1、Cytokines Cytokines are proteins secreted by the cells of innate and adaptive immunity that mediate many of the functions of these cells. Cytokines are produced in response to microbes and other antigens, and different cytokines stimulate diverse responses of cells involved in immunity and inflammat
2、ion. In the activation phase of adaptive immune responses, cytokines stimulate the growth and differentiation of lymphocytes, and in the effector phases of innate and adaptive immunity, they activate different effector cells to eliminate microbes and other antigens. Cytokines also stimulate the deve
3、lopment of hematopoietic cells. In clinical medicine, cytokines are important as therapeutic agents and as targets for specific antagonists in numerous immune and inflammatory diseases. The nomenclature of cytokines is often based on their cellular sources. Cytokine that are produced by mononuclear
4、phageocytes were called monokines, and those produced by lymphocytes were called lymphokines. With the development of anticytokine antibodies and molecular probes, it became clear that the same protein may be synthesized by lymphocytes, monocytes, and a variety of tissue cells, including endothelial
5、 cells and some epithelial cells,. Therefore, the generic term cytokines is the preferred name for this class of mediators. General Properties of Cytokines Cytokines are polypeptides produced in response to microbes and other antigens that mediate and regulate immune and inflammatory reactions. Alth
6、ough cytokines are structurally diverse, they share several properties. Cytokine secretion is a brief, self-limited event. Cytokines are not usually stored as preformed molecules, and their synthesis is initiated by new gene transcription as a result of cellular activation. Such transcriptional acti
7、vation is transient, and the messenger RNAs encoding most cytokines are unstable, so cytokine synthesis is also transient. The production of some cytokines may additionally be controlled by RNA processing and by post-transcriptional mechanisms, such as proteolytic release of an active product from a
8、n inactive precursor. Once synthesized, cytokines are rapidly secreted, resulting in a burst of release as needed. The actions of cytokines are often pleiotropic and redundant. Pleiotropism refers to the ability of one cytokine to act on different cell types. This property allows a cytokine to media
9、te diverse biologic effects, but it greatly limits the therapeutic use of cytokines because administration of a cytokine for a desired clinical effect may result in numerous unwanted side effects. Redundancy refers to the property of multiple cytokines having the same functional effects. Because of
10、this redundancy, antagonists against a single cytokine or mutation of one cytokine gene may not have functional consequences, as other cytokines may compensate. Cytokines often influence the synthesis and actions of other cytokines. The ability of one cytokine to simulate production of others leads
11、to cascades in which a second or third cytokine may mediate the biologic effects of the first. Two cytokines may antagonize each others action, produce additive effects, or, in some cases, produce greater than anticipated, or synergistic, effects. Cytokine actions may be local and systemic. Most cyt
12、okines act close to where they are produced either on the same cell that secretes the cytokine (autocrine action) or on a nearby cell (paracrine action). T cells often secrete cytokines at the site of contact with antigen-presenting cells, the so-called immune synapse. This may be one reason that cy
13、tokines often act on cells in contact with the cytokine producers. When produced in large amounts, cytokines may enter the circulation and act at a distance from the site of production (endocrine action). Cytokines initiate their actions by binding to specific membrane receptors on target cells. Rec
14、eptors for cytokines often bind their ligands with high affinities, with dissociation constants (Kd values) in the range of 10-10 to 10-12M. (For comparison, recall that antibodies typically bind antigens with a Kd of 10-7 to 10-11M and that major histocompatibility complex (MHC) molecules bind pept
15、ides with a Kd of only about 10-6M.) As a consequence, only small quantities of a cytokine are needed to occupy receptors and elicit biologic effects. Most cells express low levels of cytokine receptors (on the order of 100 to 1000 receptors per cell), but this is adequate for inducing responses. Ex
16、ternal signals regulate the expression of cytokine receptors and thus the responsiveness of cells to cytokines. For instance, stimulation of T or B lymphocytes by antigens leads to increased expression of cytokine receptors. For this reason, during an immune response, the antigen-specific lymphocyte
17、s are the preferential responders to secreted cytokines. This is one mechanism for maintaining the specificity of immune responses, even though cytokines themselves are not antigen specific. Receptor expression is also regulated by cytokines themselves, including the same cytokine that binds to the
18、receptor, permitting positive amplification or negative feedback. The cellular responses to most cytokines consist of changes in gene expression in target cells, resulting in the expression of new functions and sometimes in the proliferation of the target cells. Many of the changes in gene expressio
19、n induced by cytokines result in differentiation of T and B lymphocytes and activation of effector cells such as macrophages. For instance, cytokines stimulate switching of antibody isotypes in B cells, differentiation of helper T cells into TH1 and TH2 subsets, and activation of microbicidal mechan
20、isms in phagocytes. Exceptions to the rule that cytokines work by changing gene expression patterns are chemokines, which elicit rapid cell migration, and a cytokine called tumor necrosis factor (TNF), which induces apoptosis by activating cellular enzymes, without new gene transcription or protein
21、synthesis. Functional Categories of Cytokines cytokines were classified into three main functional categories based on their principal biologic actions. 1. Mediators and regulators of innate immunity are produced mainly by mononuclear phagocytes in response to infectious agents. Bacterial products,
22、such as lipopolysaccharide (LPS), and viral products, such as double-stranded RNA, directly stimulate macrophages to secrete these cytokines as part of innate immunity. The same cytokines may also be secreted by macrophages that are activated by antigen-stimulated T cells (i.e., as part of adaptive
23、cell-mediated immunity). Most members of this group of cytokines act on endothelial cells and leukocytes to stimulate the early inflammatory reactions to microbes, and some function to control these responses. NK (natural killer) cells also produce cytokines during innate immune reactions. 2. Mediat
24、ors and regulators of adaptive immunity are produced mainly by T lymphocytes in response to specific recognition of foreign antigens. Some T cell cytokines function primarily to regulate the growth and differentiation of various lymphocyte populations and thus play important roles in the activation
25、phase of T cell-dependent immune responses. Other T cell-derived cytokines recruit, activate, and regulate specialized effector cells, such as mononuclear phagocytes, neutrophils, and eosinophils, to eliminate antigens in the effector phase of adaptive immune responses. 3. Stimulators of hematopoies
26、is are produced by bone marrow stromal cells, leukocytes, and other cells, and stimulate the growth and differentiation of immature leukocytes. In general, the cytokines of innate and adaptive immunity are produced by different cell populations and act on different target cells. However, these disti
27、nctions are not absolute because the same cytokine may be produced during innate and adaptive immune reactions, and different cytokines produced during such reactions may have overlapping actions. Cytokine Receptors and Signaling All cytokine receptors consist of one or more transmembrane proteins w
28、hose extracellular portions are responsible for cytokine binding and whose cytoplasmic portions are responsible for initiating intracellular signaling pathways. These signaling pathways are typically activated by ligand-induced receptor clustering, bringing together the cytoplasmic portions of two o
29、r more receptor molecules in a process analogous to signaling by T and B cell receptors for antigens. The most widely used classification of cytokine receptors is based on structural homologies among the extracellular cytokine-binding domains. According to this classification, cytokine receptors are
30、 divided into five families. Type I cytokine receptors, also called hemopoietim receptors, contain one or more copies of a domain with two conserved pairs of cysteine residues and membrane proximal sequence of tryptophan serine X tryptophan serine (WSXWS), where X is and amino acid. These receptors
31、typically bind cytokine that fold into four -helical strands. The conserved features of the receptors presumable form structure that bind four -helical cytokines, but the specific for individual cytokines is determined by amino acid residues that vary from one receptor to another. These receptors co
32、nsist of unique ligand-binding chains and one or more signal-transducing chain which are often shared by receptors for different cytokines. Type cytokine receptors are similar to type receptors by virtue of two extracellular domains which conserved cysteines, but type receptors do not contain the WS
33、XWS motif. These receptors consist of one ligand-binding polypeptide chain and signal-transducing chain. Some cytokine receptors contain extracellular immunoglobulin (Ig) domains and are therefore classified as members of the Ig superfamily. This group of receptors binds diverse cytokines that signa
34、l by different mechanisms. TNF receptors belong to a family of receptors (some of which are not cytokine receptors) with conserved cysteine-rich extracellular domains. On ligand binding, these receptors activate associated intracellular proteins that induce apoptosis or stimulate gene expression, or
35、 both. Seven-transmembrane -helical receptors are also called serpentine receptors, because their transmembrane domains appear to “snake” back and forth through the membrane, and G protein-coupled receptors, because their signaling pathways involve GTP-binding (G) proteins. The mammalian genome enco
36、des many such receptors involved in sensing environmental stimuli. In the immune system, members of this receptor class mediate rapid and transient responses to a family of cytokines called chemokines. Cytokine receptors can also be grouped according to signal transduction pathway they activate. Suc
37、h a grouping will correspond to structural homologies in the cytoplasmic regions of the signaling chains of the receptors. In many cases, members of a family defined by extracellular domains engage similar signal transduction pathways. Roles of cytokines in innate immunity and inflammation Different
38、 cytokines play key roles in innate immunity to different classes of microbes. In infections by pyogenic extracellular bacteria, macrophages respond to bacterial endotoxins and perhaps to other bacterial products by producing TNF, IL-1, and chemokines. TNF and IL-1 act on vascular endothelium at the
39、 site of the infection to induce the expression of adhesion molecules that promote stable attachment of blood neutrophils and monocytes to the endothelium at this site. C hemokines produced by the macrophages and by endothelial cells stimulate the extravasation of the leukocytes to the infection, wh
40、ere the innate immune reaction is mounted to eliminate the infectious microbes. Macrophages also respond to many microbes, including intracellular bacteria and LPS-producing bacteria, by secreting IL-12, which induces the local production of IFN-r from NK cells and T-lymphocytes. IFN-r then activate
41、s the macrophages to destroy phageocytosed microbes. IL-12 also stimulates the subsequent adaptive immune response and directs it forward TH1 cells, which are the mediators of IL-12 are complemented by IL-12. Cytokine-mediated leukocyte recruitment and activation are responsible for the injury to no
42、rmal tissues that often accompanies innate immune reactions to infections. These macrophage-derived cytokines, especially TNF, IL-1, and IL-12, are also responsible for the systemic manifestations of infection. In viral infection, type I IFNs are secreted by infected cells and macrophages and functi
43、on to inhibit viral replication and infection. IL-15 stimulates the expansion of NK cells, and IL-12 enhances the cytolytic activity of NK cells. NK cell-mediated killing of virus-infected cells eliminates the reservoir of infection. The dominant cytokines produced in response to different microbes
44、account for the nature of the innate immune reactions to these microbes. For instance, the early response to pyogenic bacteria consists mainly of neutrophils, the response to intracellular bacteria is dominated by activated macrophages, and the response to viruses consists of NK cells in addition to
45、 other inflammatory cells. There may be considerable overlap, however, and there varied cellular reactions may be seen to different degrees in many infections. Roles of T cell cytokines in specialized adaptive immune responses The cytokines of adaptive immunity are critical for the development of im
46、mune responses and for the activation of effector cells that serves to eliminate microbes and other antigens. Much of specialization of adaptive immunity is due to the actions of cytokines, which may be produced by subpopulations of helper T cells. Different types of microbes stimulate na ve CD4+ T
47、cells to differentiate into effector cells that produce distinct sets of cytokines and perform distinct functions. The best defined of these subsets are the TH1 and TH2 cells. Many intracellular microbes (bacteria and viruses) induce the development of TH1 cells, which produce IFN-r, the cytokine th
48、at activates phageocytes to destroy intracellular microbes and stimulates the production of opsonizing antibodies that promote more phageocytosis. Hwlminthic parasites, in contrast, stimulate the development of TH2 cells, which produce IL-4 and IL-5. IL-4 enhances production of helminth-specific IgE
49、 antibodies, which coat the parasites, and IL-5 activates eosinphils, which bind to the IgE-coated parasites and destroy them. Thus, cytokines are essential for the development and effectiveness of adaptive immune responses. Summary Cytokines are a family of proteins that mediate many of the responses of innate and adaptive immunity. The same cytokines may be produced by many cell types, and individual cytokines often act on diverse cell types. Cytokines are synthesized in response to inflammatory or antigenic stimuli and usually act locally, in an autocrine or paracrine fashion
