Introduction
Inflammatory and immune responses play an important role in the immune system. Exposure to substances (allergens) can cause damage to internal or external structures, e.g. tissue damage, or subsequently induce an adequate immune response [1–4]. The first and fundamental step of the immune system is to recognize the danger and subsequently react to what threatens the organism. The immune system recognizes anything that causes stress or can cause tissue damage as a threat. Exogenous molecules (pathogenic molecular patterns – PAMPs) can activate immune cells. In addition to exogenous molecules, endogenous alarmins (produced in stressful situations) can also activate immune cells. According to Castellheim et al., damage-associated molecular patterns (DAMPs) can be categorized as exogenous and endogenous molecular patterns. The innate immune system is the first to respond, followed by lymphocyte activation and production of pro-inflammatory cytokines. The inflammatory response contributes to further tissue damage. The main prerequisite for the development of inflammation is the activation of immune system cells. Subsequently, pattern-recognition receptors (PRRs) trigger the production of inflammatory mediators that can alter tissue or organ function [3–5].
Immune system, innate and adaptive immunity
The immune system is a collection of cells, chemicals and processes that protect the human body from foreign antigens such as microbes, cancer cells, viruses and others. The immune system fights against various pathogens of biological, chemical or physical nature that may be present in the blood, tissues or skin [4, 6]. The regulation of the immune response is mediated by antigen presenting cells (APCs) – monocytes, dendritic cells, phagocytic cells, which are incorporated under innate immunity, and T helper (Th) lymphocyte subclasses Th1, Th2, which are a part of adaptive immunity [7, 8].
Innate immunity is a rapid immune response that takes place within minutes (or hours) of being attacked by an agent. It is the first and general mechanism against a pathogen [4, 5, 9]. Since it has no immunological memory, it is unable to recognize (or remember) a pathogen that has also infected the body in the past. It can be argued that innate immunity consists of four protective barriers: anatomical (skin, mucosa), physiological (pH, temperature, chemical mediators), endocytic and phagocytic, inflammatory barrier, and cells that release cytokines and inflammatory mediators (e.g., macrophages, mast cells, natural killer cells). Innate immunity includes pattern recognition receptors (PRRs). Through these receptors, a certain number of immune cells can find and rapidly respond to a wide range of pathogens that have molecular patterns associated with the pathogen (common structures – bacterial wall components, lipopolysaccharides, RNA produced during viral infection etc.) – molecular patterns associated with pathogens – PAMPs [9, 10]. Innate recognition initiates basic cellular responses to host cell interaction with invading microbes. PAMP innate recognition activates innate immune responses to generate immunogenic signals. These in turn induce some specific components of adaptive immunity [11].
Adaptive (staggered) immunity is antigen-dependent and involves a time lag between antigen exposure and the maximal response. The hallmark of adaptive immunity is its memory capacity in generating a faster and more effective immune response [9, 12]. The cells of the adaptive immune system are T-lymphocytes and B-lymphocytes, which are highly motile. After development in primary lymphoid organs (thymus, bone marrow), they move to secondary lymphoid organs including the spleen and lymph nodes. In these organs, they serve to capture antigens circulating in the blood and lymph. Adaptive immune responses may also respond to indirect stimuli from mucosal antigen-presenting cells (APCs) that migrate to secondary organs. Lymphocytes can then travel to many sites in the body where they perform effector functions [13, 14].
Inflammation
The body’s response to injury, chemical toxins, invading microorganisms or hypersensitivity characterised by increased blood flow or permeability of blood vessels, leukocytes and inflammatory mediators (cytokines) is called inflammation. Infection causing inflammation in the body may be bacterial, viral, fungal or parasitic in nature. Currently, inflammation is present in many diseases, but in recent decades, inflammation that is at the cellular or molecular level has become more prevalent. The number of individual diseases that are closely associated with molecular markers of inflammation continues to increase. An anti-inflammatory therapy that is effective in a given disease may be equally effective in another, opening up the possibility for intervention [15]. The chronic phase involves the development of humoral cellular responses to factors present at the site of damage [16, 17]. The immediate activation of the innate immune system depends on the detection of conserved microbial motifs (PAMPs), in which macrophages and mast cells are involved [18]. Once their presence is detected, innate immunity triggers defence mechanisms that lead to the development of inflammation and host resistance to infection. These include the release of antimicrobial agents, phagocyte clumping, peptide release, and the production of cytokine, chemokine, and prostanoid groups [19, 20]. Inflammation is defined as a complicated process consisting of several steps, the main function of which is to prevent the multiplication of pathogens in order to destroy or eliminate them. It is caused by the coordinated secretion of substances, mainly from leukocytes (white blood cells), which cause redness, swelling or pain, dilatation of blood vessels, and serve as a marker of the site of infection for other leukocytes. Once the leukocytes are activated, a subset of PRRs activate the protease caspase-1, which causes the maturation of cytokines IL1β and IL18. Cell adhesion molecules and chemokines facilitate extravasation of leukocytes from the circulation to the affected site; receptors (G-protein coupled) are stimulated by chemokines. Binding-activated signals regulate effector functions and leukocyte motility [21]. Inflammation leads to an increase in temperature at the site of infection, which is detrimental to the spread of pathogens. Depending on the site of action, it can be local or systemic (total) [22] (Figure 1).
Production of pro-inflammatory cytokines that promote activation of CD4+T- cells and their subsequent differentiation into T-helper subsets.
Cytokines as key modulators
These small proteins represent a key modulator of inflammation and are important for tissue immunity. They have a low molecular weight and act as messengers that alter the behaviour of their own or another cell [23]. Through a network of interactions, they are involved in acute and chronic inflammation. Cytokine receptors are localized on the surface of human cells. Those that are soluble can be found in small amounts in the plasma. They are also referred to as cells regulating cytokine function, thereby influencing the nature of disease states [24–26]. Through binding to specific receptors, cytokines transmit intracellular signals. Mostly, they influence cell activation, division, apoptosis or movement. Their action is endocrine, autocrine or paracrine. Interleukins are products of leukocytes acting on other white blood cells. Interferons have a defensive role; colony-stimulating factors serve for differentiation and proliferation of stem cells [27, 28]. Cytokines are divided into several classes based on their structure, function, or source, but a particular cytokine may also belong to multiple classes within a single structure or origin.
Currently, 18 types of cytokines are classified under the name interleukin (IL). Other cytokines are retained under their original name, e.g. tumour necrosis factor (TNF). Cytokines play an important role in inflammation and the subsequent immune response. Species that promote inflammation are referred to as pro-inflammatory, while others suppress the activity of pro-inflammatory cytokines and are referred to as anti-inflammatory cytokines [29, 30].
Different cytokines can have positive and negative effects on cell function, playing a role not only in the immune response and inflammation, but also in reproduction, trauma, and disease formation (cancer, asthma, heart and endocrine diseases, and others). The nature of the immune response depends on the nature of the cytokines that are produced, but often a synergy of multiple cytokines is required to manifest a response. Depending on the cellular source or immune response, individual cytokines may have different functions. Nuclear factor kappa B (NF-κB) is a major mediator of inflammatory action [30–33]. Depending on the nature of inflammation, cytokines can be divided into acute inflammation-inducing cytokines (IL-1, TNF-α, IL-6, IL-11, IL-8, chemokines, G-CSF, and others) and chronic inflammation-inducing cytokines (humoral – IL-4, IL-5, IL-6, IL-7, IL-13, and cellular – IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, and others) [17]. The pro-inflammatory cytokines IL-1 and TNF have multiple pro-inflammatory properties that contribute to the disease. In studies where a cytokine injection has been given to animals or humans, most of the known findings to date have been elucidated. Due to the establishment of a specific blockade of either IL-1 or TNF, or both, a reduction in the severity of inflammation has been noted. These forms are considered to be the primary cytokines involved in inflammation [34]. Specifically, the type 2 cytokines interleukin-4 (IL-4), IL-5 and IL-13 are associated with asthma, which is defined as a chronic inflammatory disease. These cytokines increase mucus production, airway eosinophilia and bronchial hyperresponsiveness [35].
Interleukin-1
This interleukin represents a major endogenous pyrogen that is significantly involved in the pathogenesis of many diseases. Because of its important role in inflammatory responses and on the basis of cDNA clones, IL-1 has been subdivided and concretized into IL-1α and IL-1β. These two pro-inflammatory cytokines have been intensively studied in the field of immunology precisely because of the inflammatory response [36]. It is produced in epithelial and mucosal cells, organs (kidney, lung, liver and heart). IL-1β is constitutive only in resident macrophages with low expression. When tissue damage occurs, IL-1α is released by necrotic cells. It acts as a warning signal to leukocytes and initiates sterile inflammatory responses that subsequently activate their own IL-1α production. In this way, a loop of self-inflammation is established, resulting in tissue damage [37, 38]. IL-1β represents an inflammatory mediator that promotes the attraction of granulocytes to the site of inflammation and induces the expression of prostaglandins during the acute inflammatory response. It is linked to adaptive and innate immunity via T cells. It also ensures the production of cytokines by Th17 cells, resulting in the development of chronic diseases. IL-1β has an important defensive function, particularly against infections caused by microorganisms such as Candida, Salmonella, Listeria and Mycobacterium tuberculosis [39–41].
Interleukin-2
It is one of the first characterized cytokines of the lymphocyte hormone family. It is essential for the generation and regulation of the immune response, maintenance of homeostasis and is an important expansion factor for most T cells. It is predominantly produced by activated CD4+ and CD8+ T-lymphocytes [42, 43]. Its function is to stimulate NK (natural killer) cells and induce cytolytic activity. At high levels, it stimulates B cells to divide and subsequently produce antibodies. Through suppression of Th17 differentiation and increase in cell death, it is a crucial factor for the induction and resolution of inflammatory processes [44].
Interleukin-3
IL-3 is one of the basic representatives of glycoproteins with a characteristic three-dimensional structure. It is a hemopoietic factor with the ability to stimulate the production and activity of various types of blood cells. This cytokine usually acts at the site of inflammation, close to the cellular source, since it mainly targets cells belonging to the lymph haemopoietic system [45]. The interface between the blood component and the tissues is the vascular endothelium, which is involved not only in the regulation of haematopoiesis but also in inflammatory responses. Its central role is to control the infiltration of leukocytes to the site of inflammation and to promote their adhesion and transmigration. Endothelial cells are the source of granulocyte colony-stimulating factors (G-CSF) and granulocyte and macrophage colony-stimulating factors (GM-CSF). These in turn stimulate the production and function of granulocytes, monocytes and IL-6, which represent an important role in the acute phase of inflammation [46–48].
Interleukin-4
IL-4 is defined as a complex glycoprotein that is produced by mast cells, basophils, eosinophils, neutrophils and Th cells. This interleukin increases the expression of the major histocompatibility complex (MHC) and promotes the secretion of IgE and IgG1. It also inhibits the secretion of pro-inflammatory cytokines (TNF-α, IL-1 and IL-6). It upregulates CD13 on the cell surface, thereby inactivating inflammatory peptides [49, 50]. IL-4 elicits many responses that are closely linked to allergy and asthma through the regulation of Th2, which down-regulates IL-4, IL-5, IL-9, and IL-13, which are involved in the allergic response [51].
Interleukin-5
This dimeric cytokine controls differentiation from B-cells to antibody-secreting cells, and also plays an important role in the growth and differentiation of eosinophils [52]. Although it is not involved in IgE production, it acts on mast cells, resulting in the release of histamine, which acts in allergies. In the pharmaceutical industry, IL-5 is an investigational subject, mainly due to its less pleiotropic nature, which could make a drug targeting this cytokine significantly alleviate asthma attacks without compromising the patient’s health [53].
Interleukin-6
It belongs to a group of pleiotropic cytokines with a wide range of functions. It is produced by lymphoid and non-lymphoid cells. Its functions include regulation of oncogenesis, inflammation, immune response, acute response and haematopoiesis, induction of B-cell differentiation, and enhancement of IL-3-induced multipotential colony formation of hematopoietic stem cells [54, 55]. However, excessive IL-6 production may be one of the consequences of the development of many diseases – psoriasis, myeloma, Castleman’s disease, rheumatoid arthritis, and others [56].
Interleukin-7
It represents a stromal cell product, providing critical signals to lymphoid cells. It also promotes the growth of progenitor B-cells, regulates the development of immune system cell homeostasis (T-cells, B-cells and NK cells). Its important role is maintenance of health and prevention against diseases, since immunodeficiency occurs in congenital IL-7 deficiency [57]. Due to the positive results of IL-7 effects, it is likely to be an effective immunotherapy in various acute and chronic diseases. In the treatment of sepsis, through immunoadjuvant therapy, IL-7 has been shown to restore lymphocytes after septic shock [58]. Therapy has also shown its positive effects in coronavirus disease, which has posed a huge challenge to the field of medicine and science [59].
Chemokines
Chemokines are small proteins that belong to the cytokine family. They are structurally related to cytokines, but contain four cysteines at certain positions. Their role is to control the migration of cells to sites of tissue damage or infection by binding appropriate receptors, thereby modulating the movement and function of target cells, especially leukocytes [60, 61]. In addition to the central role of chemotactic migration, they can also stimulate targeted and nontargeted migratory behaviours (chemokinesis, hypoxia, haptokinesis) [62]. The key role of chemokines lies in inflammation and the body’s immune response. Chemokines are essential mediators of cancer-related inflammation and are present in the tumour area in chronic inflammation [63]. The role of inflammatory chemokines is to activate leukocytes to initiate wound healing through the immune response. Homeostatic and maintenance chemokines are involved in adaptive immune responses. Homeostatic chemokines are expressed in specific tissues, whereas the production of inflammatory chemokines can be mediated by many cell types at multiple sites [33].
Interleukin-8
During the inflammatory process, this tumorigenic, angiogenic, and chemotactic cytokine attracts basophils, neutrophils, and T cells to the site of inflammation or tissue damage, defining it as an inflammatory mediator. It is involved in neutrophil activation, with its secretion being increased by multiple cell types (monocytes, macrophages, neutrophils, bone marrow cells, etc.) in response to an inflammatory response [64].
Interleukin-9
Interleukin-9 is a multifunctional cytokine that is produced by CD4+ cells, specifically Th2, and also plays an important role as a T-cell growth factor. It ensures the proliferation and differentiation of mast cells and hematopoietic progenitor cells. IL-9 promotes the secretion of IgE receptors by mast cells, thereby promoting the growth of eosinophils. This implies that it has an important role in the development of allergic reactions, as confirmed by the increased expression of IL-9 in lymphocytes from the bronchoalveolar lavage fluid in asthmatic patients [65]. During an allergic reaction it is responsible for the negative course, but is highly effective during parasitic infection when it helps to eliminate the pathogen [66, 67].
Interleukin-10
An important role of IL-10 is to promote immune tolerance. This immunosuppressive cytokine is produced by Th2 monocytes and other cells of innate and adaptive immunity. Through the reduction of Th1 cytokines, it can prevent antigen presentation in macrophages, while suppressing cytokine secretion, thus representing an important role in allergies [68, 69]. It plays a key role in the prevention of inflammatory and autoimmune diseases. Insufficient expression of IL-10 may lead to an increased risk of inflammatory response which may lead to tissue damage or impaired immunopathology. However, certain pathogens have the ability to use immunosuppression of IL-10 to limit the body’s immune response, which in turn leads to persistent inflammation. Therefore, identification of the cellular sources and mechanisms of IL-10 is critical for the development of therapeutic implications that will lead to overcoming pathological disorders [70–72].
Interleukin-11
This cytokine is expressed in the central nervous system and gastrointestinal tract. It has hematopoietic effects on thrombopoietic activity [73]. It stimulates proliferation of megakaryocyte progenitor cells and induces their maturation, resulting in increased platelet expression. It produces fibroblasts, epithelial cells and various stromal cells. It is required for inhibition of adipocytes, activation of osteoclasts, stimulation of tissue fibrosis, regulation of chondrocyte and B-cell fibrosis. IL-11 plays a key role not only in haematopoiesis, but also in bone metabolism, tissue remodelling, and, due to its effects, it has a protective function in mucosal tissues [74].
Interleukin-12
IL-12 is produced by transformed B-cells and is defined as a heterodimeric protein. Its properties link innate and adaptive immunity, and through induction of Th1 differentiation it can act as a key regulator of the immune response. It induces cell-mediated immunity through T cells and also has immunomodulatory and antiangiogenic effects which subsequently lead to the use of IL-12, in combination with other cytokines, as an antitumor agent whose future use represents a therapeutic agent in cancer patients [75].
Interleukin-13
The role of this cytokine is immunoregulation of B-cell and monocyte lineages, inhibiting the production of inflammatory cytokines. It plays an important role in allergy or asthma, where it causes the Ig isotype in B lymphocytes to change to IgE [76]. Despite sharing common signalling components with IL-4, IL-13 has distinct functions, particularly with respect to the phenotype of asthma, helminth infections or tumour growth. Through the release of excessive mucus and the promotion of bronchial hyperreactivity, IL-13 is an important component in the development of allergic inflammation. It is hypothesized that inhibition of IL-13 could be an important milestone in the treatment of asthma or allergic diseases [77, 78].
Interleukin-14
It represents a high molecular weight B-cell growth factor. Although its function is not fully elucidated, it is involved in the pathogenesis of autoimmune diseases e.g. Gravers’ disease, Hashimoto’s thyroiditis, sepsis etc. [79].
Interleukin-15
The function of pro-inflammatory cytokine IL-15 lies in the immune system through controlled inflammation. It is produced by multiple tissues or cell types: placenta, kidney, lung, skeletal muscle, cardiac tissue, fibroblasts, epithelial cells, monocytes, nerve cells, dendritic cells, macrophages. It provides initiation of proliferation and immunoglobulin production, stimulates proliferation of NK cells and activated CD4+ and CD8+ T cells. It is also able to differentiate malignant cells from normal B-lymphocytes, which proliferate in response to IL-15 as opposed to normal B-lymphocytes [80, 81].
Interleukin-16
Because of its ability to recruit CD4 T cells, it has been referred to as a lymphocyte chemoattractant. It is secreted by CD4 T cells, eosinophils and mast cells. It serves as a pro-inflammatory factor that is chemotactic for immune cells. It is of great importance in allergic reactions, where it is found in increased amounts in nasal tissues or bronchoalveolar lavage fluid of asthmatic patients [78, 82].
Interleukin-17
This cytokine represents a subset of Th17. Its role is protection against extracellular pathogens and stimulation of the inflammatory response in autoimmune diseases [83]. It is expressed by activated CD4+ and CD8+ T-lymphocytes. It is defined as a pro-inflammatory cytokine due to induction of the expression of mediators of inflammation. Elevated levels of IL-17 have been reported in several diseases including airway inflammation, arthritis, abscesses, cancer, psoriasis, and multiple sclerosis [84].
Interleukin-18
IL-18 is classified as an essential regulator of innate and acquired immune responses. It is expressed at sites of chronic inflammation, in cancer, autoimmune diseases and also in association with many infectious diseases [85]. This pro-inflammatory cytokine has multiple effects including the ability to promote Th1 development, inhibition of the production of anti-inflammatory cytokine IL-10, and induction of the expression of pro-inflammatory cytokines and chemokines. Its role is not only in the immune system, but also interferes with the nervous system, endocrine system or bone metabolism [86].
Tumour necrosis factor
It has been described as a central cytokine in inflammatory responses, where it induces the expression of inflammatory genes, induces cell death and stimulates inflammatory immune responses [87]. The tumour necrosis factor is divided into two subunits, each with characteristic functions. TNF-α acts as a pathological component of autoimmune diseases. However, excessive activation of TNF-α results in chronic inflammation, which can lead to complications with a pathological character. Considering the mechanism, TNF-α is used to treat immune diseases in the form of various inhibitors [88]. This pro-inflammatory cytokine is produced by macrophages, monocytes, T cells, smooth muscle cells, fibroblasts or adipocytes [89]. One of the necessary steps for the development of inflammation is the interaction of cytokines, thus amplifying the reactions that these cytokines induce. TNF-α is usually released with interleukins, the most common of which is IL-1. When these cytokines work together, they modulate proinflammatory signals, increase chemokine expression, and initiate the first-line response of the body’s immune system [90]. TNF-β (lymphotoxin-α) is produced by T-lymphocytes and leukocytes, fibroblasts, astrocytes, and endothelial cells. It is involved in autoimmune disorders, lymph node development, and mediates the inflammatory process of the immune system [91]. It is essential for maintaining homeostasis; if TNF-β activity is reduced, autoimmune diseases occur [92].
Granulocyte macrophage-colony stimulating factor
This master regulator controls granulocyte and macrophage functions at all stages of maturation. This factor plays its role locally, at the site of inflammation. Inflammation mediated by this pro-inflammatory cytokine is involved in several types of autoimmune diseases (multiple sclerosis, rheumatoid arthritis). Therapeutic implications include the use of agents that block GM-CSF or its receptor. However, the effects of an inflammatory nature depend on the amount and presence of other cytokines [93] (Table 1).
Cancer immunotherapy
According to the WHO (2022), cancer caused nearly 10 million deaths worldwide in 2020 [94]. So far, the recommended treatment is surgery or chemotherapy. These methods are effective in terms of removing the tumour itself. However, they are not very effective in preventing metastatic spread through tumour cells. In the context of cancer immunotherapy, elimination of disseminated tumour cells and micrometastases represents a great potential [95, 96]. Several strategies are known in the use of immune cells: monoclonal antibodies against tumour antigens, immune checkpoint inhibitors, vaccination, adoptive cell therapy (e.g., CAR-T cells), and cytokine administration. The chemokine system represents a potential treatment target in immunotherapy. Through their altered expression in malignant cells, leukocyte activation, tumour cell proliferation and metastases are enhanced in all stages of cancer [97, 98]. The role of cytokines in immunotherapy is to directly stimulate effector and stromal cells at the tumour site. It is known from various studies that cytokines have a rich antitumor response [99, 100]. Combination approaches have brought clinical success to many and have also improved the overall response rate of patients [101–103]. The current approach to cancer treatment through immunotherapy suggests that IL-7 has great potential to treat cancer by increasing the number of circulating CD4+ and CD8+ T cells [104].
Conclusions
Inflammatory immune responses are conditioned by a variety of mediators. In this study, we specifically focused on the key modulators, inflammatory and anti-inflammatory cytokines and chemokines, which have important roles in acute and chronic inflammation. A deeper exploration of this issue is essential not only in understanding the response of the immune system, but also in mediating immunotherapy in cancer treatment.
Acknowledgments
This study was supported by the Ministry of Education, Science, Research and Sport of the Slovak Republic (APVV-15-0556) and Grant agency of University of Prešov in Prešov (GaPU 12/2023).
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