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Cytokines and their Receptors Web Sites: Cytokine Family Database Cytokines are soluble proteins produced by mononuclear cells of the immune system (usually lymphocytes or monocytes) that have regulatory actions on other cells of the immune system or target cells involved in immune reactions (cells which produce cytokines). Cytokines constitute a large family of small proteins that regulate diverse biological processes including hematopoiesis, organogenesis, leukocyte trafficking, and cellular signaling. . Cytokines are a group of low molecular weight (usually less than 30 kDa) glycosylated proteins. Cytokines play a key role in directing and targeting immune cells during the development of the immune response. They bind to specific receptors on the membrane of target cells and elicit biochemical changes responsible for signal transduction that results in an altered pattern of gene expression in the target cells. They are mediators of both innate immunity and adaptive immunity. They are often pleiotropic in that they possess the capacity to influence many elements of the immune system as well as redundant in that more than one cytokine can do the same thing. Due to their redundant and pleiotropic actions, they form a network in which one cytokine can induce its own production or even secondary generation of other cytokines. As with hormones and growth factors, cytokines are secreted soluble factors that elicit their biological effects at picomolar concentrations by binding to receptors on target cells. But growth factors tend to be produced constitutively, whereas cytokines and hormones are secreted in response to discrete stimuli, and secretion is short-lived, ranging from a few hours to a few days. Unlike hormones, which generally act long range in an endocrine fashion (binding to target cells in distant parts of the body), most cytokines act over a short distance in an autocrine (binding to receptors on the membrane of the same cell) or paracrine fashion (binding to receptors on a target cell in close proximity). Specific cytokine receptors start specific JAK-STAT pathways. In addition, it has been shown that most cytokine actions involve the activation of transcription factors (e.g., NF-kB and AP-1) and protein kinases (e.g., MAPK and PKC) that, in turn, regulated the expression of many target genes indispensable to the maintenance of the inflammatory state. A distinct group of cytokines called chemokines have the ability to chemoattract and activate leukocytes at the site of inflammation. Chemokine effects are mediated via interaction with G protein-coupled receptors. Binding of chemokines to their specific receptors allows rolling leukocytes to become firmly adherent and able to transmigrate to the target tissues, a process largely dependent on the activation of adhesion molecules, mainly integrins. How Cytokines are Classified: Cytokine Families: There are over 200 different cytokines which can be grouped into structural cytokine families: 1) hematopoietin, 2) interferons, 3) tumor necrosis factor and 4) chemokines. Although the immune response to a specific antigen may include the production of cytokines, cytokines themselves act in an antigen-nonspecific manner. Structural Relationships: Ligands: Type I cytokines are a superfamily of immunomodulators that are defined on the basis of structural motifs, such as the common FOUR-HELIX BUNDLE and the HAEMATOPOIETIN-RECEPTOR DOMAIN that are common to these ligands and their receptors respectiively. Many of these factors are involved in the regulation of cell survival, differentiation, haematopoiesis and immune function. 34 known type I cytokine receptors have been described and although the ligands are more difficult to identify, there are at least 27 that can be clustered into 50 distinct families. One of these groupins is composed of the ligands for a series of cytokine receptors that use gp130 or one of several gp130 related proteins. Receptors They Bind: Most cytokines that function in the immune system bind to either the Class I or Class II receptor families. Two other important receptor families are the immunoglobulin superfamily receptor and TNF receptor family. A common feature of all these receptor families is that they do not exhibit any intrinsic tyrosine kinase activity. Receptor signaling is initiated through recruitment of kinases and through recruitment of cytosolic proteins to the receptor. One way that the nonspecificity of cytokines is regulated is by regulation of the expression of cytokine receptors on cells which are classified as follows:
Class I receptors usually consist of two polypeptide chains; one chain for the cytokine binding and the other for triggering of the signal transduction pathway. The class I receptors are further classified by the number of amino acids contained in their four alpha helical bundle structure. Short chain receptors have helices of 15 amino acids and include the IL-2 family (IL-2, IL-4, IL-7, IL-9 and IL15). Long chain receptors have helices of 25 amino acids and include IL-6, IL-11, and IL-12.
Pro-inflammatory vs. Anti-inflammatory: Cytokines can be classified as pro- or anti-inflammatory, depending on the way they influence inflammation. It is important to note that cytokines are pleiotropic, possessing the capacity to influence many elements of the immune system. So although they are classified based on being pro-inflammatory and anti-inflammatory, this dichotomy is often murky. For example, IL-2, IL-6, TNF and the IFNs have well characterized pro-inflammatory activties, but they also have suppressive effects. Similarly, IL-10, one of the most potent inhibitors of cell-mediated immune responses can also provide stimualtory signals for B cell growth and NK cell production of IFNy. An important challenge is to understand the molecular events that determine whether the outcome of these cytokine-receptor interactions is a pro or anti-inflammatory signal. Pro-Inflammatory and T-helper 1 Cytokines: Pro-inflammatory or T-helper 1 cytokines include IL-1β, IL-2, IFN-y, IL-12, TNF-α., and IL-18 Pro-inflammatory cytokines not specifically classified as Th1 cytokines include IL-1. Anti-Inflammatory and T-helper 2 Cytokines Anti-inflammatory or T-helper 2 cytokines include IL-4, IL-5, IL-10, IL-13 and TGF-β. These downregulate both the innate and the adaptive immune responses. Regulation of Cytokine Production Effects of Various Molecules/Drugs which Affect the Production of Cytokines Role of Cytokines in Disease/Infection Cytokines Secreted During T Cell Development
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