Cytokiner og reguleringsmekanismer Del I Immunresponsen Cytokiner og reguleringsmekanismer Del I

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

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

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

Cytokinreseptorer

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

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).

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

IL-1/IL-6/TNF

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.

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

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

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.

11-7

Type I interferoner: IFN-a/IFN-b 11-8

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

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.

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

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.

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.

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.

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.

Interleukin-5, IL-5 TH2 celler og mast celler Aktivator av eosinofile Helmint-infeksjoner

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.

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.

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.

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

IL-9 IL-22 IL-9 produserende T celler, Th9 Nematode infeksjon, atopi IL-22 produserende T celler, Th22 Patogene hudresponser

T celle differensiering

Gjensidig regulering

Synergier

Mikrobe influerer cytokiner

IL-10 TGF