Tumor necrosis factor (TNF) is one of the most extensively studied cytokine with about 19 distinct superfamily members and many more to be found.Prominent among these members is tumor necrosis factor alpha (TNF-α) that is known to be a potent promoter of inflammation, as well as many normal physiological functions in homeostasis and health and antimicrobial immunity.Nuclear factor kappa-light-chain enhancer of activated B cells (NFκB) is one of the most important transcription factors that activate transcription of many proinflammatory genes, and the unraveling of TNF-α induced NFκB activation forms the foundation of TNF-α as major cytokine of neuroinflammation.This review discusses summary of literature on unique role of TNF-α in neuroinflammation and various agents that mediate neuroinflammation via TNF-α modulation.
The bacterial challenge on the periodontal tissues triggers an inflammatory reaction, driven by pro-inflammatory cytokines, that eventually leads to the periodontal structures' damage. The pathogenic mechanisms of this inflammatory reaction are complex and are influenced by the type of host-immune response and certain local and systemic factors. These factors can influence periodontal inflammation, through the action of the various pro-inflammatory cytokines. Periodontal disease and certain systemic conditions can have a mutual association, as the pathogenic mechanisms of these diseases can involve similar molecular and cellular elements. The concept of 'periodontal medicine' comprises these pathogenic connections, focusing on the key role that periodontal health has on the general homeostasis and well-being.
Behçet's disease (BD) is a complex, multisystemic inflammatory disorder characterized by recurrent oral aphthous ulcers, ocular symptoms, skin lesions, and genital ulcerations. The etiology of BD is not yet clear though various factors including environmental, genetic and immunological ones have been implicated. Genetic predisposition is a major factor in disease susceptibility and multiple host genetic factors have been suggested to be involved in the development of BD. In addition to the positive association of HLAB*51, recent studies report additional independent associations in the non HLA loci. Single nucleotide polymorphisms (SNPs) in various genes including cytokines have been implicated in susceptibility to BD. However, the results are inconsistent and variation are found in several ethnic populations. Therefore, further genetic studies on BD patients of different ethnicity and genes associated with immunity are expected to elucidate BD pathogenesis and will contribute to the development of more targeted therapies and biomarkers.
Human cell-based assays for in vitro testing of drugs in preclinical and research studies, as well as in clinical practice, are gaining greater importance especially in view of personalized medicine, which is tailored to the individual needs and benefits of a patient.This chapter begins with an overview of contemporary cell-based assays, routinely used for a comparative in vitro potency testing of anti-TNF-α innovator biologics and their biosimilars.In sequel, based on the results of our original work, we will further discuss the establishment and use of 2D normal and osteoarthritic primary chondrocyte monolayer cultures and 3D microspheroidal articular cartilage tissues, prepared in hanging drops from osteoarthritic chondrocytes and chondrogenically differentiated mesenchymal stem cells.Both 2D and 3D cultures will be presented as models for assessing the neutralizing potency of the three wellknown anti-TNF-α biological drugs: adalimumab, etanercept, and infliximab.
The historical background of immunologyWhen we are reading or investigating the topics of cellular and molecular immunology including cytokines, our unconscious mind suddenly goes back to the Iranian "Immunologist King," Mithridates VI Eupator of Pontus.Pontus is a Greek term referring to the Sea; but conceptually -in accordance with geographic evidences of that time period -it refers to the Black Sea.Indeed, he is known as the first immunologist in the ancient world [1][2][3][4].Mithridates VI Eupator of Pontus (reigned 120-163 BC), the son of Mithridates V Euergetes, was proud over his Iranian heritage and ruled the Pontus region (Asia Minor, The Great Persia Empire Region; Present-day Turkey) throughout the Hellenistic and Mithridatic Kingdoms.Despite accepting Hellenism, he always considered himself as an Iranian king from royal Achaemenid lineages.Indeed, his Iranian origin went back as far as Darius I and Cyrus the Great (The King of Kings).His name Mithridates depicts the God of Light (Mithradatha: sent (given) by Mithra, the ancient Iranian God of Sun) [1,2,[5][6][7].Mithridates VI Eupator of Pontus is the founder of the Mithridatism theory which refers to the phenomenon of acquired immunity against poisons, by using determined doses of the poison to expose the individual to the agent little by little [8].Hence, he used cocktails of antidotes against currently known poisons every day.The potion of Mithridates VI Eupator of Pontus was a mixture of 54 currently known poisons which was termed "Antidotum Mithridaticum."His popular poisonous potion was consumed by people from all walks of life for about two millennia [6,9,10].This process is very similar to the act of vaccination and may be considered as a preliminary form of preventive medicine [11].Mithridates VI Eupator of Pontus was a genius because he was not only an exceptional expert in immunization and toxicology, but he could also talk in 22-25 different languages.Moreover, he was interested in medicine and pharmacology; therefore, Mithridates VI Eupator of Pontus has written several treatises regarding the characteristics of "materia medica" together with the related cases.These invaluable Mithridatic treatises were translated into Latin between 95 and 25 BC by Lenaeus, which were recognized as unique and effective prescriptions in Rome [12].He was a researcher in the fields of immunology, toxicology, pharmacology, and medicine [4,11,12].Due to this fact, the Iranian king, Mithridates VI Eupator of Pontus is a shining star in the treasure of science and history of Iran.
TNF has both proinflammatory and antiinflammatory effects. It binds to two structurally related but functionally distinct receptors TNFR1 and TNFR2. Unlike TNFR1 that is ubiquitously expressed, TNFR2 expression is more limited to myeloid and lymphoid cell lineages including a fraction of regulatory T cells (Treg). In general, TNFR1 is responsible for TNF-mediated cell apoptosis and death, and mostly induces proinflammatory reactions. However, TNFR2 mainly leads to functions related to cell survival and immune suppression. Treg play an indispensable role in maintaining immunological self-tolerance and restraining excessive immune reactions deleterious to the host. Impaired Treg-mediated immune regulation has been observed in various autoimmune diseases as well as in cancers. Therefore, Treg might provide an ideal therapeutic target for diseases where the immune balance is impaired and could benefit from the regulation of Treg properties. TNFR2 is highly expressed on Treg in mice and in humans, and TNFR2+ Treg reveal the most potent suppressive capacity. TNF-TNFR2 ligation benefits Treg proliferation, although the effect on Treg suppressive function remains controversial. Here, we will describe in detail the TNF-mediated regulation of Treg and the potential clinical applications in cancer immunotherapy as well as in autoimmune diseases, with the focus on human Treg subsets.
Interleukin-21 (IL-21) is produced by activated T cells and it plays many diverse roles by regulating the functions of normal and abnormal cells. Its roles include regulation of proliferation, promotion of immune system and activation of apoptosis in B cells. IL-21R is a type-1 cytokine receptor and belongs to the IL-2R and IL-15R family. The signaling mechanisms of IL-21 in different cell types have been identified. However, we know less about the biological effects of IL-21 and its signaling mechanisms in leukemia cells and monocytes. In this chapter, we will focus on IL-21's biological effects and signaling pathways as well as discuss the potential implications and applications of IL-21 in leukemia cells. In these cells, IL-21 does not promote proliferation but enhances apoptosis and chemotaxis. Furthermore, IL-21 promotes differential expression of many cytokines including interleukins and chemokines. IL-21 activates both the Raf-ERK-MAPK and the Jak/STAT signaling pathways. These pathways mediate some of the effects of IL-21. Lastly, IL-21 also promotes activation of the STAT3 promoter and other transcriptional factors. These findings may be relevant to IL-21's potential clinical implications and applications.
The inflammatory response after a spinal cord injury (SCI) is a secondary mechanism of damage, this involves alterations at the local and systemic level, and it is mediated by cytokine participation that takes part actively. The excessive inflammatory response causes an autoreactive response that targets against components of the nervous tissue; this response lengthens the inflammatory process initiated during the acute phase. The participation of immune cells in acute phases is characterized by the arrival of neutrophils, macrophages, and microglia, as well as T lymphocytes, which express their peaks on different days post-injury (1st, 3rd, and 11th respectively). The chronic phase of the injury begins 14 days after it occurred, reaching its highest point at 60 days, and can still be detected the following 180 days. One of the outcomes of the inflammatory process and cytokine synthesis is the generation of glial scar. In this chapter, we will review the different cytokine mechanisms involved in the formation of glial scar in acute and chronic phases, as well as the modulating treatments of glial scar.
The neuroimmune network represents a dense network of multiple signals mediated by neurotransmitters, hormones, growth factors, and cytokines produced by multiple lineage cells and is crucial for maintaining neuroimmune homeostasis.Endogenous and exogenous stimuli, which are dangerous to the body, are detected by sensor cells, and they rapidly inform the brain through this network.Innate immunity is thought to play a major role in the neuroimmune network, through cytokines and other mediators released from secretary innate immune cells.Recent research has revealed that innate immunity has its own memory.This is accomplished by metabolic and epigenetic changes.Such changes may result in augmenting immune protection with a risk of excessive inflammatory responses to subsequent stimuli (trained immunity).Alternatively, innate immune memory can induce suppressive effects (tolerance), which may impose a risk of impaired immune defense.Innate immune memory affects the neuroimmune network for a prolonged period, and dysregulated innate immune memory has been implicated with pathogenesis of neuropsychiatric conditions.This chapter summarizes a role of innate immune memory (trained immunity vs. tolerance) in neuroinflammation in association with neuropsychiatric conditions including autism spectrum disorders (ASD).
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.
