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Receptors and Signaling: Cytokines and Chemokines Cytokines Low-molecular weight regulatory proteins or glycoproteins Secreted by WBC and various other cells Assist in regulating development of immune effector cells Referred to as Interleukins ○ IL-1 through IL-37 have been described Chemokines subpopulation of cytokines that share the specific purpose of mobilizing immune cells from one organ, or indeed, from one part of an organ, to another. Subpopulation of cytokines Mobilize immune cells from one area to another Class of chemoattractants General Properties of Cytokines and Chemokines 1. Cytokines Mediate the Activation, Proliferation, and Differentiation of Target Cells: Cytokines bind to specific receptors on the membranes of target cells, triggering signal transduction pathways that ultimately alter enzyme activity and gene expression. The susceptibility of a target cell to a particular cytokine is determined by the presence of specific membrane receptors and exhibit very high affinity for one another. Cytokines bind to specific receptors Trigger signal transduction pathways that alter gene expression in target cells Exhibit pleiotropy, redundancy, synergy, antagonism, cascade induction A cytokine that induces different biological effects depending on the nature of the target cells is said to have a pleiotropic action Two or more cytokines that mediate similar functions are said to be redundant Cytokine synergy occurs when the combined effect of two cytokines on cellular activity is greater than the additive effects of the individual cytokines The effects of one cytokine inhibit or antagonize the effects of another Cascade induction occurs when the action of one cytokine on a target cell induces that cell to produce one or more additional cytokines. 2. Cytokines Can Elicit and Support the Activation of Specific T-Cell Subpopulations; TH1 cells secrete cytokines that ▬▬▬▬► promote the differentiation and activity of macrophages and cytotoxic Tcells, (intracellular bacteria are recognized and destroyed). How ?? The cytokines IL-12 and interferon (IFN) γ induce TH1 differentiation. TH2 cells activate B cells to make antibodies, which ▬▬▬▬► neutralize and bind extracellular pathogens, ▬▬▬►making them susceptible to phagocytosis and complement-mediated lysis. How ?? IL-4 and IL-5 support the generation of TH2 cells. TH17 cells promote the ▬▬▬▬► differentiation of activated macrophages and neutrophils, and support the inflammatory state; How ?? their generation is induced by IL-17 and IL-23. 3. Cell Activation May Alter the Expression of Receptors and Adhesion Molecules What keeps cytokines from activating all T cells, for example, in a nonspecific fashion during the immune response? In order for a cell to respond to a signaling molecule, it must express receptors for that molecule, and responsiveness to a molecular signal can thus be controlled by signal receptor expression. 4. Cytokines Are Concentrated Between Secreting and Target Cells; The close nature of the cell-cell interaction and the directional release of cytokines by the secretory apparatus. effective concentration of cytokines in the region of the membrane receptors may be more important than that experienced outside the contact region of the two cells. the half-life of cytokines in the bloodstream or other extracellular fluids into which they are secreted is usually very short, ensuring that cytokines usually act for only a limited time and over a short distance 5. Signaling Through Multiple Receptors Can Fine Tune a Cellular Response; Cytokines can bind to more than one receptor, & receptors can bind to more than one signaling molecule. cytokines can be classifyed on the basis of the distance between the cell secreting the signaling ligand & the cell receiving that chemical signal : Cytokines that act on cells some distance away from the secreting cell, such that they must pass through the bloodstream before reaching their target, are referred to as endocrine Those that act on cells near the secreting cell, such that the cytokine merely has to diffuse a few Ångstroms through tissue fluids or across an immunological synapse, are referred to as paracrine Sometimes, a cell needs to receive a signal through its own membrane receptors from a cytokine that it, itself, has secreted. This type of signaling is referred to as autocrine. Of note, the T-cell interleukin IL-2 acts effectively in all three modes. Cytokines belong to 6 families ○ Interleukin 1 (IL-1) ○ Hematopoietin family (Class I) ○ Interferon family (Class II) ○ Chemokine family ○ Tumor necrosis family ○ Interleukin 17 (IL-17) Based on structural studies All have molecular mass less than 30kDa All have similarities and few rarely act alone Interleukin 1 (IL-1) Family typically secreted very early in the immune response ii. by dendritic cells and monocytes or macrophages. iii. IL-1 secretion is stimulated by recognition of viral, parasitic, or bacterial antigens by innate immune receptors. iv. IL-1 family members are generally proinflammatory, (what does this mean)? i. they induce an increase in the capillary permeability at the site of cytokine secretion, amplification of the level of leukocyte migration into the infected tissues. IL-1 has systemic (whole body) effects and signals the liver to produce acute phase These proteins further induce multiple protective effects, including the destruction of viral RNA generation of a systemic fever response (which helps to eliminate many temperature-sensitive bacterial strains). innate immune response IL-1 also activates both T and B cells at the induction of the adaptive immune response. E.X. IL-1α and IL-1β ,IL-18 The IL-1 Family of Cytokine Receptors; Two different receptors for IL-1 are known. are members of the immunoglobulin superfamily: Only the type I IL-1R (IL-1RI), which is expressed on many cell types, the type II IL-1R (IL-1RII) is limited to B cells Note that both the IL-1RI and the IL-1RII receptor chains exist in both soluble and membrane-bound forms. Hematopoietin (Class I) Family ○ Called Class I because earliest to be structurally characterized (not first to be discovered) ○ Not all involved in hematopoietic functions Their cellular origins and target cells are as diverse as their ultimate functions, which range from; signaling the onset of T- and B-cell proliferation (e.g., IL-2), to signaling the onset of B-cell differentiation to plasma cells and antibody secretion (e.g., IL-6), to signaling the differentiation of a T helper cell along one particular differentiation pathway versus another (e.g., IL-4 vs. IL-12) and finally, to initiating the differentiation of particular leukocyte lineages (e.g., GM-CSF, GCSF). The Hematopoietin or Class I Receptor Family The γ-Chain Bearing, or IL-2 Receptor, Subfamily: Expression of a common γ chain defines the IL-2 receptor subfamily, which includes receptors for IL-2, IL-4, ……. The IL-2 receptors are heterotrimers, consisting of α chain and —β and γ—responsible for both signal transduction and cytokine recognition. The IL-2 receptor γ chain also functions as the signaltransducing subunit for the other receptors in this subfamily, which are all dimers. The IL-2 receptor occurs in three forms, each exhibiting a different affinity for IL-2: the low-affinity monomeric IL-2Rα (which can bind to IL-2, but is incapable of transducing a signal from it), the intermediate-affinity dimeric IL-2Rβγ (which is capable of signal transduction), and the high-affinity trimeric IL-2Rαβγ (which is responsible for most physiologically relevant IL-2 signaling). The β Chain Bearing, Receptor Subfamily which includes the receptors for IL-3, IL-5….. share the β signaling subunit. binds with low affinity α subunit of a dimeric receptor. All three low-affinity subunits associate noncovalently with the common signaltransducing subunit. The resulting αβ dimeric receptor has a higher affinity for the cytokine than the specific α chain alone, and is also capable of transducing a signal across the membrane upon cytokine binding. Interferon (Class II) ○ First cytokines to be discovered ○ Type I - Secreted by not only macrophages and dendritic cells but also by virus infected cells: (1) Interferons α, and (2) interferon-β, ○ Type II – produced by activate T and NK cells , known as interferon-γ & cytokines include IL-10 o Third class, interferon-λ . This type up-regulate the expression of genes controlling viral replication and host cell proliferation. All three interferons (1) increase the expression of MHC complex proteins on the surface of cells, thus enhancing their antigen-presentation capabilities. (2) Interferon-γ is used medically to bias the adaptive immune system toward a cytotoxic response in diseases such as leprosy and toxoplasmosis, in which antibody responses are less effective than those that destroy infected cells. Interferon Receptors are heterodimers that share the same with members of the Hematopoietin receptor family The JAK-STAT Signaling Pathway Tumor Necrosis Family (TNF) ○ Can signal development, activation, or death of certain cells Cytokines of the TNF Family ○ There are two members having the same name of the TNF family: TNF-α and TNF-β. Both of these are secreted as soluble proteins. TNF Receptors TNF-R1, Fas Receptor: Which induce apoptosis, or programmed cell death, is a mechanism of cell death in which the cell dies from within and is fragmented into membrane-bound vesicles that can be rapidly phagocytosed by neighboring macrophages. IL-17 Family ○ Most recently described cytokines ○ Proinflammatory cytokine cluster interleukins 17A, 17B, 17C, 17D, and 17F T cells secreting IL-17A represent a new lineage, the TH17 cell subset, IL-17 family share the property of operating at the interface of innate and adaptive immunity, serving to coordinate the release of proinflammatory and neutrophilmobilizing cytokines. IL-17E promot the differentiation of the antiinflammatory TH2 subclass, suppressing further TH17 cell responses, Chemokines Direct the Migration of Leukocytes Through the Body; Are structurally related family of small cytokines that bind to cell-surface receptors and induce the movement of leukocytes up a concentration gradient and toward the chemokine source. located on the surfaces of endothelial cells, enables them to bind to the inner surfaces of blood vessels and directing leukocyte movement. The grouping of chemokines into the subclasses has functional, as well as structural,significance. The seven human CXC chemokines share the same receptor (CXCR2), attract neutrophils, are angiogenic Members of the two, structurally distinct CC groups are chemoattractants that attract monocytes and macrophages (although not neutrophils) to the site of infection. Cytokine Antagonists Number of proteins can inhibit cytokine activity ○ Can bind to receptor but fail to activate the cell, thus blocking the active cytokine from binding, OR ○ Can bind to cytokine, inhibiting its ability to bind to the receptors Cytokine Related Diseases Sever combined immunodeficiency (SCID) Genetic defects in cytokines, their receptors Defective receptor for IFN-γ Susceptible to mycobacterial infections Cytokine Related Diseases Bacterial Septic Shock Certain bacteria: Staphyloccocus aureus, E. coli, Klebsiella pneumoniae ….. Symptoms: drop in blood pressure, fever, diarrhea, blood clotting Endotoxins (cell wall) bind TLRs on dendritic cells and macrophages leading them to produce ○ Over-produce IL-1β and TNF-α ○ Cytokine imbalance causes abnormal temp, abnormal respiration, capillary leakage, tissue injury, organ failure ○ Neutralization by monoclonal antibodies may help Cytokine Related Diseases Bacterial Toxic Shock Microorganisms produce toxins that act as Superantigens ○ Bind simultaneously to Class II MHC and T cell receptor, activating T cell despite antigenic specificity ,,induce extremely high levels of TNF-α and IL-1β Symptoms similar to sepsis Cytokine Related Diseases Abnormalities in production of cytokines or receptors are associated with certain types of cancer (abnormally high levels of IL-6 are secreted by cardiac myxoma) Historical documents detailing the symptoms of the 1918 Spanish influenza with massive fatalities resulted from cytokine storms, unregulated, immune cell cytokine secretion….. Cytokine-Based Therapies; Soluble TNF-α receptor and monoclonal antibodies against TNF-α have been used to treat rheumatoid arthritis and ankylosing spondylitis in more than a million patients. Which reduce proinflamatory cytokine cascades; help to alleviate pain, stiffness, and joint swelling; and promote healing and tissue repair. The recombinant form of IL-1Ra has been shown to be relatively effective in the treatment of rheumatoid arthritis. Monoclonal antibodies directed against the α chain of the IL-2R are also in clinical use for the prevention of transplantation rejection reactions Q1//How might a cytokine signal result in the alteration of the location of a lymphocyte? A cytokine may induce the expression on the cell surface of new chemokine receptors and/or new adhesion molecules that would cause the cell to move to a new location and, once present, to be retained there.