression of cytokines are suggested to be the main determinants of therapeutic failure in myocardial infarction and angina. Therefore, altered cytokine concentrations may influence therapeutic outcomes of pharmacotherapy and result in treatment failure.     

P1 receptors and cytokine secretion

Evidence has accumulated in the last three decades to suggest tissue protection and regeneration by adenosine in multiple different cell types. Adenosine produced in hypoxic or inflamed environments reduces tissue injury and promotes repair by receptor-mediated mechanisms. Among other actions, regulation of cytokine production and secretion by immune cells, astrocytes and microglia (the brain immunocytes) has emerged as a main mechanism at the basis of adenosine effects in diseases characterized by a marked inflammatory component. Many recent studies have highlighted that signalling through A₁ and A_2A adenosine receptors can powerfully prevent the release of pro-inflammatory cytokines, thus inhibiting inflammation and reperfusion injury. However, the activation of adenosine receptors is not invariably protective of tissues, as signalling through the A_2B adenosine receptor has been linked to pro-inflammatory actions which are, at least in part, mediated by increased release of pro-inflammatory cytokines from epithelial cells, astrocytes and fibroblasts. Here, we discuss the multiple actions of P1 receptors on cytokine secretion, by analyzing, in particular, the role of the various adenosine receptor subtypes, the complex reciprocal interplay between the adenosine and the cytokine systems, their pathophysiological significance and the potential of adenosine receptor ligands as new anti-inflammatory agents.     

Cytokines and endotoxin induce cytokine receptors in skeletal muscle

Proinflammatory cytokines are important factors in the regulation of diverse aspects of skeletal muscle function; however, the muscle cytokine receptors mediating these functions are uncharacterized. Binding kinetics (dissociation constant = 39+/-4.7 x 10(-9) M, maximal binding = 3.5+/-0.23 x 10(-12) mol/mg membrane protein) of muscle tumor necrosis factor (TNF) receptors were obtained. Skeletal muscle was found to express mRNAs encoding interleukin-1 type I and II receptors, interleukin-6 receptor (IL-6R), and interferon-gamma receptor by RT-PCR, but these receptors were below limits of detection of ligand-binding assay (> or =1 fmol binding sites/mg protein). Twenty-four hours after intraperitoneal administration of endotoxin to rats, TNF receptor type II (TNFRII) and IL-6R mRNA were increased in skeletal muscle (P<0.05). In cultured L6 cells, the expression of mRNA encoding TNFRII and IL-6R receptors was induced by TNF-alpha, and all six cytokine receptor mRNA were induced by a mixture of TNF-alpha, IFN-gamma, and endotoxin (P<0.05). This suggests that the low level of cytokine receptor expression is complemented by a capacity for receptor induction, providing a clear mechanism for amplification of cytokine responses at the muscle level.     

Cytokine Actions in the Central Nervous System

Cytokines and chemokines have been implicated in contributing to the initiation, propagation and regulation of immune and inflammatory responses. Also, these soluble mediators have important roles in contributing to a wide array of neurological diseases such as multiple sclerosis, AIDS Dementia Complex, stroke and Alzheimers disease. Cytokines and chemokines are synthesized within the central nervous system by glial cells and neurons, and have modulatory functions on these same cells via interactions with specific cell-surface receptors. In this article, I will discuss the ability of glial cells and neurons to both respond to, and synthesize, a variety of cytokines. The emphasize will be on three select cytokines; interferon-gamma (IFN-γ), a cytokine with predominantly proinflammatory effects; interleukin-6 (IL-6), a cytokine with both pro- and anti-inflammatory properties; and transforming growth factor-beta (TGF-β), a cytokine with predominantly immunosuppressive actions. The significance of these cytokines to neurological diseases with an immunological component will be discussed.     

Th细胞亚群自身免疫病的发病及治疗中作用的实验研究进展

本文回顾了Ｔｈ细胞亚群的功能、交互调节、影响其分化的因素以及Ｔｈ细胞亚群自身免疫病发病中的可能作用;概括了通过调节Ｔｈ细胞亚群来治疗自身免疫病的方法,包括：上调ＣＤ１ｄ治疗、给予相关细胞因子治疗、佐剂治疗、用抗细胞因了、细胞因了受体、ＣＤ４０配体和Ｂ７分子的单克隆抗体治疗以及ＣＴＬＡ和ＣＴＬＡＩｇ治疗。这些方法为自身免疫病的治疗提供了新的思路。     

Bmx regulates LPS-induced IL-6 and VEGF production via mRNA stability in rheumatoid synovial fibroblasts

Discordant cytokine production is characteristic of chronic inflammatory conditions like rheumatoid arthritis (RA), and anti-cytokine therapeutics are becoming routinely used to treat RA in the clinic. Fibroblasts from rheumatoid synovium have been shown to contribute to cytokine production in inflamed joints; likewise these cells also produce cytokines in response to inflammatory mediators signalling through Toll like receptors (TLRs). Tyrosine kinase activity is essential to LPS-induced cytokine production, and we have previously implicated a role for the Tec kinase, Bmx, in inflammatory cytokine production. Here we show that Bmx kinase activity in RASF is increased following LPS stimulation and that Bmx is involved in the regulation of LPS-induced IL-6 and VEGF production via mRNA stabilisation. This is an important insight into the regulation of VEGF, which is involved in a wide range of different pathologies, and may lead to more effective design of novel anti-inflammatory/angiogenic therapeutics for conditions such as RA.     

Phagocytosis of Myelin in Demyelinative Disease: A Review

In the cell-mediated demyelinating diseases such as experimental allergic encephalomyelitis and multiple sclerosis, as well as their peripheral nerve counterparts, the phagocytic cells are the agent of myelin destruction. Both resident microglia and peripheral macrophages invading the nervous system have been shown to phagocytize myelin, although microglia appear to be more active, especially at early stages of disease. Several different receptors on these cells have been implicated as myelin receptors, with the Fc- and complement receptors receiving the most attention. Other receptors, especially the macrophage scavenger receptor with its broad specificity deserves further exploration, especially in view of its affinity for phosphatidylserine, which becomes externalized with membrane disruption. Evidence is shown for cytokine regulation of phagocytic activity in both macrophages and microglia. Further investigation of the pathways of cytokine action on myelin phagocytosis through signal transduction molecules will be important for a further understanding of the events leading to myelin destruction in demyelinating diseases.     

Involvement of ERK-1/2 in IL-21-induced cytokine production in leukemia cells and human monocytes

Cytokines play an important role in the immune system, and abnormalities in their production have been found in many human diseases. Interleukin-21 (IL-21), a type I cytokine produced by activated T cells, has diverse effects on the immune system, but its ability to induce production of other cytokines is not well delineated. Furthermore, the signaling pathway underlying its action is poorly understood. Here, we have evaluated IL-21-induced cytokine production in human monocytes and U937 leukemia cells. We found that IL-21 induces upregulation of a variety of cytokines from multiple cytokine families. We also found that IL-21 triggers rapid activation of ERK1/2. Neutralizing antibody to the IL-21R prevented both IL-21-induced cytokine production and IL-21-induced activation of ERK1/2. Inhibition of ERK1/2 activity by the ERK-selective inhibitor U0126 reverses the ability of IL-21 to upregulate cytokine production, suggesting that IL-21-induced cytokine production is dependent on ERK1/2 activation.     

Inhibition of cytokine function: Potential in autoimmune disease

Multiple lines of evidence implicate cytokines in the pathogenesis of autoimmune and inflammatory diseases. Neutralization of the biological activities of cytokines by interfering with ligand binding to specific cell-surface cytokine receptors thus represents an approach to controlling such diseases. Several agents, including novel, receptor-based antagonists, are being developed and tested in disease models.     

The role of soluble receptors in cytokine biology: the agonistic properties of the sIL-6R/IL-6 complex

Cytokines perform ever-increasing roles in both, the regulation of general homeostasis and in orchestrating the immune response during disease. To ensure that control of the cytokine network is tightly regulated, nature has developed a series of systems designed for this purpose. In this respect, researchers have placed considerable emphasis on identifying and characterising the regulatory properties of soluble cytokine receptors. These proteins bind their ligands with similar affinities to those of their cognate transmembrane receptors and are effective at prolonging the circulating half-life of cytokines they bind. However, it is the individual capacity of these soluble receptors to act as either antagonists or agonists which has been the principal focus of most research studies. This review provides an overview of the activities of soluble cytokine receptors, but primarily concentrates on those that possess agonistic properties.     

Impact of glycosylation on the effect of cytokines. A special focus on oncology

The clinical use of cytokines is largely confined to the field of cancer treatment. Industrial procedures for the preparation of cytokines may or may not affect the glycosylation status of several cytokines. The glycosylation of cytokines may be of importance for the accomplishment of their biological functions, including their biological stability, their interaction with specific receptors and their pharmacokinetic behavior. The purpose of this review is thus to describe and discuss the role of cytokine glycosylation, based on experimental data, and with the clinical perspective on oncology. There is no general rule governing the effects induced by the presence of glycosylation on cytokine activity. Among different cytokines concerned by glycosylation status, data concerning G-CSF are sufficient to translate experimental findings into clinical evidence. For this cytokine, glycosylation confers advantages for both stability and biological activity. Although at weight equivalence, the glycosylated form confers greater biological activity than the non-glycosylated form, clinical studies have demonstrated that efficacy remains the same when glycosylated and non-glycosylated G-CSF are prescribed at bioequivalent doses.