Presentasjon lastes. Vennligst vent

Presentasjon lastes. Vennligst vent

Cytokiner og reguleringsmekanismer Del I

Liknende presentasjoner

Presentasjon om: "Cytokiner og reguleringsmekanismer Del I"— Utskrift av presentasjonen:

1 Cytokiner og reguleringsmekanismer Del I
Immunresponsen Cytokiner og reguleringsmekanismer Del I

2 Cytokiner Polypeptider sekrert av celler
Dannet som respons på mikrober og antigen Medierer og regulerer immunresponser og inflammatoriske reaksjoner Nomenklatur: opprinnelig etter celletyper (monkiner, lymfokiner etc) Generisk cytokiner. Interleukiner for deres effekt på leukocytter. IL-n

3 Cytokiners egenskaper
Sekresjon kortvarig og selvbegrensende Pleiotropisk og rikelig Influerer syntese og virkning av andre Lokal og systemiske effekter Modulerer målceller Nye gener og nye funksjoner Proliferasjon


5 Cytokiner: inndeling Cytokiner i innate immunrespons
TNF, IL-1, kjemokiner, IL-12, INF, IL-10, m.fl. Cytokiner i adaptiv immunrespons IL-2/4/5, INF, TGF, m.fl. Cytokiner i hematopoiese SCF, IL-7/3, m-fl

6 Cytokinreseptorer



9 Innate cytokiner TNF IL-1 Kjemokiner IL-6 IL-10 IL-12 IL-15

10 Tumor nekrose faktor, TNF(alfa)
Viktigste inflammatoriske G- o.a. Obs sepsis Hovedsaklig fra aktiverte makrofager Målceller Endotelceller, nøytrofile, hypotalamus. Lever, muskel, fett TNF reseptor familie Proinflammatoriske (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 products two 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 makrofager Andre Målceller Endotelceller, Hypothalamus, Lever Reseptorer Ig-superfamilie, IL-1R type I og type II IL-1Ra produced by many cell types other than macrophages, such as neutrophils, epithelial cells (e.g., keratinocytes), and endothelial cells two forms of IL-1, called IL-1α and IL-1β bind to the same cell surface receptors and have the same biologic activities type I IL-1 receptor, which engages signal transduction pathways that activate NF-κB and AP-1 transcription factors Acts 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

13 IL-1/IL-6/TNF

14 Interleukin-6, IL-6 Inflammatorisk Produsenter Målceller/vev
Makrofager, endotelceller, T celler, dendrittiske Målceller/vev Akuttfaseproteiner fra lever B celle proliferasjon, plasmacelle vekst T 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 family JAK1 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 cytokiner Stimulerer og regulerer leukocytt bevegelser Polypeptider, 8-12 kD, to interne disulfid bind CXC familien Nøytrofile CC familien Monocytter, lymfocytter og eosinofile C og CX3C gruppen Produseres av leukocytter, endo/epitel, oa Reseptor familier: CXCR, CCR

16 Kjemokiner: biologisk effekt
Tiltrekker leukocytter mot inflammasjons-lokus Regulerer lymfocytters migrering i lymfevev Andre Signalering i organogenese Virale coreseptorer HIV: CCR5 og CXCR4

17 Interleukin-12, IL-12 Aktiverte makrofager og dendrittiske celler
Etter TLR stim Av ag. Aktiverte T celler Effekt Stimulerer NK og T celler til INFg produksjon Differensiering av CD4 celler Øker NK og CD8 T cellers cytotoksisitet Prinsipal initiator tidlig innat immunrespons intracellulære mikrober, nøkkel cytokin for å indusere cellemediert immunitet IL-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 infections In 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.

18 11-7

19 Type I interferoner: IFN-a/IFN-b

20 Interleukin-10, IL-10 Aktiverte makrofager, T celler (Th2)
Monoc, B celler, nonhematopoietiske Viktig anti-inflammatorisk, inhiberer: IL-12 fra makrofager og dendrittiske IFN indirekte MHC klasse II og costimulatoriske molekyl Makrofager 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.

22 ”Adaptive cytokiner” IL-2 IL-4 IL-5 INF TGF LT IL-17, IL-9 IL-13

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 celler Proliferasjon og differensiering andre Regulatoriske T celler og apoptose It 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 APC L-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 regulering Resting (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-2 IL-2 is required for the survival and perhaps function of regulatory T cells, which suppress immune responses against self and other antigens IL-2 stimulates the survival, proliferation, and differentiation of antigen-activated T cells. IL-2 promotes the proliferation and differentiation of NK cells IL-2 acts on B cells both as a growth factor and as a stimulus for antibody synthesis.

26 Interleukin-4, IL-4 IL-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

28 Interferon-, IFN NK, CD4 Th1 og CD8 T celler
Viktigste makrofagaktiverende cytokin Stimulerer MHC og stimulatorer APC Endotelceller Fremmer TH1 differensiering B celle klassebytte til IgG1 og IgG3 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.

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, Treg Viktig anti-inflammatorisk, inhiberer: T celle proliferasjon og differensiering Makrofag aktivering Nøytrofile og endotel celler Klassebytte til IgA The 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 kjemokinprod Makrofager øker d.o. Epitelceller: GM-CSF/G-CSF Funksjon Inflammasjon Bakterie infeksjoner Sopp infeksjon (vaksine) Familie 6 beslektede IL17(A). IL17F, IL25 (17E), IL21. IL22, IL26 IL-17A and F stimulate endothelial cells and macrophages to produce IL-1, TNF, and various chemokines, which promote neutrophil recruitment IL-17 also induces cells to produce hematopoietic cytokines, described later in this chapter, which stimulate neutrophil production by the bone marrow IL-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, atopi IL-22 produserende T celler, Th22 Patogene hudresponser

33 T celle differensiering

34 Gjensidig regulering

35 Synergier

36 Mikrobe influerer cytokiner

37 IL-10 TGF


Laste ned ppt "Cytokiner og reguleringsmekanismer Del I"

Liknende presentasjoner

Annonser fra Google