大学精品课件：专业外语Cytokines

1、CytokinesCytok ines are prote ins secreted by the cells of inn ate 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 inflamm

2、ation. In the activation phase of adaptive immune responses, cytokines stimulate the growth and differe ntiati on of lymphocytes, and in the effector phases of inn ate and adaptive immunity, they activate different effector cells to eliminate microbes and other antigens. Cytokines also stimulate the

3、 development of hematopoietic cells. In clinical medicine, cytokines are importa nt as therapeutic age nts and as targets for specific an tag oni sts in nu merous immune and in flammatory diseases.The nomenclature of cytokines is often based on their cellular sources. Cytokine that are produced by m

4、ononuclear 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

5、endothelial cells and some epithelial cells,. Therefore, the gen eric term cytok ines is the preferred n ame for this class of mediators.General Properties of CytokinesCytok ines are polypeptides produced in resp onse to microbes and other an tige ns that mediate and regulate immune and in flammator

6、y react ions. Although cytok ines 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 activati on. Such t

7、ran scriptio nal activati on is tran sie nt, and the messe nger RNAs en codi ng most cytok ines are un stable, so cytok ine syn thesis is also tran sie nt. The product ion of some cytok ines may additi on ally be con trolled by RNA process ing and by post-tra nscripti onal mecha ni sms, such as prot

8、eolytic release of an active product from an in active precursor. Once syn thesized, cytok ines are rapidly secreted, result ing in a burst of release as n eeded.The actions of cytokines are often pleiotropic and redundant. Pleiotropism refers to the ability of one cytokine to act on different cell

9、types. This property allows a cytokine to mediate diverse biologic effects, but it greatly limits the therapeutic use of cytokines becauseadmi nistrati on of a cytok ine for a desired cli nical effect may result in nu merous unwan ted side effects. Redundancy refers to the property of multiple cytok

10、ines having the same functional effects. Because of this redundancy, an tag oni sts aga inst a sin gle cytok ine or mutati on of one cytok ine gene may not have functional con seque nces, as other cytok ines may compe nsate.s actCytokines often influence the synthesis and actions of other cytokines.

11、The ability of one cytok ine to simulate product ion of others leads to cascades in which a sec ond or third cytok ine may mediate th e biologic effects of the first. Two cytokines may antagonize each other produce additive effects, or, i n some cases, produce greater tha n an ticipated, or syn ergi

12、stic, effects.Cytokine actions may be local and systemic. Most cytokines act close to where they are produced either on the same cell that secretes the cytok ine (autocri ne action) or on a n earby cell (paracri ne action). T cells ofte n secrete cytok ines at the site of con tact with an tige n-pre

13、se nti ng cells, the so-called immune synapse. This may be one reason that cytokines often act on cells in con tact with the cytok ine producers. When produced in large amoun ts, cytok ines may en ter the circulation and act at a distance from the site of production (endocrine action).Cytokines init

14、iate their actions by binding to specific membrane receptors on target cells.Receptors for cytokines often bind their ligands with high affinities, with dissociation constants-10 -12(Kd values) in the range of 10 to 10 M. (For comparis on, recall that an tibodies typically bi nd-7-11antigens with a

15、K d of 10 to 10 M and that major histocompatibility complex (MHC) molecules-6bind peptides with a Kd of only about 10 M.) As a consequence, only small quantities of a cytok ine are n eeded to occupy receptors and elicit biologic effects. Most cells express low levels of cytokine receptors (on the or

16、der of 100 to 1000 receptors per cell), but this is adequate for in duci ng resp on ses.vn.i)plxma merbrinecyLDkrsereceptorviral chemotoineclrririokiineviral khcjriLciiwrewp：cirrecefrto*cyiajpfdswExternal signals regulate the expression of cytokine receptors and thus the responsiveness of cells to c

17、ytokines. For instanee, stimulation of T or B lymphocytes by antigens leads to in creased expressi on of cytok ine receptors. For this reas on, duri ng an immune resp on se, the antigen-specific lymphocytes are the preferential responders to secreted cytokines. This is one mechanism for maintaining

18、the specificity of immune responses, even though cytokines themselves are not an tige n specific. Receptor expressi on is also regulated by cytok ines themselves, including the same cytokine that binds to the receptor, permitting positive amplification or n egative feedback.The cellular responses to

19、 most cytokines consist of changes in gene expression in target cells, resulting in the expression of new functions and sometimesin the proliferation of the target cells. Many of the cha nges in gene expressi on in duced by cytok ines result in differe ntiati on of T and B lymphocytes and activation

20、 of effector cells such as macrophages. For instanee, cytokines stimulate switching of antibody isotypes in B cells, differentiation of helper T cells into Th1 and Th2 subsets, and activati on of microbicidal mecha ni sms in phagocytes. Excepti ons to the rule that cytok ines work by cha nging gene

21、expressi on patter ns are chemok in es, which elicit rapid cell migratio n, and a cytok ine called tumor n ecrosis factor (TNF), which in duces apoptosis by activating cellular enzymes, without new gene transcription or protein synthesis.Functional Categories of Cytokinescytok ines were classified i

22、n to three main fun ctio nal categories based on their prin cipal biologic actio ns.1. Mediators and regulators of innate immunity are produced mainly by mononu clear phagocytes in response to infectious agents. Bacterial products, such as lipopolysaccharide (LPS), and viral products, such as double

23、-stra nded RNA, directly stimulate macrophages to secrete these cytok ines as part of inn ate immuni ty. The same cytokines may also be secreted by macrophages that are activated by antigen-stimulated T cells (i.e., as part of adaptive cell-mediated immunity). Most members of this group of cytokines

24、 act on endothelial cells and leukocytes to stimulate the early in flammatory reacti ons to microbes, and some fun cti on to con trol these resp on ses. NK (n atural killer) cells also produce cytok ines duri ng inn ate immune reacti ons.2. Mediators and regulators of adaptive immunity are produced

25、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 populati ons and thus play importa nt roles in the activati on phase of T cell-dependent immune responses. Other

26、T cell-derived cytokines recruit, activate, and regulate specialized effector cells, such as mononu clear phagocytes, n eutrophils, and eos in ophils, to elim in ate an tige ns in the effector phase of adaptive immune resp on ses.3. Stimulators of hematopoiesis are produced by bone marrow stromal ce

27、lls, leukocytes, and other cells, and stimulate the growth and differe ntiati on of immature leukocytes.In gen eral, the cytok ines of inn ate and adaptive immun ity are produced by differe nt cell populati ons and act on differe nt target cells. However, these dist inctions are not absolute because

28、 the same cytok ine may be produced duri ng inn ate and adaptive immune react ions, and differe nt cytok ines produced duri ng such react ions may have overlapp ing actions.Cytokine Receptors and SignalingAll cytokine receptors consist of one or more transmembrane proteins whose extracellular portio

29、ns 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 or more receptor molecules

30、 in a process an alogous to sig nali ng by T and B cell receptors for an tige ns.The most widely used classificati on of cytok ine receptors is based on structural homologies among the extracellular cytokine-binding domains. According to this classification, cytokine receptors are divided into five

31、families.Type I cytokine receptors, also called hemopoietim receptors, contain one or more copies of a domai n with two con served pairs of cystei ne residues and membra ne proximal seque nee of tryptopha n seri ne X tryptopha n seri ne (WSXWS), where X is and ami no acid. These receptors typically

32、bi nd cytok ine that fold in to four ahelical stra nds. The con served features of the receptors presumable form structure that bind four a-helical cytokines, but the specific for in dividual cytok ines is determ ined by amino acid residues that vary from one receptor to ano ther. These receptors co

33、n sist of unique liga nd-b inding cha ins and one or more sig nal-tra nsduci ng cha in which are ofte n shared by receptors for differe nt cytok in es.Type n cytokine receptors are similar to type receptors by virtue of two extracellular doma ins which con served cyste in es, but type n receptors do

34、 not contain the WSXWS motif. These receptors con sist of one liga nd-b inding polypeptide cha in and sig nal-tra nsduc ing cha in.Some cytokine receptors contain extracellular immunoglobulin (Ig) domains and are therefore classified as members of the Ig superfamily. This group of receptors binds di

35、verse cytok ines that sig nal by differe nt mecha ni sms.TNF receptors bel ong to a family of receptors (some of which are not cytok ine receptors) with con served cystei ne-rich extracellular doma ins. On liga nd bi ndi ng, these receptors activate associated in tracellular prote ins that in duce a

36、poptosis or stimulate gene expressi on, or both.Seven-transmembrane a-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-bindi

37、ng (G) proteins. The mammalia n genome en codes many such receptors in volved in sensing en viro nmen tal stimuli. In the immune system, members of this receptor class mediate rapid and transient responses to a family of cytok ines called chemok in es.Cytokine receptors can also be grouped according

38、 to signal transduction pathway they activate. Such a group ing will corresp ond to structural homologies in the cytoplasmic regio ns of the sig nali ng cha ins of the receptors .In many cases, members of a family defi ned by extracellular doma ins en gage similar sig nal tran sducti on pathways.Rol

39、es of cytokines in innate immunity and inflammationDiffere nt cytok ines play key roles in inn ate immu nity to differe nt classes of microbes. In infections by pyoge nic extracellular bacteria, macrophages resp ond to bacterial en dotox ins and perhaps to other bacterial products by produc ing TNF,

40、 IL-1, and chemok in es. TNF and IL-1 act on vascular en dothelium at the site of the in fectio n to in duce the expressi on of adhesi on molecules that promote stable attachme nt of blood n eutrophils and mono cytes to the en dothelium at this site. C hemok ines produced by the macrophages and by e

41、n dothelial cells stimulate the extravasati on of the leukocytes to the in fecti on, where the inn ate immune reactio n is moun ted to elimi nate the in fectious microbes.Macrophages also respond to many microbes, including intracellular bacteria and LPS-produci ng bacteria, by secreti ng IL-12, whi

42、ch in duces the local product ion of IFN-r from NK cells and T-lymphocytes. IFN-r the n activates the macrophages to destroy phageocytosed microbes. IL-12 also stimulates the subseque nt adaptive immune resp on se a nd directs it forward TH1 cells, which are the mediators of IL-12 are complemented b

43、y IL-12. Cytokine-mediated leukocyte recruitme nt and activati on are resp on sible for the injury to no rmal tissues that ofte n accompa nies inn ate immune react ions to in fecti ons. These macrophage-derived cytok in es, especially TNF, IL-1, and IL-12, are also responsible for the systemic manif

44、estations of infection.In viral in fectio n, type I IFNs are secreted by in fected cells and macrophages and function 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-infec

45、ted cells elim in ates the reservoir of infection.The dominant cytok ines produced in resp onse to differe nt microbes acco unt for the n ature of the inn ate immune react ions to these microbes. For in sta nee, the early resp onse to pyoge nic bacteria consists mainly of neutrophils, the response t

46、o intracellular bacteria is dominated by activated macrophages, and the response to viruses consists of NK cells in addition to other inflammatory cells. There may be considerable overlap, however, and there varied cellular reacti ons may be see n to differe nt degrees in many in fectio ns.Roles of

47、T cell cytokines in specialized adaptive immune responsesThe cytokines of adaptive immunity are critical for the development of immune 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 ac

48、tions of cytokines, which may be produced by subpopulations of helper T cells. Different types of microbes stimulate na? ve CD4+ T 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

49、cells. Many intracellular microbes (bacteria and viruses) induce the development of TH1 cells, which produce IFN-r, the cytokine that activates phageocytes to destroy intracellular microbes and stimulates the production of opsonizing antibodies that promote more phageocytosis. Hwlminthic parasites,

50、in contrast, stimulate the development of TH2 cells, which produce IL-4 and IL-5. IL-4 enhances production of helminth-specific IgE 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 deve

51、lopment and effectiveness of adaptive immune responses.SummaryCytokines 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 synthesi

52、zed in response to inflammatory or antigenic stimuli and usually act locally, in an autocrine or paracrine fashion, by binding to high-affinity receptors on target cells. Certain cytokines may be produced in sufficient quantity to circulate and exert endocrine actions. For many cell types, cytokines

53、 serve as growth factors.Cytokines mediate their actions by binding with high affinity to receptors belonging to a limited number of structural families. Different cytokines use specialized signaling pathways, such as the JAK/STAT pathway.The cytokines that mediate innate immunity are produced mainl

54、y by activated macrophages and include the following: TNF and IL-1 are mediators of acute inflammatory reactions to microbes; chemokines recruit leukocytes to sites of inflammation; IL-12 stimulates production of the macrophage-activating cytokine IFN-r; type I IFNs are antiviral cytokines;and IL-10

55、 is an inhibitor of macrophages. These cytokines function in innate immune responses to different classes of microbes.The cytokines that mediate and regulate adaptive immune responses are produced mainly byantigen-stimulated T lymphocytes, and they include the following: IL-2 is the principle T cell

56、 growth factor; IL-4 stimulates IgE production and the development of TH2 cells from na?vehelper T cells; IL-5 activates eosinophils; IFN-r is an activator of macrophages; and TGF-b inhibits the proliferation of T lymphocytes and the activation of leukocytes.The colony-stimulating factors (CSFs) con

57、sist of cytokines produced by bone marrow stromal cells, T lymphocytes, and other cells that stimulate the growth of bone marrow progenitors, thereby providing a source of additional inflammatory leukocytes. Several of these (e.g., stem cell factor and IL-7) play important roles in lymphopoiesis.Cyt

58、okines serve many functions that are critical to host defense against pathogens and provide links between innate and adaptive immunity. Cytokines contribute to the specialization of immune responses by activating different types of effector cells. Cytokines also regulate the magnitude and nature of immune responses by influencing the growth and differentiation of l