Presentasjon om: "Cytokiner og reguleringsmekanismer Del I"— Utskrift av presentasjonen:
1 Cytokiner og reguleringsmekanismer Del I ImmunresponsenCytokiner og reguleringsmekanismerDel I
2 Cytokiner Polypeptider sekrert av celler Dannet som respons på mikrober og antigenMedierer og regulerer immunresponser og inflammatoriske reaksjonerNomenklatur: opprinnelig etter celletyper (monkiner, lymfokiner etc) Generisk cytokiner. Interleukiner for deres effekt på leukocytter. IL-n
3 Cytokiners egenskaper Sekresjon kortvarig og selvbegrensendePleiotropisk og rikeligInfluerer syntese og virkning av andreLokal og systemiske effekterModulerer målcellerNye gener og nye funksjonerProliferasjon
10 Tumor nekrose faktor, TNF(alfa) Viktigste inflammatoriske G- o.a.Obs sepsisHovedsaklig fra aktiverte makrofagerMålcellerEndotelceller, nøytrofile, hypotalamus. Lever, muskel, fettTNF reseptor familieProinflammatoriske (NF-B, AP-1)Apoptotiske (caspase 8)The major cellular source of TNF is activated mononuclear phagocytes, although antigen-stimulated T cells, NK cells, and mast cells can also secrete this protein.TLR engagement with LPS and other microbial productstwo distinct TNF receptors of molecular sizes 55 kD (type I TNF receptor [TNF-RI]) and 75 kD (TNF-RII)Cytokine binding to some TNF receptor family members, such as TNF-RI, TNF-RII, and CD40 leads to the recruitment of proteins, called TNF receptor-associated factors (TRAFs), to the cytoplasmic domains of the receptors. The TRAFs activate transcription factors, notably nuclear factor κB (NF-κB) and activation protein-1 (AP-1).
12 Interleukin-1, IL-1 Viktig inflammatorisk Hovedsaklig fra aktiverte makrofagerAndreMålcellerEndotelceller, Hypothalamus, LeverReseptorerIg-superfamilie, IL-1R type I og type IIIL-1Raproduced by many cell types other than macrophages, such as neutrophils, epithelial cells (e.g., keratinocytes), and endothelial cellstwo forms of IL-1, called IL-1α and IL-1β bind to the same cell surface receptors and have the same biologic activitiestype I IL-1 receptor, which engages signal transduction pathways that activate NF-κB and AP-1 transcription factorsActs like TNF but fro: IL-1 does not induce the apoptotic death of cells, and even at high systemic concentrations, by itself it does not cause the pathophysiologic changes of septic shock
14 Interleukin-6, IL-6 Inflammatorisk Produsenter Målceller/vev Makrofager, endotelceller, T celler, dendrittiskeMålceller/vevAkuttfaseproteiner fra leverB celle proliferasjon, plasmacelle vekstT celle Th17 differensiering (med TGFβ)The receptor for IL-6 consists of a cytokine-binding protein and a signal-transducing subunit, both of which belong to the type I cytokine receptor familyJAK1 STAT3 aktiveringsvei,Emerging: IL-6 promotes cell-mediated immune reactions by stimulating production of some proinflammatory cytokines (notably IL-17) and by inhibiting the generation and actions of regulatory T cells.
15 Kjemokiner: (kjemotakstiske cytokiner) Stor familie m/homologe cytokinerStimulerer og regulerer leukocytt bevegelserPolypeptider, 8-12 kD, to interne disulfid bindCXC familienNøytrofileCC familienMonocytter, lymfocytter og eosinofileC og CX3C gruppenProduseres av leukocytter, endo/epitel, oaReseptor familier: CXCR, CCR
16 Kjemokiner: biologisk effekt Tiltrekker leukocytter mot inflammasjons-lokusRegulerer lymfocytters migrering i lymfevevAndreSignalering i organogeneseVirale coreseptorerHIV: CCR5 og CXCR4
17 Interleukin-12, IL-12 Aktiverte makrofager og dendrittiske celler Etter TLR stimAv ag. Aktiverte T cellerEffektStimulerer NK og T celler til INFg produksjonDifferensiering av CD4 cellerØker NK og CD8 T cellers cytotoksisitetPrinsipal initiator tidlig innat immunrespons intracellulære mikrober, nøkkel cytokin for å indusere cellemediert immunitetIL-12 is produced in response to TLR signaling induced by many microbial stimuli, including LPS, infection by intracellular bacteria (such as Listeria and mycobacteria), and virus infectionsIn addition, antigen-stimulated helper T cells induce the production of IL-12 from macrophages and dendritic cells, mainly by CD40 ligand on the T cells engaging CD40 on the macrophages and dendritic cells. Thus, IL-12 is produced by APCs when they present antigens to T cells, during the induction and effector phases of cell-mediated immune responses (see Chapter 13). IFN-γ produced by NK cells or T cells also stimulates IL-12 production.
20 Interleukin-10, IL-10 Aktiverte makrofager, T celler (Th2) Monoc, B celler, nonhematopoietiskeViktig anti-inflammatorisk, inhiberer:IL-12 fra makrofager og dendrittiskeIFN indirekteMHC klasse II og costimulatoriske molekylMakrofager og dendrittiske celler (B celle økt)Inhiberer T celle aktivering (TH1)Viral IL-10 homolog
21 Innate immunitet og inflammasjon LPS acts on macrophages to induce the secretion of multiple cytokines, including TNF, IL-1, and IL-12, which can be measured in the serum of individuals treated with LPS or infected with LPS-producing bacteria. TNF and IL-1 stimulate acute inflammation by their actions on endothelial cells and leukocytes. IL-12 stimulates the production of IFN-γ, which can also be measured in the serum. Note that chemokines may be produced by many cell populations; only endothelial cells are shown as the source in this illustration.
23 Interleukin-2, IL-2 Hovedsakelig produsert av T celler (CD4) Vekstfaktor for aktiverte T celler (Treg)Stim cellesyklus apparat,Oppregulering av IL-2R (CD25)Stimulerer cytokinproduksjon T cellerProliferasjon og differensiering andreRegulatoriske T celler og apoptoseIt acts on the same cells that produce it or on adjacent cells (i.e., it functions as an autocrine or paracrine growth and survival factor)CD4+ T cells secrete IL-2 into the immunological synapse formed between the T cell and APCL-2 receptors on T cells also tend to localize to the synapse, so that the cytokine and its receptor reach sufficiently high local concentrations to initiate cellular responses.
24 IL-2R reguleringResting (naive) T lymphocytes express the IL-2Rβγ complex, which has a moderate affinity for IL-2. Activation of the T cells by antigen, costimulators, and IL-2 itself leads to expression of the IL-2Rα chain and high levels of the high-affinity IL-2Rαβγ complex. APC, antigen-presenting cell.
25 IL-2IL-2 is required for the survival and perhaps function of regulatory T cells, which suppress immune responses against self and other antigensIL-2 stimulates the survival, proliferation, and differentiation of antigen-activated T cells.IL-2 promotes the proliferation and differentiation of NK cellsIL-2 acts on B cells both as a growth factor and as a stimulus for antibody synthesis.
26 Interleukin-4, IL-4IL-4 is the principal cytokine that stimulates B cell Ig heavy chain class switching to the IgE isotype.L-4 stimulates the development of TH2 cells from naive CD4+ T cells and functions as an autocrine growth factor for differentiated TH2 cells.+ regulering av metabolisme? through activation of signal transducer and activator of transcription 6 (STAT6), enhances the anabolic actions of insulin to promote storage of glucose. This is mediated by inhibition of catabolic metabolism in the liverand attenuation of inflammation in white adipose tissue.
27 Interleukin-5, IL-5 TH2 celler og mast celler Aktivator av eosinofile Helmint-infeksjoner
28 Interferon-, IFN NK, CD4 Th1 og CD8 T celler Viktigste makrofagaktiverende cytokinStimulerer MHC og stimulatorer APCEndotelcellerFremmer TH1 differensieringB celle klassebytte til IgG1 og IgG3IFN-γ activates macrophages to kill phagocytosed microbes.FN-γ promotes the differentiation of naive CD4+ T cells to the TH1 subset and inhibits the differentiation of TH2 cells.IFN-γ acts on B cells to promote switching to certain IgG subclasses, notably IgG2a in mice, and to inhibit switching to IL-4-dependent isotypes, such as IgE and IgG1 in mice.IFN-γ stimulates expression of class I and class II MHC molecules and costimulators on APCs.
29 IFN IFN-γ activates macrophages to kill phagocytosed microbes. FN-γ promotes the differentiation of naive CD4+ T cells to the TH1 subset and inhibits the differentiation of TH2 cells.IFN-γ acts on B cells to promote switching to certain IgG subclasses, notably IgG2a in mice, and to inhibit switching to IL-4-dependent isotypes, such as IgE and IgG1 in mice.IFN-γ stimulates expression of class I and class II MHC molecules and costimulators on APCs.
30 Transforming growth factor , TGF Antigen-stim T celler, makrofager, TregViktig anti-inflammatorisk, inhiberer:T celle proliferasjon og differensieringMakrofag aktiveringNøytrofile og endotel cellerKlassebytte til IgAThe principal action of TGF-β in the immune system is to inhibit the proliferation and activation of lymphocytes and other leukocytes. However, TGF-β can exert either anti-inflammatory or proinflammatory effects depending on the timing of its appearance, the amount produced, and systemic versus local expression.TGF-β inhibits the proliferation and effector functions of T cells and the activation of macrophages.TGF-β regulates differentiation of functionally distinct subsets of T cells.TGF-β regulates tissue repair after local immune and inflammatory reactions subside.
31 Interleukin-17, IL-17 Hovedsakelig T celle subset (Th17) Målceller Endotelceller øker kjemokinprodMakrofager øker d.o.Epitelceller: GM-CSF/G-CSFFunksjonInflammasjonBakterie infeksjonerSopp infeksjon (vaksine)Familie 6 beslektede IL17(A). IL17F, IL25 (17E), IL21. IL22, IL26IL-17A and F stimulate endothelial cells and macrophages to produce IL-1, TNF, and various chemokines, which promote neutrophil recruitmentIL-17 also induces cells to produce hematopoietic cytokines, described later in this chapter, which stimulate neutrophil production by the bone marrowIL-17 produced by T cells is thought to be responsible for the destructive inflammation characteristic of several mouse models of autoimmune disease. A role of IL-17 in human inflammatory bowel disease is also suspected.IL-17F = IL-25 også anti-inflammatorisk
32 IL-9 IL-22 IL-9 produserende T celler, Th9 Nematode infeksjon, atopiIL-22 produserende T celler, Th22Patogene hudresponser