Cytokins.pptx

CYTOKINS ''This course content has been prepared for educational purposes. Printing, duplication and sharing is prohibited. Cannot be used for commercial purposes'' DEFINITION They are low molecular weight, soluble protein or glycoprotei...

CYTOKINS ''This course content has been prepared for educational purposes. Printing, duplication and sharing is prohibited. Cannot be used for commercial purposes'' DEFINITION They are low molecular weight, soluble protein or glycoprotein molecules that play a role in the regulation of immune response, inflammation and hematopoiesis and serve as chemical messengers. It also has roles in mitosis, cell differentiation, apoptosis and oncogenesis. DEFINITIONS INTERLEUKINES : Cytokines released by leukocytes and affecting other leukocytes INTERFERONS : Cytokines released from virus-infected cells and also involved in immunoregulation CHEMOKINES : cytokines that increase chemotaxis COLONY STIMULATING FACTORS : Cytokines that ensure differentiation and proliferation of stem cells COMMON FEATURES  Produced primarily by T-lymphocytes and monocytes/macrophages  Pleiotropic molecules (A cytokine can act on different cells)  If two or more cytokines have a similar effect on the target cell, it is called a redundant effect.  They can be multifunctional  Different cytokines can perform the same function  They are not stored, they are synthesized as a result of gene transcription that takes place in a short time.  Target cells have specific receptors  The effects of cytokines can be additive, synergistic or antagonistic to each other. Pleiotropic effect Redundant effect Synergism Antagonism Cytokines A cytokine binds to its receptor in the cell where it is secreted and has an autocrine effect. It binds to target cell receptors in its immediate surroundings and exerts paracrine effects. In rare cases, it can bind to its receptors at a distant target and exert endocrine effects. MECHANISMS OF IMPACT Cytokines act by binding to receptors on the cell membrane. The intracellular effects of cytokines occur in two ways: 1--Tyrosine kinase activation ( Janus kinase or Jack ) 2--Phospholipase C activation  CLASSIFICATION 1-CYTOKINS RESPONSIBLE FOR NATURAL (NONSPECIFIC) IMMUNITY: TNF, IL-1, IL -6, IL-10 and IL-12, interferons 2- CYTOKINS RESPONSIBLE FOR SPECIFIC (ADAPTIVE) IMMUNITY: IL-2, IL-4, IL-5, interferons 3-CYTOKINS THAT STIMULATE HEMATOPOESIS: CSFs, IL-3 and IL-7 1. CYTOKINES IN NATURAL IMMUNITY They have a role in the formation of the early inflammatory response Primarily synthesized by cells of the monocyte/macrophage series (Also fibroblast and endothelial cells) Warnings for their synthesis: Bacterial endotoxins (LPS, teichoic acid, peptidoglycan monomers) 2. CYTOKINS IN ADAPTIVE IMMUNITY They are formed by T-lymphocytes that recognize a particular antigen They induce proliferation of T and B lymphocytes in response to recognition of a specific antigen. These cytokines : IL-2, IL-4, IL-5, IFN- γ Th1 lymphocytes induce cellular immunity and proinflammation, Th2 lymphocytes induce humoral immunity and anti- inflammatory mechanisms 3. STIMULANTS OF HEMATOPOESIS: These cytokines produced by bone marrow stroma cells and leukocytes exert growth and differentiation effects on leukocyte precursors. Examples of these cytokines are stem factor, IL-3, IL-7, IL-9 and GM-CSF. CLASSIFICATION Proinflammatory cytokines : TNF- α, β , IL-1, IL-6, IL-8, IL-12, IFN- γ Anti-inflammatory cytokines : TGF- β , IL-4, IL-10, IL-13 Granuloma- forming cytokines : IL-2, IL-12, IFN- γ , TNF Cytokines that stimulate Killer Natural: IL-2, IL-12, IL-15, IFN- g  TNF (Tumor necrosis factor) Tumor necrosis factor (TNF); It is a polypeptide cytokine that has important roles in innate immunity, cell regulation, cell differentiation and apoptosis processes, and also ensures the destruction of cancerous cells. Together with interleukin-1 and 6, it is one of the primary mediators of acute inflammation. It has two forms: TNF- α and β TNF- α (Cachectin) First released proinflammatory cytokine Released by activated mononuclear cells (mostly by activated macrophages and monocytes) Allows migration of PML and macrophages to the site of inflammation Vascular permeability ↑ Induces phagocytosis and cytotoxicity It causes fever by acting on the hypothalamus. Synthesis of acute phase reactants from the liver Catabolism ↑ Responsible for the development of septic shock TNF- β It is released by T-lymphocytes. Phagocytosis in monocytes ↑ TNF- alpha and beta are cytotoxic to some tumor cells. Its effects on the host cell are similar to TNF- α , but it is known to have a weaker effect. Tumor necrosis factor (TNF) The main stimulus that initiates the synthesis and release of TNF is the lipopolysaccharides produced by Gram- negative bacteria. In addition, cell wall structural components of Gram-positive bacteria (peptidoglycan and teichoic acids), capsule antigens and exotoxins, cell wall antigens of fungi, viral and parasitic antigens can also initiate TNF synthesis. Biological Effects of Tumor Necrosis Factor (TNF) INTERLEUKIN-1 Released from activated monocytes/macrophages Effective synergistically with TNF- α. Fever Proinflammatory effects are almost the same as TNF- α. Also: It shows mitogenic effect for T and B- lymphocytes. It increases interleukin-2 synthesis and IL-2 receptor expression from T-helper lymphocytes. Stimulation of IL-6, 8 and adhesion molecules synthesis INTERLEUKIN-2 It is released by activated Th1 cells. It is a T cell growth factor. T lymphocyte proliferation, helper and cytotoxic T lymphocyte activation  IL-3 , IL-7 (CYTOKINES STIMULATING HEMATOPOESIS) Interleukin-3: ( Pan-specific CSF*) Promotes proliferation of pluripotent stem cells in the bone marrow Interleukin-7: Induces proliferation and differentiation of immature T and B lymphocytes in the bone marrow They are synthesized by cells in the bone marrow stroma. * Colony-stimulating factors INTERLEUKIN-4 and 5 IL-4 and IL-5 are formed by the Th2 subset of helper T-lymphocytes IL-4: Anti-inflammatory cytokine induces conversion to TH2. B lymphocyte proliferation factor, IgG1, IgE production IL-5: growth factor for eosinophils, B lymphocyte plasmocyte differentiation factor, IgA production  INTERLEUKIN-6 Synthesized by mononuclear cells, lymphocytes, fibroblasts Primer stimulating the synthesis of acute phase reactants in the liver cytokine B lymphocyte differentiation Acute phase protein synthesis (hepatocyte stimulating factor) and adhesion Both anti and pro inflammatory cytokine, Reduction of TNF- α and IL-1 activity Indicator of systemic inflammatory response  Interleukin-8, MCP ( Monocyte Chemotactic Protein), MIP ( Macrophage) Inflammatory Protein) (Chemokines): Chemotaxis and migration of leukocytes to the site of inflammation. Chemoattractant They are synthesized by leukocytes, epithelial and endothelial cells, and fibroblasts. IL-8 is accepted as an indicator of multi-organ failure risk.  IL-10 Anti-inflammatory cytokine; Inhibition of IFN-γ production in TH1, Inhibition of MHC class II production in macrophage It reduces TNF- α levels and its harmful effects IL-12 Proinflammatory cytokine; Stimulation of TH1 lymphocyte transformation, Synergistic effect with IL-2 Inhibition of IL-10 production from TH2 lymphocyte NK activation IL-13 Anti-inflammatory cytokine Excessive airway response to allergens in asthma (IL-9) IL-15, IL-18 IL-15 : Increases neutrophil phagocytosis IL-18: It is elevated in sepsis, especially in gram- positive infections.  High mobility group box-1 (HMGB- 1) It is responsible for the weight loss, aversion to food, sick appearance and shock seen in systemic inflammatory response syndrome. INTERFERONS : They are cytokines, some of which are antiviral, that regulate the activity of the immune system at every stage. Type 1 Interferons: They are released from virus- infected cells. The main ones: IFN- α and β Type 2 Interferons: Only IFN- γ is present, It has an immunomodulatory effect TYPE 1 INTERFERONS INTERFERON- α: Released from monocytes/macrophages, lymphocytes, and virus-infected cells Macrophage, NK and B cell activation Activation of genes with antiviral effects (Mx gene) IFNs released from virus-infected cells enable the synthesis of enzymes capable of degrading mRNA in infected cells. INTERFERON- β It is synthesized by virus-infected cells, macrophages and fibroblasts. Increased Cytotoxicity of NK cells against virus- infected cells. Type 2 Interferon: INTERFERON- γ TH1 lymphocyte, NK cell is formed. Immune regulation Proinflammatory cytokine, macrophage and cytotoxic T lymphocyte activation Stimulation of MHC production Suppression of viral replication. PML, NK, macrophage activity ↑ Inhibits proliferation of Th2 cells Weak antiviral effect TGF- β ( Transforming grow factor ) Released by T-lymphocytes and macrophages Inhibits T and B lymphocyte proliferation Macrophage activity ↓ Stopping inflammation Initiation of collagen synthesis and healing process GROWTH FACTORS Molecules in polypeptide structure that act similar to cytokines. They regulate cell migration, proliferation and differentiation PDGF, FGF, EGF, Erythropoietin, IGF, VGEF PDGF (Platelet Derived Growth factor)  Synthesized by platelets, macrophages, endothelial cells and keratinocytes  Major cytokine that promotes the proliferation of connective tissue cells.  Important in wound healing  Chemotaxis ↑  Fibroblast and smooth muscle proliferation ↑ FGF ( Fibroblast growth factor ) Released from connective tissue and keratinocytes Its most important feature is to induce angiogenesis (chemotactic for endothelial cells). EGF ( Epidermal Growth factor ) Synthesize by Epidermal cells and macrophages Increase Migration and proliferation of keratinocytes and fibroblasts Erythropoietin It is released from the kidney Promotes differentiation and development of Erythroid precursor cells  IGF (Insulin like Growth factor ) IGF-1 ( Somatomedin ): It is released from the liver with the effect of GH Responsible for growth and development in many cells (especially bone) Shows its effect through tyrosine kinase IGF-2: Responsible for growth and development in fetal life CSF (Colony Stimulating Factors) G-CSF: Granulocytes-CSF M-CSF: Monocytes-CSF GM-CSF: Effective against granulocytes and monocytes CSFs are synthesized by lymphocytes and macrophages. Activates leukocyte colonies Increase the adhesion, cytotoxicity and phagocytosis ability of leukocytes