Cytokines.pdf

Cytokines George Nadăș,Professor of Immunology, [email protected] Cytokines Introduction The immune system form complex networks involving many different cell types, each sending and receiving multiple messages from many different sources. Intercellular signals are transmitted in two general ways...

Cytokines George Nadăș,Professor of Immunology, [email protected] Cytokines Introduction The immune system form complex networks involving many different cell types, each sending and receiving multiple messages from many different sources. Intercellular signals are transmitted in two general ways One method is called volume transmission - a mediator molecule is released by the signaling cell and diffuses through the extracellular fluid to the receiving cell, where it binds to cell surface receptors The second method, called network transmission - two cells come into direct contact using complementary receptors. Signals are then transmitted directly between these two receptors 2 Cytokines Introduction The most important molecular mediators (cytokines) are leukins (interleukin), monokins, prostaglandins and interferons 3 Cytokines Introduction The cells of the immune system can synthesize and secrete hundreds of different proteins that control the immune responses by communicating among cells cytokines Cytokines differ from conventional hormones in several important respects: 1. unlike conventional hormones, which tend to affect a single target cell type, cytokines can affect many different cell types 2. immune system cells rarely secrete a single cytokine at a time - macrophages secrete at least four interleukins (IL-1, IL-6, IL-12, IL-18) as well as tumor necrosis factor-α (TNF-α) 4 Cytokines Introduction 3. cytokines are “redundant” in their biological activities in that many different cytokines have similar effects - IL-1, TNFα,TNF-β,IL-6, high mobility group box protein-1 (HMGB1), and the chemokine CCL3 all act on the brain to cause a fever 4. cytokine-mediated signals are transient, and the messages delivered may vary over time as the cytokine environment changes 5 Cytokines Properties of cytokines Short-lived proteins Highly diverse structures and receptors Can act locally and/or systemically Pleiotropic: affect many different cells Redundant: exhibit biologically overlapping functions Carefully regulated Toxic in high doses 6 Cytokines Cytokine nomenclature The nomenclature and classification of the cytokines is not based on any systematic relationship among these proteins Many were originally named after their cell of origin or the bioassay used to identify them The interleukins, for example, are cytokines that mediate signaling between lymphocytes and other leukocytes They are numbered sequentially in the order of their discovery 7 Cytokines Cytokine nomenclature Because their definition is so broad, the interleukins are a heterogeneous mixture of proteins with little in common except their name 39 different numbered interleukins have been described Some are clearly critical to a successful immune response, whereas others appear to be much less essential The interferons are cytokines produced in response to virus infection or immune stimulation - that they interfere with viral RNA and protein synthesis and so have antiviral activity 8 Cytokines Cytokine nomenclature There are three types of interferon – all posses antiviral activity Type I interferons are a diverse family, the most important of which are interferon-α (IFN-α)and IFN-β There is a single type II interferon, called IFN-γ Three type III interferons (IFN–λ)have been identified Type I interferons are primarily antiviral with a secondary immunoregulatory role For type II and type III interferons such as IFN-γ and IFN–λ,the reverse is the case Many type I interferons also play an important role in the maintenance of pregnancy 9 Cytokines Cytokine nomenclature TNFs are cytokines secreted by macrophages and T cells. As their name suggests, they can kill tumor cells, although this is not their primary function Thus TNF-α is the key mediator of acute inflammation. The TNFs belong to a large family of related cytokines, the TNF superfamily, which is involved in immune regulation and inflammation Other important members of the TNF superfamily include CD178 (also called CD95L or Fas ligand), and CD154 (CD40 ligand) Many cytokines are growth factors (or colony-stimulating factors) and regulate blood cell production by regulating stem cell activities 10 Cytokines Cytokine nomenclature Overall cytokines secreted by lymphocytes are called lymphokines (interleukin), while those secreted by monocytes-macrophages are monokines Chemokines are a family of at least 50 small cytokines that play an important role in leukocyte chemotaxis, circulation, migration, and activation, especially in inflammation A typical example of a chemokine is CXCL8 (also known as IL-8) Interleukins are cytokines that regulate the interactions between lymphocytes and other leucocytes. They are in number of 39: IL-1 – IL-39 11 Cytokine functions Cytokines Cytokines are produced in response to many different stimuli: 1. antigens acting through the T cell or B cell antigen receptors 2. antigen-antibody complexes acting through antibody receptors (FcR) 3. pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides acting through toll-like receptors (TLRs) Three of the most important pathways that trigger cytokine release are the combination of antigens with their receptors on T and B cells, the combination of PAMPs with tolllike receptors on sentinel cells; and the combination of antibodies with Fc receptors on phagocytic cells 4. and other cytokines acting through cytokine receptors 12 Cytokines Cytokine functions Cytokines act on many different cellular targets. They may, for example, bind to receptors on the cell that produced them and thus have an autocrine effect Alternatively, they may bind only to receptors on nearby cells; this is called a paracrine effect Some cytokines may spread throughout the body, affecting target cells in distant locations, and thus have an endocrine effect The distinction among autocrine, paracrine, and endocrine effects. Cytokines differ from hormones in that most of their effects are autocrine or paracrine, whereas hormones usually act on distant cells in an endocrine fashion 13 Cytokine functions Cytokines When cytokines bind to receptors on target cells, they affect cell behavior They may induce the target cell to divide or differentiate, or they may stimulate the production of new proteins Alternatively they may inhibit these effects—preventing division, differentiation, or new protein synthesis Most cytokines act on many different target cell types, perhaps inducing different responses in each one, a feature that is called pleiotropy Conversely, many different cytokines may act on a single target, a feature known as redundancy e.g. IL-3, IL-4, IL-5, and IL-6 all affect B cell function 14 Cytokines Cytokine functions Some cytokines work best when paired with other cytokines in a process called synergy e.g. the combination of IL-4 and IL-5 stimulates B cells to make immunoglobulin E (IgE) and hence triggers an allergic response Synergy can also occur in sequence when, for example, one cytokine induces the target cell to express the receptor for another cytokine Finally, some cytokines have opposing effects and may antagonize the effects of others - mutual antagonism of IL-4 and IFN-γ 15 Cytokines Cytokines produced by macrophages and dendritic cells The major cytokines produced by macrophages are represented by IL-1, IL-6, IL12, IL-18 and TNF-α Interleukin 1 plays a critical role in inflammation but its activities are not restricted to inflammation, being also involved in fever, hematopoiesis, appetite control and acquired immunity Beside macrophages, IL-1 is also produced by DCs, T cells, B cells, NK cells 16 Cytokines Cytokines produced by macrophages and dendritic cells Interleukin 6 is produced not only by activated macrophages but also by T and B cells, mast cells, vascular endothelial cells, fibroblasts and keratinocytes It is also produced by muscle cells during exercise Il-6 acts on T cells, B cells, hepatocytes, promotes Th2 differentiation, is required for the final maturation of B cells into plasma cells 17 Cytokines Cytokines produced by macrophages and dendritic cells Interleukin 12 is produced by monocytes and macrophages, DCs, B cells and keratinocytes Promotes Th1 cell activity and enhances T and NK cell proliferation and cytotoxicity TNF-α and IL-12 synergize in promoting IFN-γ production Interleukin 18 acts on Th1 cells to promote the production of IFN-γ,IFN-α,IL-1 and several chemokines 18 Cytokines Cytokines produced by macrophages and dendritic cells Tumor necrosis factor-α is produced by macrophages, mast cells, T cells, endothelial cells, B cells and fibroblasts TNF-α is a potent proinflamatory molecule and many of its activities are shared with IL-1 TNF-α enhances the expression of adhesive molecules, promotes fibroblast proliferation and collagen production, a feature of importance in chronic inflammation 19 Cytokines Cytokines produced by T cells Helper T cells cytokines fall into two major groups: those produced by Th1 cells and those produced by Th2 cells In general, the Th1 derived cytokines tend to have biological activities that counteract the activities of the Th2-derived cytokines Thus the balance between these two groups determines the nature of the immune response to an specific antigen 20 Cytokines Cytokines produced by Th1 cells IL-12 and IL-18 produced by DCs, macrophages and B cells specifically stimulate Th1 cell activity in producing IL-2 and TNF-γ Interleukin 2 is only produced by Th1 cells and activates helper and cytotoxic T cells and NK cells IL-2 also induces production of TNF-γ and IL-5 21 Cytokines Cytokines produced by Th1 cells Interferon-γ is produced by Th1 cells, Tc cells, NK cells and macrophages stimulating B cell production of IgG Enhances T cell production of MHC class I molecules but not production of MHC class II molecules It enhances the activities of NK cells and is thus a potent stimulator of innate immunity 22 Cytokines Cytokines produced by Th2 cells Th2 cells secrete a complex mixture of cytokines including IL-4, IL-5, IL-9, IL-10, and IL-13 and generally provide helper activity for B cell immunoglobulin production They are stimulated to produce these cytokines by IL-1 Interleukin 4 is produced by activated Th2 cells, mast cells and basophils It acts on B cells, T cells, macrophages and mast cells stimulating the growth and differentiation of B cells It induces B cells to switch to IgE production and is therefore of major importance in the development of allergic reactions 23 Cytokines Cytokines produced by Th2 cells Interleukin 5 is produced by activated Th2 cells, mast cells and eosinophils controlling the eosinophil production by stimulating growth and differentiation of eosinophil precursors in the bone marrow IL-5 also enhances B cell growth Interleukin 9 is a stem cell growth factor produced only by Th2 cells It promotes the growth of helper T cells and mast cells 24 Cytokines Cytokines produced by Th2 cells Interleukin 10 is an immunosuppressive and antiinflammatory cytokine that regulates inflammation as well as T cell, NK cell and macrophages function Its targets are Th1 cells, B cells, macrophages, NK cells and mast cells IL-10 suppresses the secretion of IL-1, IL-6 and TNF-α by macrophages Interleukin 13 is produced by Th2 cells, cytotoxic T cells, mast cells and DCs It has similar effects on IL-4 and B cells, stimulating their proliferation and increasing immunoglobulin secretion It enhances macrophage activity and is a chemoattractant for monocytes 25 Cytokines Chemokines FYI 26 Chemokines Cytokines Chemokines or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells Chemokines have been classified into 4 main subfamilies: CXC, CC, CX3C and C Chemokines are functionally divided into two groups: 1. Homeostatic: are constitutively produced in certain tissues and are responsible for basal leukocyte migration: CCL14, CCL19, CCL20, CXCL12 and CXCL13 2. Inflammatory: these are formed under pathological conditions and actively participate in the inflammatory response attracting immune cells to the site of inflammation: CXCL-8, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL10 27 Cytokines ©2024 Ross University School of Veterinary Medicine. All rights reserved.