Rheumatoid arthritis (RA) is a common chronic autoimmune disease leading to significant morbidity and mortality. Various cytokines are involved in RA pathogenesis forming a complex network with multidirectional relationships at different levels. Cytokines probably have a role in all stages of RA development from loss of tolerance to joint localized inflammation and its systemic consequences such as accelerated atherosclerosis. In this chapter, cytokines of different families, such as the TNF superfamily, IL-6 family, IL-10 superfamily, IL-2/ 15 superfamily, and some other cytokines are reviewed. Based on preclinical data and animal models, as well as findings on local expression of cytokines in inflamed joints, many cytokines have been shown to play a role in RA. The most overwhelming evidence comes from clinical studies exploring the efficacy of therapeutic disruption of particular cytokine pathways. To date, the most efficient strategies of anti-cytokine treatment have been the blocking of either TNF-alpha or IL-6. Therefore, these cytokines are currently considered of paramount importance in inflamed synovium. However, the above-mentioned therapeutic approaches are not universally effective, suggesting alternative pathways of regulation in synovial inflammation. Many newer cytokines are being studied in both experimental and clinical settings and, in the future, we hope to gain a greater understanding of the cytokine regulatory network and its interactions in RA.
Type 1 diabetes (T1D) is autoimmune-mediated destruction of pancreatic beta cells resulting in insulin deficiency. Cytokines are vital in diabetes development. They drive the development of autoreactive T cells and are important for activation and maintenance of the autoimmune response. Genetic and cell intrinsic defects in patients with T1D and in animal models of the disease lead to dysregulation of cytokine production and responses, which contributes to loss of immune tolerance and destruction of beta cells. Pro-inflammatory cytokines are produced locally in the islet where they induce expression of thousands of genes, many of which promote islet inflammation. IL-1, TNF and IFN gamma are toxic to beta cells in vitro and have been proposed to contribute to beta cell destruction by mechanisms involving free radical production and endoplasmic reticulum stress. However, in vivo, proinflammatory cytokines are likely to play an immunomodulatory role, increasing beta-cell recognition by T cells and promoting infiltration of macrophages and lymphocytes into the islets. Studying the role of cytokines in T1D has led to identification of important pathways in disease pathogenesis that could be specifically blocked to prevent diabetes.
Insulin resistance is the linchpin for development of the cardiometabolic syndrome and type 2 diabetes. Resistance to the actions of insulin in skeletal muscle is important in development of systemic insulin resistance given that skeletal muscle normally accounts for approximately 75% of all insulin-mediated glucose disposal. However, the molecular mechanisms responsible for skeletal muscle insulin resistance remain poorly defined. Understanding the mechanisms by which skeletal muscle tissue develops resistance to insulin could provide attractive targets for therapeutic interventions. There is emerging evidence of an integral relationship between chronic inflammation, oxidative stress, and skeletal muscle insulin resistance due to circulating inflammatory cytokines derived from adipose tissue (e.g., adipokines) or from local autocrine/paracrine effects of skeletal muscle-derived cytokines (e.g., myokines). This chapter is focused on the effects of inflammatory cytokines and oxidative stress on insulin signaling in skeletal muscle and consequent development of systemic insulin resistance.
This review summarizes our understanding of the role that the cancer cytokine network plays in tumor survival and growth. The tumor cytokine network comprises tumor and stroma-produced factors and receptors. Cytokines produced by tumor cells and stroma cells are critical for tumor cell proliferation and for the formation of neovasculature that provides the oxygen and nutrients necessary for progressive tumor growth. Increasing amounts of experimental evidence indicate that chemotherapeutic drug treatment could stimulate the production of multiple cytokines. This drug-induced cytokine production enrichment is the adaptive response by which tumor cells attempt to protect themselves from the genotoxic stress induced by these drugs. Numerous growth factors and chemokines share angiogenic and growth-stimulating properties; thus, reducing a single factor is insufficient for complete blockage of tumor growth. Instead, a broad disruption of the tumor cytokine network should improve the efficacy of current anticancer strategy. Drug-resistant and self-renewing cancer stem cells (CSCs) are thought to be responsible for the failure of current cancer chemotherapy. CSCs, in comparison to bulk tumor cells, manifest higher levels of growth and angiogenic factor production and over-express certain receptors. Because these characteristics are unique to CSCs, they may be potent targets for cancer therapy. Combining standard chemotherapy with the targeting of specific axes of cytokine network in bulk tumor cells and CSCs could increase the efficacy of cancer therapy.
Alzheimer's disease pathology involves β-amyloid and tau. Various potential pharmacological targets are discussed that may be able to alleviate the accumulation of β-amyloid and tau. Possible causes of Alzheimer's disease are discussed involving impaired glucose and lipid metabolism and obesity. Adipokines may be involved in the etiology of Alzheimer's disease. An extensive discussion of the evidence concerning the adipokines leptin, adiponectin, resistin, visfatin, plasminogen activator inhibitor, interleukin-6 and transforming growth factor β1 as causes of Alzheimer's disease is presented.
There are changes in the immune system and the responsiveness of the system slows with advancing age. It is suggested that dysregulation of cytokines plays a significant role in this alteration of the immune response. Here the role of some cytokines in mortality, longevity, and in two clinical conditions with high prevalence in elderly population, frailty and delirium, is presented and discussed.The levels of IL-6 and possibly of TNF-alpha increase with age, while the levels of IL-2 decrease. Similarly, high levels of IL-6 and perhaps of TNF-a are associated with mortality. However, genetic studies have produced conflicting results regarding longevity and cytokines.Furthermore, there is evidence that frailty, which is characterized by weight loss, low activity, functional decline, slow motor performance and cognitive decline, is associated with high levels of IL-1 alpha, IL-6 and TNF-alpha.Finally, in delirium, which is oft en caused by infections and frequently is a side effect of therapeutic use of cytokines, a close relationship is expected with cytokines. However, only few studies have investigated this relationship and the results are contradictory.Despite the conflicting results, it seems that levels of cytokines change with age, elevated levels of pro-inflammatory cytokines are associated with frailty in older adults, and they possibly have a direct effect in cognitive and functional decline, while their relationship with delirium needs to be further evaluated. The mechanisms of the above effects are not fully understood and further studies, preferably longitudinal and in groups of cytokines, are needed to elucidate those mechanisms.
Cytokines constitute a broad family of inflammatory and regulatory mediators that play outstanding roles in organic complications of alcoholism, contributing to the protean manifestations of this disease. Alcohol increases gut permeability to endotoxin, leading to Kupffer cell activation and pro-inflammatory cytokine secretion. This initiates a cascade of events characterized by inflammation, lipid peroxidation, neutrophil recruitment, and immune activation, closing a positive feedback loop, ultimately leading to liver cell necrosis and apoptosis. Therefore, alcoholic hepatitis can be considered as a TNF-alpha-mediated disease; in more advanced stages of the disease, TGF-beta plays a more important role, promoting fibrosis both in the liver (leading to cirrhosis) and in the pancreas (leading to chronic pancreatitis). Increased TNF-alpha favours muscle atrophy, is probably involved in neurodegeneration and brain atrophy, and contributes to alcoholic cardio-myopathy and bone alterations, together with other cytokines, especially IL-6, a well-known activator of osteoclasts. Moreover, altered cytokine secretion in alcoholics may predispose them to sepsis and severe pneumonia. However, despite the proven action of TNF-alpha in some organs, such as the liver, anti-TNF treatment trials in alcoholic hepatitis have led to disappointing results, suggesting that vigorous research is still needed to fully elucidate the role of these inflammatory modulators in alcohol-related organic dysfunction.
Cytokines, as messengers of the immune system, are being used in cancer therapy to enhance anti-tumor immunity. IL-2 and IFN-alpha are two FDA-approved cytokines for the treatment of cancers. GM-CSF and IL-12 are also being used as vaccine adjuvant to enhance immune responses against cancers. However, side effects associated with the injection of these cytokines and their limited efficacy in only a fraction of cancer patients remain major issues. Recently, certain cytokines with potential activity on expanding tumor-reactive T cells have been tested ex vivo rather than in vivo in order to overcome safety issues and facilitate the differentiation of tumor-specific T cells for adoptive T cell immunotherapy (AIT). Identification of key cytokines that enhance proliferation and differentiation of tumor-reactive T cells for producing an objective response upon AIT is crucial for manipulating immune responses against cancer. Thus far, common gamma chain cytokines (IL-2, IL-7, IL-15, IL-21) have been shown to be promising candidates for the generation of T cells that can induce tumor regression upon AIT. The present review will focus on ex vivo use of common gamma chain cytokines either alone or in combination by introducing different ex vivo protocols for the expansion of tumor-specific T cells for AIT of cancer.
NK cells are important lymphocytes characterized by a CD56(+) CD3(-) phenotype. Based on the expression of CD56 and CD16, NK cells are divided into CD56(bright)CD16(-) and CD56(dim)CD16(+) subsets. These two NK cell subsets differ in cytokine secretion and cytoxicity; CD56(bright)CD16 cells are more proficient in cytokine secretion, while CD56dimCD16(+) cells are better at mediating cytotoxicity. IL-15 transpresented by dendritic cells plays a critical role in the normal development, homeostasis and activation of NK cells. NK cells secrete several cytokines and chemokines, which play a key role in orchestrating an immune response early aft er exposure to pathogens. The importance of NK cells in clearing viral infections is underscored by the recurrent life-threatening viral infections in patients with absent or dysfunctional NK cells. This has led to studies on NK cells in viral infections such as HIV, cytomegalovirus and hepatitis. Yet, not all NK cell reactions are beneficial. There is some evidence of their overzealous role in a mouse model of diabetes mellitus and other autoimmune diseases. We have been interested in the role of NK cells in immune surveillance against malignant cells to treat cancers that have failed standard therapy. NK cells are thought to contribute to what is called a graft versus leukemia (GvL) effect in the setting of allogeneic hematopoietic cell transplantation (allo-HCT). The goal of this chapter is to provide an overview of NK cell biology and ways in which to exploit this knowledge to treat human disease
Breast tumors develop within a specialized tumor microenvironment that consists of numerous cell types, including cancer cells, stromal cells, adipose tissue, and infiltrating immune cells. These cells release a wide range of factors that can modulate tumor development by regulating cancer cell proliferation, survival, invasion and motility, as well as local blood vessel formation, or angiogenesis. In particular, cytokines are highly expressed in the breast tumor microenvironment and can play a crucial role in many of these processes during breast tumorigenesis. Cytokines also appear to be important in breast tumor metastasis, particularly to the bone, where cytokines are abundantly expressed. Interestingly, the effects of cytokines can be pro-tumorigenic and lead to enhanced tumor development and progression to a more aggressive disease, or anti-tumorigenic with reduced tumor growth and inhibition of tumor angiogenesis. Furthermore, the effects of cytokines can result from both modulation of the immune system and direct effects of cytokines on the tumor itself, independent of the immune system. The direct effects, rather than the immuno-modulatory effects, of cytokines on breast tumor growth, invasion, and metastasis are the focus of this chapter.
Bone turnover is due to cyclic bone resorption followed by bone apposition; these processes are due to the coordinated actions of osteoclasts (OCs) and osteoblasts (OBs). The actions of these two cellular types are orchestrated by osteocytes (OSs) that differentiate from osteoblasts and are the most abundant cells in bone. OCs are formed by the attraction of myelomonocytic precursors to the resorption site; the fusion of these cells generates a multinucleated cell attached to the bone surface. OBs derive from a mesenchymal stem cell precursor shared with adipocytes. OSs are thought to be the cells primarily responsible for mechanosensing in bone. Numerous cytokines are thought to be responsible for the regulation of bone turnover; most of them have pleiotropic actions and are involved in the regulation of systems other than skeleton. OC formation and function are mainly regulated by the essential factor RANKL, whereas other cytokines increased during inflammation up-regulate OCs and are involved in inflammation-induced bone loss. OB formation and activity are believed to be mainly regulated by the Wnt and BMP signaling pathways.This review will focus on the main cytokines involved in the regulation of osteoclastogenesis, osteoblastogenesis, and coupling of osteoclasts and osteoblasts under physiological and pathological conditions.
Parkinson's disease (PD) is characterized by tremor, rigidity, and slowness of movements and is associated with progressive neuronal loss of the substantia nigra (SN) and other brain structures. Ample evidence of chronic inflammatory reactions in the brain of PD patients is shown. Neuroinflammatory responses in the brain involve different cells of the immune system (e.g., macrophages, mast cells, T and B lymphocytes, dendritic cells), resident cells of the central nervous system (CNS) (e.g., microglia, astrocytes, neurons), many protein components (e.g., complement, adhesion molecules, chemokines, cytokines) and cytotoxic substances (e.g., reactive oxygen and nitrogen species). Soluble molecules or cytokines released by immuno-competent cells may be responsible for the bidirectional communication between cells of the nervous and immune systems. One hypothesis is that inflammation starts within the CNS, where several inflammatory products are formed and are quickly removed into the bloodstream. On the other hand, it has also been proposed that inflammation develops at first in the periphery and then will contribute to brain damage and finally neurodegeneration. Elevated levels of pro-inflammatory cytokines, such as tumour necrosis factor a (TNF-alpha), interleukin (IL) 1 beta, IL-6 and the colony-stimulating factor, have been demonstrated in the brain and cerebrospinal fluid (CSF) as well as basal ganglia of PD patients. Peripheral blood mononuclear cells deriving from patients with PD have been reported to have an altered production of TNF alpha-as well as IL-1 alpha and -1 beta compared to healthy controls, while IL-2, IFN-gamma, IL-6 and plasma-soluble interleukin-2 receptor (sIL-2R) are no different from healthy controls.The identification of biomarkers for neurodegenerative diseases such as PD is required to improve the accuracy of clinical diagnosis and monitor both disease progression and response to treatments.
There is increasing interest in the roles of inflammation and of pro-inflammatory cytokines in cardiovascular disease (CVD), including coronary heart disease (CHD), stroke, peripheral arterial disease (PAD) and venous thromboembolism. Worldwide, inter-individual differences in CVD risk are largely explained by well-established cardiovascular risk factors. These may be non-modifiable (age, male sex) or modifiable (tobacco smoke exposure, arterial blood pressure, blood cholesterol, obesity, diabetes, psychosocial factors).We have hypothesized that the effects of these risk factors on CVD may be partly mediated by pro-inflammatory cytokines and their effects on atherosclerosis, thrombosis and blood rheology. In this chapter, we review large epidemiological studies of the associations of their circulating levels (and their functional genotypes) with risk factors, and with risk of CVD. Most published information is available for circulating interleukin-6 (IL-6), levels of which are associated with most risk factors, risk of CHD, outcome of stroke, progression of PAD, and blood viscosity. These associations of IL-6 may partly explain the associations of circulating "downstream" inflammatory markers-C-reactive protein (CRP), fibrinogen, white cell count, erythrocyte sedimentation rate (ESR), blood viscosity-with risk of CVD: a hypothesis that can be tested by Mendelian randomization studies, or by randomized controlled trials of cytokine-antagonist drugs. Less epidemiological information is currently available for other pro-inflammatory cytokines such as interleukin-18 (IL-18), tumour necrosis factor alpha (TNF alpha), matrix metalloproteinase-9 (MMP-9) and leptin, and anti-inflammatory cytokines such as adiponectin and interleukin-10 (IL-10). Ongoing studies should clarify their associations with risk factors and with risk of CVD and, where appropriate, assess their causality.
Physical activity and exercise not only provide health benefits that contribute to the quality of life in healthy subjects, but also mitigate many aspects of disease or chronic conditions, particularly cardiovascular disease (CVD), by reducing risk and controlling disease progress. Atherosclerosis, the underlying pathological process for CVD, occurs as the result of imbalance between endothelial injury resulting from chronic inflammation and production of reactive oxygen species (ROS) and vascular repair induced at least in part by circulating endothelial progenitor cells (EPCs). Importantly, pro-inflammatory cytokines stimulate the production of ROS that in turn activate various intracellular signaling pathways leading to further increase in ROS production, creating a positive feedback loop. Considerable evidence suggests that exercise can disrupt the positive feedback loop, thus suppressing inflammation and ROS production. Exercise also mobilizes EPCs from the bone marrow and improves their self-renewal potential and differentiation capability, although the mechanisms for such effects are less well understood. Acute exercise can, however, trigger a cardiovascular event. Thus, exercise appears to be a double-edge sword, which in the long run can maintain the equilibrium between vascular injury and repair. As with pharmacological approaches, individuals respond to exercise differently. The Genetics, Exercise and Research (GEAR) program at the University of Miami uses genomic and epigenomic approaches to decipher the molecular mechanisms underlying EPC mobilization and the spectrum of responses to various forms of exercise, in an attempt to provide the scientific basis for optimized personalized training programs.
Cytokines are small secretory proteins produced de novo in various cell types in response to immune stimuli and serve as molecular messengers between cells. They provide important intercellular signals in inflammation, immunity, and tumorigenesis. Cytokines and their receptors are associated with cancer development and progression. The mechanisms of involvement of cytokines in cancer are diverse. They include leukocyte infiltration into cancer tissue, regulation of cell cycles, programmed cell death of cancer cells, and immune response to cancer cells. Th us, locally and/or systemically deregulated levels of cytokines and receptors can be detected in all types of cancer patients. Many types of cytokines, including various interleukins and interferons, have been studied for their relationship with various cancers, including lung cancer. Intratumoral or serum cytokine or growth factor levels can be used as valuable markers for diagnosis, prognosis, and prediction for patient types, indicating whether a patient might positively or negatively benefit from a particular treatment; these markers also help in monitoring treatment response and disease recurrence. In addition, the potential tumoricidal effects and therapeutic efficacy of various types of cytokines have been examined in pre-clinical animal studies and clinical trials. Many pre-clinical studies revealed that local injection of various interleukins and multiple cytokine gene therapies caused regression of multiple cancers, including non-small cell lung cancer. However, their effect on established tumors is limited, primarily due to their cytotoxicity and short half life. Therapies with antibody-cytokine fusion proteins and tumoritropic cell-based gene therapy can overcome this limitation of cytokine cancer therapy. Recent studies with mesenchymal stem cell-based interferon-beta gene therapy using either human bone marrow stem cells or human umbilical cord matrix stem cells demonstrated significant tumor regression in lung bronchioloalveolar carcinoma, a subset of adenocarcinoma, in mouse studies. Stem cell-based cytokine gene therapy is feasible in lung cancer-targeted, safe cytokine gene therapy.
Obesity, particularly abdominal obesity, is a well-established risk factor for MetS, T2DM and CVD. The primary goal for obesity treatment is to prevent and treat these chronic diseases. MetS is a cluster of cardiovascular risk factors including abdominal obesity, elevated plasma glucose, dyslipidemia, hypertension and prothrombotic/pro-inflammatory state. Inflammation is now recognized as a central mediator in CVD and T2DM. In the state of obesity, pro-inflammatory and pro-thrombotic factors are produced in the adipose tissue. Via producing chemokines, macrophage migration to the adipose tissue is strongly amplified. Thus, it is evident that adipose tissue participates actively in the development of insulin resistance and inflammation.Unhealthy diet, as well as sedentary lifestyle, also plays a key role in the development of inflammation. It has been hypothesized that postprandial dysmetabolism, characterized as repeated high and long-term increases of glucose and lipid concentrations aft er meals, may result in inflammation, endothelial dysfunction and development of atherosclerotic damage. There is solid evidence that many chronic health problems could be overcome by effective lifestyle modification.Weight loss markedly decreases macrophage accumulation and production of inflammatory markers in adipose tissue. It has been indicated that decreasing energy intake and increasing physical activity may be effective in reducing overall inflammation. It is the aim of the present chapter to introduce some of the key cytokines/adipokines and their function during the development of inflammation in MetS, with a focus on adipose tissue function in the state of obesity.
Cytokines are mediators of inter-and intracellular communications. These peptides contribute to a chemical signaling language that regulates homeostasis, tissue repair and immune responses.We have shown that glycemic excursions are associated with elevation of pro-inflammatory cytokines. We noted the increased levels of pro-inflammatory cytokines (including IL-8, IL-6, IL-1 beta and TNF-alpha) and markers of oxidative stress and cardiovascular risks concomitant with increased levels of the counter-regulatory hormones and leukocytes in hyperglycemic crises. Similarly, the acute stress of hypoglycemia by insulin-induced tolerance test in non-diabetic subjects resulted in the stimulation of pro-inflammatory cytokines, leukocytosis and markers of oxidative stress and lipid peroxidation. We conclude that the elevation of pro-inflammatory cytokines and markers of oxidative stress in glycemic excursions are the result of adaptive responses of hypothalamus-pituitary-adrenal and sympathoadrenal systems to non-inflammatory stressors such as hypo-or hyperglycemia.
CD4(+) T cells, also called T helper (Th) cells, are an important part of the adaptive immune system. A number of distinct CD4(+) T cell subsets have been elucidated that presumably evolved to control a diverse array of microbial pathogens. These subsets are adapted to the tissue in which they reside such that they have unique activities and functions that govern different aspects of the immune system. CD4(+) T cells exert their control largely via the regulated production and release of cytokines. Although a number of distinct effector CD4(+) T cell subsets have been described, the best characterized to date include Th 1, Th 2, and Th 17 cells. Th 1 cells are important in protection from intracellular bacteria, viruses and fungi and secrete the cytokines IL-2, IFN-gamma, TNF-alpha and LT-alpha. Th 2 cells are a critical part of the immune response to helminth infections and produce IL-4, IL-5, IL-13 and IL-25. Th 17 cells are a more recently characterized group of Th effectors that play a role in clearing extracellular bacteria and other pathogens and also help maintain epithelial barrier integrity. Th is is largely achieved by secretion of IL-17A, IL-17F and IL-22. Another group of CD4(+) T cells includes regulatory T cells (Treg), which control effector Th cells and suppress other inflammatory pathways oft en by the production of cytokines IL-10 and TGF-beta 1. Although CD4(+) T cells and cytokines have an important role in host defense, uncontrolled or dysregulated Th responses contribute to a number of autoimmune and inflammatory diseases.
Cytokines are small proteins excreted by cells with the purpose of intercellular communication. They are known to modulate a host's immune response to infection, particularly viral infections, by recruiting immune cells to the site of infection and signaling defense mechanisms in both infected and un-infected cells. As such, cytokines are part of a strong antiviral defense mechanism by the host and represent a formidable obstacle to the virus surviving in the infected individual. They can also be used by viruses to aid in the replication and persistence of the virus. As a result, while many viruses have evolved different mechanisms to subvert the action of cytokines, others produce homologues of cytokines that assist in their replication and/or pathogenicity. In this chapter, we discuss these different viral responses to cytokines. Hepatitis B and C and influenza viruses are used as examples to demonstrate the up-regulation of cytokine production by virus infection and ways in which the virus combats this response. Herpesviruses are used as examples of how expression of viral homologues of cytokines can influence the immune response, producing a different response than their cellular counterparts. We review how viral cytokines can assist in fighting a host's immune response as well as benefit viral replication.
The human immunodeficiency virus (HIV) is a pathogenic exogenous human retrovirus responsible for the death of millions of people in the world. It infects and spreads mainly in CD4+ cells (mostly T lymphocytes and mononuclear phagocytes), but it can also profoundly interfere with the host innate and adaptive immune responses inducing their profound dysregulation and exhaustion. In this scenario, HIV alters the production of chemokines and cytokines (regulators of the immune system that are necessary for cellular proliferation, trafficking and activation against viral and bacterial pathogens) in order to favor either its own replication or latency. Conversely, cytokines and chemokines regulate most if not all of the crucial steps of HIV replication, including the regulation of its latent state.This chapter will review these mutual aspects of the interaction between HIV and the cytokine/chemokine network.
