Cytokines and HIV infection

Infection with the human immunodeficiency virus (HIV) results in the production of cytokines by cells that comprise the immune system. Such cytokines regulate both immune function and viral replication, and thereby complicate their contribution to the progression to AIDS. Certain cytokines that regulate immune function exert opposing effects, such that some promote mainly cellular immune function, whereas others enhance antibody production. It has been suggested that an imbalance in cytokine production is responsible in part for the immune dysregulation characteristic of progression to AIDS. Different cytokines can also have different effects on HIV expression and replication. Cytokine-based therapy has been suggested for preventing or delaying progression to AIDS. If such therapy is to be successful, it will be necessary to identify the correlate of immune protection, as well as to determine which cytokines enhance or suppress protective immunity, and the effects of these cytokines on viral replication.     

The neuropoietic cytokine family in development, plasticity, disease and injury

Neuropoietic cytokines are well known for their role in the control of neuronal, glial and immune responses to injury or disease. Since this discovery, it has emerged that several of these proteins are also involved in nervous system development, in particular in the regulation of neurogenesis and stem cell fate. Recent data indicate that these proteins have yet more functions, as key modulators of synaptic plasticity and of various behaviours. In addition, neuropoietic cytokines might be a factor in the aetiology of psychiatric disorders.     

Dual biological effects of the cytokines interleukin-10 and interferon-γ

It is generally thought that each cytokine exerts either immune stimulatory (inflammatory) or immune inhibitory (antiinflammatory or regulatory) biological activities. However, multiple cytokines can enact both inhibitory and stimulatory effects on the immune system. Two of these cytokines are interleukin (IL)-10 and interferon-gamma (IFNγ). IL-10 has demonstrated antitumor immunity even though it has been known for years as an immunoregulatory protein. Generally perceived as an immune stimulatory cytokine, IFNγ can also induce inhibitory molecule expression including B7-H1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), and arginase on multiple cell populations (dendritic cells, tumor cells, and vascular endothelial cells). In this review, we will summarize current knowledge of the dual roles of both of these cytokines and stress the previously underappreciated stimulatory role of IL-10 and inhibitory role of IFNγ in the context of malignancy. Our progressive understanding of the dual effects of these cytokines is important for dissecting cytokine-associated pathology and provides new avenues for developing effective immune therapy against human diseases, including cancer.     

Cytokines in psoriasis

Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The disease is characterized by red, scaly and well-demarcated skin lesions formed by the hyperproliferation of epidermal keratinocytes. This hyperproliferation is driven by cytokines secreted by activated resident immune cells, an infiltrate of T cells, dendritic cells and cells of the innate immune system, as well as the keratinocytes themselves. Psoriasis has a strong hereditary character and has a complex genetic background. Genome-wide association studies have identified polymorphisms within or near a number of genes encoding cytokines, cytokine receptors or elements of their signal transduction pathways, further implicating these cytokines in the psoriasis pathomechanism. A considerable number of inflammatory cytokines have been shown to be elevated in lesional psoriasis skin, and the serum concentrations of a subset of these also correlate with psoriasis disease severity. The combined effects of the cytokines found in psoriasis lesions likely explain most of the clinical features of psoriasis, such as the hyperproliferation of keratinocytes, increased neovascularization and skin inflammation. Thus, understanding which cytokines play a pivotal role in the disease process can suggest potential therapeutic targets. A number of cytokines have been therapeutically targeted with success, revolutionizing treatment of this disease. Here we review a number of key cytokines implicated in the pathogenesis of psoriasis.     

Regulation of IGF-I function by proinflammatory cytokines: at the interface of immunology and endocrinology

During the past decade, the immune and endocrine systems have been discovered to interact in controlling physiologic processes as diverse as cell growth and differentiation, metabolism, and even human and animal behavior. The interaction between these two major physiological systems is a bi-directional process. While it has been well documented that hormones, including prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid-stimulating hormone (TSH), regulate a variety of immune events, a great deal of data have accumulated supporting the notion that cytokines from the innate immune system also affect the neuroendocrine system. Communication between these two systems coordinates processes that are necessary to maintain homeostasis. Proinflammatory cytokines often act as negative regulatory signals that temper the action of hormones and growth factors. This system of 'checks and balances' is an active, ongoing process, even in healthy individuals. Dysregulation of this process has been implicated as a potential pathogenic factor in the development of co-morbid conditions associated with several chronic inflammatory diseases, including type 2 diabetes, cardiovascular disease, cerebrovascular disease, inflammatory bowel disease, rheumatoid arthritis, major depression, and even normal aging. Over the past decade, research in our laboratory has focused on the ability of the major proinflammatory cytokines, tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta, to induce a state of IGF resistance. This review will highlight these and other new findings by explaining how proinflammatory cytokines induce resistance to the major growth factor, insulin-like growth factor-I (IGF-I). We also highlight that IGF-I can induce resistance or reduce sensitivity to brain TNFalpha and discuss how TNFalpha, IL-1beta, and IGF-I interact to regulate several aspects of behavior and cognition.     

The pathogenesis of thyroid autoimmune diseases: New T lymphocytes – Cytokines circuits beyond the Th1−Th2 paradigm

Autoimmune thyroid disease (AITD) is one of the most common organ-specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves’ disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs.     

The role of cytokines in immunological tolerance: potential for therapy

Current immunosuppression protocols, although often effective, are nonspecific and therefore hazardous. Consequently, immunological tolerance that is antigen specific and does not globally depress the patient's immune system has become one of the Holy Grails of immunology. Since the discovery that cytokines have immunomodulatory effects, extensive research has investigated the potential of these molecules to induce and maintain specific immunological tolerance in the context of transplantation, allergy and autoimmunity. In this article, we review the possible mechanisms by which cytokines can modulate the immune response and the animal models that frequently confound the theory that a single cytokine, or group of cytokines, can induce tolerance in a predictable manner. Finally, we discuss the role of cytokines at a paracrine level, particularly in the context of inducing and maintaining antigen-specific, regulatory T cells with the clinical potential to suppress specific immune responses.     

General Model of Inflammation

Dysfunctions in the immune system, due to genetics, disease or environmental factors, can cause bacterial colonization and chronic inflammation. In cystic fibrosis and chronic obstructive pulmonary disease, respiratory infections can initiate inflammation of the airway. We propose a system of nonlinear ordinary differential equations to describe interactions between macrophages, both inflammatory and anti-inflammatory cytokines, and bacteria. Small changes in parameters governing inflammatory cytokine production and macrophage sensitivity to cytokines result in dramatically different model behaviors. When the immune system is functioning properly, a non-aggressive pathogen will not provide a sufficient trigger to initiate chronic inflammation, however, in disease positive feedback of the inflammatory cytokine can induce chronic inflammation even after a bacterial infection has been resolved. In addition, if the macrophage population is more sensitive to inflammatory cytokines small perturbations initiated by bacteria will also lead to chronic inflammation. We have found nonaggressive bacteria are able to initiate chronic inflammation and propose why anti-inflammatory cytokine therapy may not be effective in resolving this inflammation.     

Central and Peripheral Cytokines Mediate Immune-Brain Connectivity

The immune system is a homeostatic system that contributes to maintain the constancy of the molecular and cellular components of the organism. Immune cells can detect the intrusion of foreign antigens or alteration of self-components and send information to the central nervous system (CNS) about this kind of perturbations, acting as a receptor sensorial organ. The brain can respond to such signals by emitting neuro/endocrine signals capable of affecting immune reactivity. Thus, the immune system, as other physiologic systems, is under brain control. Under disease conditions, when priorities for survival change, the immune system can, within defined limits, reset brain-integrated neuro-endocrine mechanisms in order to favour immune processes at the expenses of other physiologic systems. In addition, some cytokines initially conceived as immune products, such as IL-1 and IL-6, are also produced in the “healthy” brain by glial cells and even by some neurons. These and other cytokines have the capacity to affect synaptic plasticity acting as mediators of interactions between astrocytes and pre- and post-synaptic neurons that constitute what is actually defined as a tripartite synapse. Since the production of cytokines in the brain is affected by peripheral immune and central neural signals, it is conceivable that tripartite synapses can, in turn, serve as a relay system in immune-CNS communication.     

Cytokines and autoimmunity

Cytokines have crucial functions in the development, differentiation and regulation of immune cells. As a result, dysregulation of cytokine production or action is thought to have a central role in the development of autoimmunity and autoimmune disease. Some cytokines, such as interleukin-2, tumour-necrosis factor and interferons--ostensibly, the 'bad guys' in terms of disease pathogenesis--are well known for the promotion of immune and inflammatory responses. However, these cytokines also have crucial immunosuppressive functions and so, paradoxically, can also be 'good guys'. The balance between the pro-inflammatory and immunosuppressive functions of these well-known cytokines and the implications for the pathogenesis of autoimmune disease is the focus of this review.     

Hormones,Lymphohemopoietic Cytokines and the Neuroimmune Axis

The classical distinction between hormones and cytokines has become increasingly obscure with the realization that homeostatic responses to infection involve coordinated changes in both the neuroendocrine and immune systems. The hypothesis that these systems communicate with one another is supported by the ever-accruing demonstrations of a shared molecular network of ligands and receptors. For instance, leukocytes express receptors for hormones and these receptors modulate diverse biological activities such as the growth, differentiation and effector functions. Leukocyte lineages also synthesize and secrete hormones, such as insulin-like growth factor-I (IGF-I), in response to both growth hormone (GH) and also to cytokines such as tumor necrosis factor-α (TNF-α). Since hormones share intracellular signaling substrates and biological activities with classical lymphohemopoietic cytokines, neuroendocrine and immune tissues share a common molecular language. The physiological significance of this shared molecular framework is that these homeostatic systems can intercommunicate. One important example of this interaction is the mechanism by which bacterial lipopolysaccharide, by eliciting a pro-inflammatory cytokine cascade from activated leukocytes, modulate pituitary GH secretion as well as other CNS-controlled behavioral and metabolic events. This article reviews the cellular and molecular basis for this communication system and proposes novel mechanisms by which neuroendocrine-immune interactions converge to modulate disease resistance, metabolism and growth.     

Inflammatory response in preeclampsia

The origin of preeclampsia, a disease unique to pregnancy is still matter of debate and numerous theories have been proposed. The pathophysiology of the disease involves impaired trophoblast invasion, abnormal genetic polymorphism, vascular endothelial cell activation, immune intolerance by the maternal immune system, but also an exaggeration of a systemic inflammatory process. Preeclampsia is one of the major causes of maternal and perinatal morbidities including preterm births and therefore merits ongoing intensive research. The inflammatory process is determined by immunogenetic and non-immunogenetic factors. While inflammation mostly appears to be related to immunogenic determinants such as HLA antigens, paternity, monocytes, proinflammatory cytokines and NK cells, also responses not directly related to the immune system have been observed such as related to hypoxia or agonistic autoantibodies directed against vasoconstrictive angiotensin II receptors. The HIF-modulated reactions open up a new field in research as recently published data show the complexity of these factors.     

The expanding realm of heterologous immunity: friend or foe?

Antecedent or current infections can alter the immunopathologic outcome of a subsequent unrelated infection. Immunomodulation by co-infecting pathogens has been referred to as 'heterologous immunity' and has been postulated to play a role in host susceptibility to disease, tolerance to organ transplant, and autoimmune disease. The effect of various infections on heterologous immune responses has been well studied in the context of shared epitopes and cross-reactive T cells. It has been shown that prior infections can modulate protective immunity and immunopathology by forming a pool of memory T cells that can cross-react with antigens from heterologous organisms or through the generation of a network of regulatory cells and cytokines. While it is not feasible to alter a host's history of prior infection, understanding heterologous immune responses in the context of simultaneous unrelated infections could have important therapeutic implications. Here, we outline key evidence from animal and human studies demonstrating the effect of heterologous immunity on the outcome of disease. We briefly review the role of T cells, but expand our discussion to explore other immune mechanisms that may modulate the response to concurrent active infections. In particular, we underscore the role of the innate immune system, polarized responses and regulatory mechanisms on heterologous immune responses.     

Manipulation of cytokine production profiles as a therapeutic approach for immunologic pregnancy loss

Pregnancy is not as successful as one might think; it can be compromised by several complications such as recurrent spontaneous miscarriage, pre-term delivery, pre-eclampsia etc. Much attention has been paid to the possibility of the maternal immune system mediating deleterious effects on pregnancy. Research conducted during the last two decades has shed much light on cell-mediated immunologic effectors that might underlie these pregnancy complications. Of particular interest are the effects that pro-inflammatory and anti-inflammatory cytokines have on the foetus and placenta, and thus on the success and failure of pregnancy. This review presents evidences that certain cytokine profiles are associated with recurrent miscarriage and pre-term delivery and discusses possible pathways of effector function of cytokines in pregnancy loss and the redirection of cytokine profiles from one that is antagonistic to pregnancy towards one that is conducive to the success of pregnancy. Among the promising agents for the modulation of the Th1/Th2 balance are progestogens like progesterone and dydrogesterone; this review also discusses recent evidence that progestogens are capable of modulating cytokine production patterns in pregnancy loss.     

Physiology of adaptive immunity regulation via signaling pattern-recognition receptors

In the past fifty years, adaptive immune response has been studied from the standpoint of Burnet’s clonal selection theory. Much progress in understanding the mechanisms of specific cellular (T-cell) and antibody (B-cell) immune response has been made. However, it remained unclear why different pathogen types induce principally different types of immune response. Effective immune response in different cases may develop either by cellular or humoral type, and antibodies are produced on the basis of immunoglobulins of different classes. These facts could only be explained by specific regulation of differentiation of immunocompetent cells during the development of adaptive immune response to different pathogens. The discovery of the system of signaling pattern-recognition receptors (PRRs) in immunocompetent cells made it possible to understand these specific physiological mechanisms of regulation of T- and B-cell response to various pathogens. Upon interaction with pathogens, signaling PRRs activate the synthesis of various cytokines in the cells, which then regulate further activation of cells in different directions. Dendritic cells not only provide naive T cells with a processed antigen but also supply them with various cytokines inducing formation of type 1 or 2 T-helpers; as a result, adaptive immune response develops by the cellular or humoral type, respectively. Antigens of pathogens activate PRRs in B lymphocytes, which initiate the synthesis of various cytokines in cells. These are cytokines that determine predominant production by plasma cells of class A, M, G, or E antibodies depending on the pathogen type.     

A review on the effects of extremely low frequency electromagnetic field (ELF-EMF) on cytokines of innate and adaptive immunity

Extremely low frequency electromagnetic field (ELF-EMF) is produced extensively in modern technologies. Numerous in vitro and in vivo studies have shown that ELF-EMF has both stimulatory and inhibitory effects on the immune system response. This review was conducted on effects of ELF-EMF on cytokines of innate and adaptive immunity. Mechanisms of ELF-EMF, which may modulate immune cell responses, were also studied. Physical and biological parameters of ELF-EMF can interact with each other to create beneficial or harmful effect on the immune cell responses by interfering with the inflammatory or anti-inflammatory cytokines. According to the studies, it is supposed that short-term (2-24 h/d up to a week) exposure of ELF-EMF with strong density may increase innate immune response due to an increase of innate immunity cytokines. Furthermore, long-term (2-24 h/d up to 8 years) exposure to low-density ELF-EMF may cause a decrease in adaptive immune response, especially in T_h1 subset.     

Evolution of interleukin-1beta

All jawed vertebrates possess a complex immune system, which is capable of anticipatory and innate immune responses. Jawless vertebrates posses an equally complex immune system but with no evidence of an anticipatory immune response. From these findings it has been speculated that the initiation and regulation of the immune system within vertebrates will be equally complex, although very little has been done to look at the evolution of cytokine genes, despite well-known biological activities within vertebrates. In recent years, cytokines, which have been well characterised within mammals, have begun to be cloned and sequenced within non-mammalian vertebrates, with the number of cytokine sequences available from primitive vertebrates growing rapidly. The identification of cytokines, which are mammalian homologues, will give a better insight into where immune system communicators arose and may also reveal molecules, which are unique to certain organisms. Work has focussed on interleukin-1 (IL-1), a major mediator of inflammation which initiates and/or increases a wide variety of non-structural, function associated genes that are characteristically expressed during inflammation. Other than mammalian IL-1β sequences there are now full cDNA sequences and genomic organisations available from bird, amphibian, bony fish and cartilaginous fish, with many of these genes having been obtained using an homology cloning approach. This review considers how the IL-1β gene has changed through vertebrate evolution and whether its role and regulation are conserved within selected non-mammalian vertebrates.     

Selenium and Psoriasis

Psoriasis is a chronic, immune-mediated skin disease characterized by production of reactive oxygen species due to the activation of tumor necrosis factor alpha (TNF-??), which is thought to be an important factor in inducing and maintaining psoriatic lesions. As an external factor, ultraviolet B (UVB) radiation stimulates TNF-?? production and secretion by human keratinocytes in vitro and can also reach the upper dermis and suppress endothelial cells in vitro. The selenium level in psoriatic patients has been found to be lower than expected, but studies on its role in the pathogenesis of the disease are scarce. Selenium can influence immune response by changing the expression of cytokines and their receptors or by making immune cells more resistant to oxidative stress. It was reported that selenium supplementation had inhibitory effects on TNF-?? levels in patients with psoriasis, but the details are not completely elucidated. Selenium compounds are also known to prevent the in vitro release of UVB-induced proinflammatory cytokines by inhibition of mRNA in human keratinocytes. In the present review, the protective role of selenium in oxidative stress, lesions, and immune system regulation in patients with psoriasis is summarized.     

Cytokine polymorphisms in chronic inflammatory diseases with reference to occupational diseases

Genes which encode inflammatory cytokines are subject to polymorphisms in their regulatory regions that may effect both the level and ratio of cytokines produced in response to exogenous stimuli. These variant alleles are observed in a large percent of the population and are often associated with increased or decreased susceptibility or severity (modifiers) to infectious, immune or inflammatory diseases. Environmental factors can also play either a direct (i.e., causative factor) or indirect (modifying factor) role in these diseases. Thus, it would follow that gene-environment interactions would effect the expression and/or progression of the disease. In the present review, the concept that some of the common allelic variants found in cytokine genes represent modifying factors in chronic inflammatory diseases associated with occupational exposure is discussed.