IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

CYTOKINES OF THE IMMUNE SYSTEM AND THEIR ALTERATIONS IN CERTAIN DISEASES

Cytokines, Interleukins, Tumor Necrosis Factors

Cytokines (from Greek cytos - Cell, kinos - to release) are cell-produced protein-peptide factors that mediate short-range regulation of intercellular interactions. Cytokines determine cell survival, stimulation or inhibition of their growth, differentiation, functional activation, and apoptosis. Following the binding of cytokines to cell surface receptors, the signal is transduced to The Nucleus via intracellular Transduction elements, where the corresponding genes are activated. Proteins, which are products of cytokine-activated genes, are produced by Cells and regulate the processes listed above.

Soluble cytokine receptors maintain high affinity for their ligands and can be detected in serum and urine. Soluble cytokine receptors can act as competitive antagonists, participate in the transport and delivery of cytokines to the lesion site, and facilitate their elimination from the Organism. The excretion of catabolized cytokines is carried out by The Liver and Kidneys.

Depending on which Cells of the immune system predominantly synthesize a given cytokine, they are classified as interleukins, monokines, and lymphokines. Currently, 37 interleukins have numerical designations (IL-1 - IL-37), while other cytokines have letter designations: CSFs (colony-stimulating factors), OSM (oncostatin M), LIF (leukemia inhibitory factor), NGF (nerve growth factor), CNTF (ciliary neurotrophic factor), TNF (tumor necrosis factor), interferons (IFNs), and others.

Cytokines can be subdivided into 4 groups:

1. Hematopoietic factors (G-CSF, IL-3 and IL-7, Erythropoietin) - stimulators of growth and maturation of immature hematopoietic cells.

2. Regulators of innate Immunity - proinflammatory cytokines (IFN-α, -β, IL-1, 6, 12, TNF-α, chemokines - IL-8, MCP-1, RANTES, etc.). They participate in the non-specific defense of the organism against bacterial and viral infections. Their primary targets are phagocytic cells - macrophages and granulocytes.

3. Cytokines regulating specific immune responses (IL-2 and 4, transforming growth factor (TGF-β) and others). These proteins are involved in the activation, growth, and differentiation of mature lymphocytes.

4. Regulators of inflammatory reactions developing during the specific Immune Response - anti-inflammatory cytokines (IFN-γ, lymphotoxin, IL-4, 5, 10, 13, etc.). Their main function is the activation of non-specific effector cells: cytotoxic macrophages, natural killers, and B lymphocytes (IL-4).

The spectra of biological activities of cytokines overlap significantly: the same process can be stimulated in a cell by more than one cytokine. Antigenic stimulation leads to the secretion of "first-generation" cytokines - IL-1 and 6, TNF-α, which induce The Biosynthesis of the central regulatory cytokine IL-2, as well as IL-3, 4, 5, IFN-γ, etc. IL-2 appears in the Cytoplasm of T cells 2 hours after stimulation; IL-4 after 4 hours, IL-10 after 6 hours, and IL-9 after 24 hours. The peak production of various lymphokines varies: 12 hours for IL-2, 48 hours for IL-4 and 5, and 72 hours for IL-9 and IFN-γ.

The main producer cells of cytokines are T helper cells and macrophages, which perform key Functions in maintaining ACQUIRED AND INNATE immunity. Type 1 T helpers (Th1) produce IL-2 and IFN-γ, whereas type 2 T helpers (Th2) produce IL-4, 5, 6, 9, 10, and 13. The transition of Th0 to Th1 is mediated by IFN-γ and IL-12. Th2 cells are generated under METABOLISM/18.html">The Influence of IL-4. Imbalances in the cytokine-producing activity of Th1 and Th2 types play a significant role in The Development of autoimmune conditions, chronicity, and disease progression.

Cytokines are antigen-nonspecific factors. Therefore, specific Diagnosis of infectious, autoimmune, and allergic diseases by determining the levels of particular cytokines is not feasible.

Interleukin 1 (IL-1). Produced by macrophage cells. Formerly known as endogenous pyrogen. IL-1 promotes The production of IL-2 by T helper lymphocytes. IL-1 is a system consisting of three molecules: IL-1α, IL-1β, IL-1Rα (IL-1 receptor antagonist) and two receptors, IL-1RI and IL-1RII. The predominant form of IL-1 is IL-1β with a Molecular Weight of 17.5 kDa. The main producers of IL-1β are macrophages and monocytes. Lymphocytes and fibroblasts may also participate in the synthesis of this cytokine. Target cells include immunocompetent, endothelial, and epithelial cells, as well as fibroblasts. IL-1α initiates and regulates inflammatory and immune processes, activates neutrophils, T AND B lymphocytes, and stimulates the synthesis of acute-phase proteins, cytokines (IL-2, 3, 6, TNF-α), adhesion molecules (E-selectins), procoagulants, and Prostaglandins. IL-1β enhances chemotaxis, phagocytosis, hematopoiesis, vascular permeability, and cytotoxic and bactericidal activity. IL-1 is involved in body Temperature regulation, and its increased production leads to fever, thereby exerting a pyrogenic effect.

Elevated levels of IL-1 are observed in various inflammatory and autoimmune diseases, including septic Shock, inflammatory bowel disease, rheumatoid Arthritis, and type 1 Diabetes Mellitus. In multiple trauma, high levels of IL-1, IL-2, and IL-6 are observed in plasma, along with a particularly sharp increase in TNF-α levels; during renal transplant rejection, increases in IL-1, IL-6, and TNF-α are noted. The threat of Miscarriage is accompanied by increased production of IL-1 by Blood mononuclear cells and increased expression of the IL-2 receptor in the T-lymphocyte subpopulation. IL-1β plays a crucial role in the Pathogenesis of AIDS. In psoriasis, the synthesis of IL-1α and IL-1β is not decreased, but their functional activity drops. Elevated IL-1 levels are noted in acute and chronic myeloid leukemia.

Interleukin 1-β precursor (pro-IL-1-β). IL-1-β exhibits The ability to bind to the IL-1 receptor following enzymatic Cleavage. This process is catalyzed by an enzyme - IL-1-β-converting enzyme, recently renamed caspase-1. It has been shown that in endothelial and arterial cells, stimulation via the CD40 Ligand leads to the Processing of the IL-1β precursor and the release of biologically active IL-1β, thereby indicating both a mechanism for the activation of the inflammatory process in atherogenesis and other pathological states, and a novel mechanism of IL-1β activation in vascular cells.

Interleukin 1 receptors (IL-1RI, IL-1RII). Type I IL-1 receptors (IL-1RI) are expressed on many cells: T lymphocytes, thymocytes, fibroblasts, endothelial cells, hepatocytes, etc. Type II receptors (IL-1RII) are characteristic of B lymphocytes, macrophages, and monocytes. These two receptors have different binding characteristics for IL-1α and IL-1β. Typically, IL-1α binds better to RI, whereas IL-1β binds better to RII.

IL-1 receptor antagonist (IL-1Rα). IL-1Rα is a protein with a molecular weight of 25 kDa produced by monocytes and other cells. It binds to IL-1 receptors with the same affinity as IL-1, but does not trigger subsequent intracellular signal transduction. Thus, IL-1Rα acts as an inhibitor of IL-1 action. Recent studies have shown that the in vivo balance between IL-1 and IL-1Rα plays an important role in protecting the body against infection and limiting further damage to affected Tissues. In infectious diseases, the maximum increase in IL-1Rα levels is observed in Sepsis. Furthermore, elevated concentrations of IL-1Ra correlate with a favorable prognosis. Insufficient production of IL-1Rα significantly worsens the severity of tissue damage in Lyme disease, tuberculosis, and sarcoidosis. Other studies have demonstrated The Significance of IL-1Rα as an endogenous anti-inflammatory agent in ischemic stroke, inflammatory bowel disease, respiratory distress syndrome, Bronchial Asthma, and Pyelonephritis. IL-1Rα is present in high concentrations in Amniotic Fluid in the third trimester, in the urine of febrile patients, and in synovial fluid in rheumatoid arthritis. Clinical trials of pharmacological agents based on recombinant IL-1Rα are currently underway.

Interleukin 2 (IL-2). This cytokine, with a molecular weight of 15 kDa, plays a vital role in the execution of immune response mechanisms. The producers of IL-2 are type I T helpers. In addition to the participation of IL-2 in the differentiation and proliferation of T lymphocytes, this lymphokine is directly involved in antitumor defense mechanisms. Specifically, IL-2 enhances the lytic activity of NK cells and induces lymphokine-activated killer cells (LAK cells). Furthermore, IL-2 enhances the secretion of IFN-γ by T lymphocytes. The determination of IL-2 serves as an indicator of T-cell activation in in vitro tests. It has been established that IL-2 and IFN-γ form effector immunological mechanisms aimed at preventing the proliferation of nontransformed cells. In patients with acute Viral Hepatitis during the replicative period, high spontaneous production of IL-2 is recorded.

Soluble IL-2 receptor (sIL-2R). IL-2 binds to the IL-2R receptor, which consists of three subunits, including IL-2R-α (p55) and IL-2R-β (p70). The IL-2R-β subunit is a permanent component of lymphocyte membranes, whereas the IL-2R-α subunit is formed upon IL-2 binding. An increase in the number of IL-2R-α indicates cell activation. Following activation, a portion of the subunit is released from the membrane, turning into the soluble IL-2 receptor (sIL-2R), a circulating marker of cellular activation. Determining sIL-2R levels makes it possible to detect and monitor T-cell activation following organ transplantation (Kidney transplantation, etc.). An elevated level of the soluble IL-2 receptor is a diagnostic sign of lymphocyte hyperproliferation (leukemia, autoimmune diseases).

Interleukin 3 (IL-3) belongs to hematopoietic growth factors (molecular weight 15.0 - 28.0 kDa). The producer cells of IL-3 are Th1 and Th2, as well as other cells (B lymphocytes, myeloid cells, Bone Marrow stromal cells, keratinocytes). Activation of the IL-3 Gene is observed 4 hours after cell stimulation and is sustained for several days. IL-3 secretion is inhibited by cytostatics and glucocorticoids. Together with erythropoietin, IL-3 Supports the growth and differentiation of cells of the erythroid Lineage. At the same time, IL-3 is capable of regulating the early stage of B-lymphocyte differentiation, supports the growth of pre-B lymphocytes, and enhances IgG secretion. IL-3, IL-4, and GM-CSF are growth factors for mast cells and enhance their histamine production. IL-3 and GM-CSF induce The formation of eosinophil granules.

Interleukin 4 (IL-4). This lymphokine (molecular weight 15–20 kDa) is produced by T cells (type II T helpers) and acts as a differentiation factor for T and B lymphocytes. IL-4 limits the macrophage synthesis of proinflammatory IL-1β, 6, 8, 12, and TNF-α, as well as the generation of highly active oxygen and nitrogen metabolites. In addition, IL-4 activates B-lymphocyte proliferation and switches their production of IgM to the synthesis of IgE and IgG4. IL-4 stimulates lymphokine-activated killer cells (LAK cells) and enhances the antitumor activity of macrophages. Dysregulation of IL-4 secretion is pivotal in the development of allergic diseases. It has been shown that peripheral blood mononuclear cells from patients with atopic diseases exhibit an enhanced response to recombinant IL-4 compared to the response of mononuclear cells from healthy Donors. The increase in IgE synthesis in response to IL-4 stimulation leads to an enhancement of IgE-stimulated cytokine synthesis by mast cells capable of producing IL-4, IL-5, and IL-6. In Sézary syndrome, the content of IL-4 is increased. IL-4 levels are elevated in patients with chronic hepatitis C virus infection. During the acute phase, its amount increases threefold compared to normal values, whereas during remission, IL-4 levels decrease, particularly against the Background of ongoing Treatment with recombinant IL-2.

Soluble IL-4 receptor (sIL-4R). The high-affinity IL-4 receptor is a complex comprising two subunits: an α-subunit that binds IL-4 with high affinity and a γ-subunit that makes an additional contribution to binding. The IL-4R α-chain belongs to the cytokine receptor family. The soluble form of IL-4R is expressed in negligible amounts on pre-B lymphocytes and resting mature T and B lymphocytes. Cell activation leads to an increase in the number of IL-4Rs.

Interleukin 5 (IL-5) is a protein with a molecular weight of 50–60 kDa, produced by type II T helpers (Th2). IL-5 enhances the proliferation of activated B lymphocytes, the expression of the IL-2 receptor on them, and the synthesis of IgA. In unstimulated B lymphocytes, IL-5 induces the secretion of IgM and IgG. Acting as a chemoattractant, IL-5 induces eosinophil degranulation in parasitic infestations, plays a role in the pathogenesis of allergic inflammation and atopy, and exhibits antitumor activity associated with its ability to participate in apoptosis.

Interleukin-6 (IL-6), a protein with a molecular weight of 19–34 kDa, acts as a differentiation factor for B lymphocytes and promotes their maturation into antibody-producing cells. IL-6 induces the synthesis of acute-phase proteins and, therefore (along with IL-1 and TNF-α), can be classified as an inflammatory cytokine. IL-6 is involved in vascular inflammation. Elevated levels of IL-6 are observed in autoimmune diseases, Myxedema, rheumatoid arthritis, psoriasis, mesangioproliferative Glomerulonephritis, Kaposi's Sarcoma, alcoholic cirrhosis, lymphoma, myeloma, and renal carcinoma. In HIV-infected individuals, B lymphocytes produce increased amounts of TNF-α and IL-6. Evidence indicates elevated plasma levels of TNF-α and IL-6 in atopic conditions, including bronchial asthma. This cytokine regulates the proliferation of biliary epithelial cells and hepatocytes, granuloma formation, and fibrosis in liver cirrhosis. Increased IL-6 concentrations have been noted during exacerbations of PEPTIC ULCER DISEASE, pancreatitis, celiac disease, Crohn's disease, Ulcerative Colitis, viral hepatitis, and primary biliary cirrhosis.

Soluble IL-6 receptor (sIL-6R). The membrane-bound IL-6 receptor consists of two chains: IL-6R-α, an 80 kDa glycoprotein, and IL-6R-β, a 130 kDa glycoprotein. IL-6 first binds to IL-6R (IL-6R-α and IL-6R-β) to form a binary complex. This complex then associates with two IL-6R-α molecules, resulting in the phosphorylation of the formed molecules. Signal transduction is mediated by the IL-6R-β homodimer, which is also activated by IL-11. The membrane-bound IL-6 receptor can undergo cleavage to generate a circulating 55 kDa form designated as sIL-6R, which participates in hepatic processes during acute and chronic inflammation. High levels of sIL-6R are observed in HIV-infected individuals and patients with multiple myeloma and B-cell leukemia.

Interleukin-7 (IL-7) is a hemopoiesis-stimulating cytokine and a polypeptide with a molecular weight of 20–40 kDa, produced by fibroblasts and bone marrow stromal cells. IL-7 stimulates the proliferation, but not the differentiation, of pre- and pro-B lymphocytes and lacks activity on differentiated B lymphocytes. It stimulates the proliferation of immature and activated T Lymphocytes and is also effective in the immunotherapeutic destruction of tumor cells by CD4-positive T lymphocytes. Combined with IL-2, it can be used in the consolidative immunotherapy of malignancies in post-bone marrow transplant patients. IL-7 can induce tumor cell apoptosis and triggers the differentiation of cells in acute myeloblastic leukemia.

Interleukin-8 (IL-8) is an inflammatory cytokine belonging to the chemokine family. It is produced in response to bacterial endotoxins and cytokines, primarily TNF-α and IL-1. IL-8 activates neutrophils, other granular leukocytes, and monocytes, inducing their chemotaxis toward the site of inflammation. Elevated levels of IL-8 are associated with chronic and acute inflammatory states and correlate with neutrophil tissue infiltration in rheumatoid arthritis and ulcerative colitis. Appearing downstream of IL-1 and TNF-α at inflammatory sites, IL-8 plays a crucial role in psoriasis.

Interleukin-10 (IL-10) is a lymphokine with a molecular weight of 17–21 kDa produced by T helper cells (Th2) and functions as an antagonist to a range of cytokines. Specifically, IL-10 inhibits IFN-γ production by Th1 cells. Furthermore, it suppresses the proliferative response of T cells to Antigens and mitogens, as well as the secretion of IL-1β, TNF-α, and IL-6 by activated monocytes. Concurrently, IL-10 stimulates immunoglobulin secretion by B lymphocytes and can promote IgE synthesis. In its inhibitory effect on cellular immunity, IL-10 acts synergistically with IL-4. Elevated IL-10 levels have been noted in various tumors, where increased production is generally considered a poor prognostic sign associated with pronounced tumor progression.

Interleukin-11 (IL-11) is synthesized by bone marrow stromal cells. Its target cells are hematopoietic osteoclast precursors. Its functional properties include osteoclast formation and the downregulation of pro-inflammatory cytokine production. IL-11 enhances antibody production both in vitro and in vivo through a T helper-mediated mechanism. IL-11 stimulates megakaryocytopoiesis and influences the development of other blood cell lineages, notably macrophages. In addition to bone marrow stromal cells, IL-11 is produced by IL-1-stimulated fibroblasts. Similar to IL-1 and IL-6, IL-11 participates in the induction of acute-phase proteins.

Interleukin-12 (IL-12) is a 70 kDa glycoprotein composed of two subunits: p40 and p35. The p40 subunit is involved in receptor binding, while p35 is required for signal transduction. IL-12 is secreted by activated macrophages. It enhances the cytotoxicity of LAK cells, T lymphocytes, and NK cells, acts as an inducer of IFN-γ secretion, and inhibits IgE synthesis. Deficient IL-12 production impairs macrophage antitumor activity. Enhanced tumor growth, such as in Colorectal Cancer, is associated with decreased IL-12 production and increased IL-10 production. A key property of IL-12 is the upregulation of FasL expression and the induction of apoptosis. Additionally, IL-12 inhibits angiogenesis. In recent years, IL-12 has been established as a key cytokine in the development of type 1 T helper cells. It plays an essential role in resistance to bacterial and parasitic infections, as well as antiviral responses, including HIV, and serves as a vaccine adjuvant.

Interleukin-13 (IL-13) is a 10 kDa protein produced primarily by activated T lymphocytes and mast cells. Its functions are similar to the biological activity of IL-4. IL-13 acts as a modulator of monocyte and B-cell activity, stimulates the secretion of IgG4 and IgE by B lymphocytes, and has no direct biological effect on T lymphocytes. It exerts an inhibitory effect on the production of other cytokines that drive the onset of inflammatory processes in sepsis or rheumatoid arthritis. Alongside IL-4 and IL-10, IL-13 participates in type 2 T helper immune responses.

Interleukin-15 (IL-15) is produced by macrophages, monocytes, epithelial cells, and smooth Muscle cells. Functionally close to IL-2, it activates macrophages and enhances their synthesis of TNF-α. IL-15 participates in the activation of T lymphocytes by antigen-presenting cells, stimulates the proliferation and differentiation of T and B lymphocytes into effector cells, promotes the synthesis of cytokines and IMMUNOGLOBULINS, and protects hepatocytes from apoptosis. IL-15 levels are elevated in inflammatory Diseases of the Stomach, Small Intestine, and Large Intestine.

Interleukin-16 (IL-16) is a protein with a molecular weight of 14–17 kDa, produced mainly by CD8+ T lymphocytes. Its receptor belongs to the CD4 family, allowing IL-16 to interact with CD4. CD4+ T helper cells are its primary targets, for which IL-16 acts as a chemoattractant, enhances cellular adhesiveness, and generally suppresses (though occasionally induces) their proliferation. At the same time, this interleukin enhances CD25 expression and cytokine synthesis. Elevated serum levels of IL-16 are detected in patients with stage III and IV cancers of the breast, intestine, kidney, Urinary Bladder, Uterus, and Ovary.

Interleukin-17 (IL-17) is synthesized by T helper cells. Its target cells include epithelial and endothelial cells, as well as fibroblasts. Functionally similar to the anti-inflammatory cytokines IL-4 and IL-10, IL-17 regulates the release of IL-6, IL-8, and G-CSF by producer cells and stimulates fibroblasts. IL-17 can enhance antibody-dependent tumor cell destruction.

Interleukin-18 (IL-18) is synthesized as an inactive 24 kDa propeptide. Proteolytic cleavage by ICE (interleukin-1β-converting enzyme, caspase-1) yields the active 18 kDa peptide. Also known as IFN-γ-inducing factor (IGIF), IL-18 was initially characterized as a potent inducer of IFN-γ synthesis by T AND NK cells. Operating independently of IL-12, IL-18 stimulates IFN-γ secretion and activates the monocytic/macrophage system, thereby promoting antibacterial, antitumor, and antiviral immune responses. IL-18 is induced by stress signals (either neurogenic or bacterial in origin). Expression of the Fas ligand on CD4+ Th1 and NK cells is known to be driven by IL-18. Conversely, IFN-γ participates in upregulating Fas expression itself. Thus, IL-18 stimulates the initiation of apoptotic processes either independently (via FasL) or with the assistance of IFN-γ (via Fas).

Colony-stimulating factors (CSFs) are hemopoiesis-stimulating cytokines. There are three main types: G-CSF (granulocyte), GM-CSF (granulocyte-macrophage), and M-CSF (macrophage). These are Polypeptides with a molecular weight of 20–40 kDa. G-CSF, GM-CSF, and M-CSF are produced by fibroblasts, endothelial cells, and mononuclear phagocytes, respectively. GM-CSF induces the growth and differentiation of immature bone marrow cells into various myeloid lineages, accelerating the maturation of granulocyte and mononuclear macrophage precursors. High levels of GM-CSF secreted by tumor cells cause neutrophilia in cancer patients. M-CSF induces the differentiation of hematopoietic progenitor cells into mononuclear phagocytes, while G-CSF directs them toward neutrophils. CSFs are classified as pro-inflammatory cytokines, and their plasma levels increase during inflammation of various etiologies.

Tumor necrosis factor (TNF). The tumor necrosis factor group includes TNF-α and TNF-β (lymphotoxin). Both are polypeptides with a molecular weight of approximately 17 kDa. TNF-α is produced by monocytes/macrophages, endothelial and myeloid cells, mast cells, LAK cells, neuroglial cells, and, in specific cases, activated cytotoxic T lymphocytes (which are the primary producers of TNF-γ). TNF-β is produced upon antigen and mitogen stimulation of T cells significantly later than TNF-α (on days 2–3 post-activation). The antitumor action of TNF involves the necrosis of tumor cells, which inspired its name, though this does not limit the full spectrum of its biological effects. There are three Morphology/3.html">MAIN DIRECTIONS OF TNF activity:

- cytotoxic action directed against tumor cells or virus-infected cells;

- immunomodulatory and anti-inflammatory action driven by the activation of macrophages, neutrophils, eosinophils, and endothelial cells;

- metabolic effects capable of inducing hyperglycemia, bone resorption, and increased muscle Glycogenolysis, leading to cachexia, which is also observed in certain parasitic infections.

The release of TNF increases capillary permeability, damages the vascular endothelium, and triggers intravascular thrombosis. High levels of TNF-α are detected during septic shock, and persistently high levels indicate a poor prognosis with potential adverse outcomes. Studies have shown that in HIV-infected individuals, the concentrations of TNF-α and IFN-γ increase significantly during the Cytology/cytology/16.html">Early stages of the disease. Elevated TNF-α levels in AIDS promote viral Replication in infected cells via autocrine or paracrine pathways. Furthermore, by destroying virus-infected cells, TNF contributes to viremia and the infection of new lymphocytes. Opportunistic infections in HIV patients lead to the additional production of TNF-α and IL-1, further expanding the pool of HUMAN IMMUNODEFICIENCY VIRUS-reservoir cells.

Soluble tumor necrosis factor receptor I (sTNF-RI). TNF exerts its biological activity by binding to specific, high-affinity Membrane Receptors. TNF-RI, also known as CD120-α, is a 55–60 kDa protein expressed by cells across most tissue types. Activation of various cell types leads to the proteolytic cleavage of membrane receptors, generating their soluble forms. sTNF-RI stabilizes circulating TNF and extends the half-life of this cytokine. It participates in apoptosis and exhibits antiviral activity. sTNF-RI levels are elevated in the serum of patients with oncological diseases and chronic renal failure, as well as in the bronchoalveolar lavage fluid of adult patients suffering from acute respiratory distress syndrome. Furthermore, sTNF-RI levels correlate with the severity of parasitemia and malaria.

Soluble tumor necrosis factor receptor II (sTNF-RII). TNF-RII (also known as CD120-β) is a 75–80 kDa protein expressed by cells in most tissue types. Cell activation induces the proteolysis of membrane receptors, resulting in the release of soluble forms. sTNF-RII stabilizes circulating TNF and prolongs its half-Life in the blood serum. The measurement of sTNF-RII allows for the assessment of immune system status.

Interferons (IFNs) possess antiviral and immunomodulatory activities. Based on their origin and molecular Structure, human interferons are divided into 3 main types: IFN-α, produced predominantly by macrophages and B lymphocytes; IFN-β, produced by fibroblasts; and IFN-γ, synthesized mainly by activated T helper cells belonging to the Th1 subpopulation. Type 1 T helper cells produce IFN-γ in response to stimulation by T-cell mitogens, anti-CD3 Antibodies, and specific viral antigens. The effects of IFN-γ can be categorized as follows:

- exhibits a broad spectrum of antiviral, antiparasitic, and antitumor activities;

- exerts numerous immunomodulatory effects, including The stimulation of Class I and class II Major Histocompatibility Complex antigen expression;

- exerts an irreversible cytotoxic effect on transformed cells, whereas its cytostatic effect on normal cells is reversible;

- enhances cytotoxic responses mediated by T lymphocytes and NK cells;

- simultaneously and selectively increasing the resistance of normal cells to the cytopathic effects of NK cells.

Decreased IFN-γ production has been documented in Sézary syndrome, acute lymphoblastic leukemia, non-Hodgkin lymphomas, and chronic Lymphocytic Leukemia. In HIV-infected individuals, Th1 function (which produces IL-2 and IFN-γ, thereby reducing the functional activity of NK cells) is impaired to a greater extent than Th2 function (which produces IL-4 and IL-5, enhancing antibody production). In patients with AIDS, the concentration of IFN-γ increases significantly during the early stage of the disease. Plasma IFN-γ levels are also elevated in severe cytomegalovirus infection. Both IFN-γ and IFN-β levels rise in the Blood Plasma during Central Nervous system disorders and multiple sclerosis.

IFN-α exists in 20 variants with molecular weights ranging from 19 to 26 kDa. IFNα exhibits pronounced antiviral, antiparasitic, and antiproliferative activities. IFN-α is produced by macrophages, monocytes, lymphoblasts, and fibroblasts, as well as by various types of virus-activated cells. It is used in the Treatment of renal cell carcinoma and Kaposi's sarcoma. Plasma IFN-α levels are elevated in autoimmune diseases, AIDS, and myasthenia gravis.

Secretory leukocyte protease inhibitor (SLPI) is an anti-inflammatory cytokine with a molecular mass of 12 kDa. It inhibits Elastase and prevents histamine release from mast cells. Furthermore, it plays a significant role in the pathogenesis of pulmonary and dermatological diseases.

Soluble CD14 (sCD14) is a surface membrane glycoprotein expressed by monocytes, macrophages, Langerhans cells, and dendritic cells. High expression of CD14 on peripheral blood and bone marrow monocytes is observed in acute myeloblastic leukemia. In contrast, the expression of this antigen is absent in acute and chronic lymphoblastic leukemia.

Soluble CD23 (sCD23). CD23 functions as a low-affinity receptor on The Cell surface. This C-type lectin receptor is present On the surface of 30% of B lymphocytes and 1% of T cells and monocytes (this percentage increases significantly in allergic patients). Under the influence of IL-4, CD23 begins to be produced by B cells and monocytes in a soluble form. sCD23 interacts with the CD19 and CD21 receptor complex on B cells, thereby enhancing the proliferation of IgE+ B lymphocytes and their secretion of IgE. Elevated serum levels of sCD23 have been detected in B-cell chronic lymphocytic leukemia, following bone marrow transplantation, in hyper-IgE syndrome, and in the synovial fluid of patients with rheumatoid arthritis.

Polymorphonuclear granulocyte elastase (PMN-elastase). Granulocytes (neutrophils, eosinophils, basophils) utilize proteinases to destroy pathogens. One of these proteinases is polymorphonuclear granulocyte elastase, which is localized in their azurophilic granules. During the phagocytosis of foreign substances, these Enzymes are also partially secreted into the extracellular space. The activity of polymorphonuclear granulocyte elastase is regulated by α-1-proteinase inhibitor (α1-PI). Excessive release of elastase by granulocytes can overwhelm the inhibitory capacity of α1-PI. Consequently, the enzymatic activity of granulocyte elastase, together with oxidants (O₂ radicals, H₂O₂, O radicals), can cause localized tissue damage. α1-PI forms complexes with elastase. The concentration of the granulocyte elastase/α1-PI complex correlates with the level of elastase and can be used as a tool to measure granulocyte activity during inflammatory responses. Determinations of granulocyte elastase levels are performed in cases of trauma, shock, sepsis, hemodialysis, gynecological infections, Joint Diseases, intestinal disorders, pancreatitis, and cystic fibrosis. Polymorphonuclear elastase serves as a marker for chronic prostatitis. Its levels are elevated in infertile men, and measuring it can be useful in monitoring treatment efficacy and refining diagnoses of inflammatory processes in andrology.

Transforming growth factor-beta (TGF-β1) is a pleiotropic and multifunctional cytokine produced by numerous cell types, including monocytes, macrophages, activated T and B lymphocytes, and endothelial cells.