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%O =:Lecture 6 Cytokines6What are cytokines?(hA collection of polypeptides used for communications between cells Play role similar to hormones (messengers of the endocrine system) Hormones usually act at a distance Cytokines act locally Differ from growth factors that are produced constitutively, while cytokine production is carefully regulated Play an important role in both innate and adaptive immunity9&R-)FCytokine nomenclature=Interleukins (1-18) Interferons (a,b,g) Others (common names).>!$$$Cytokine -mediated effectsCell growth Cell differentiation Cell death Induce non-responsiveness to other cytokines/cells Induce responsiveness to other cytokines/cells Induce secretion of other cytokinesP(How do cytokines tell cells what to do?))Produced by cells as part of normal cellular activity and/or the result of environmental trigger Bind to receptors on cells Trigger signal transduction pathways Initiate synthesis of new proteins P$ Properties of cytokinesProteins Low molecular weight Bind to receptor on either cell which produced it or another cell Receptor binding triggers a signal Signal results in altered pattern of gene expressionP,Cytokines can act in three different manners--Autocrine Cytokine binds to receptor on cell that secreted it Paracrine Cytokine binds to receptors on near by cells Endocrine Cytokine binds cells in distant parts of the body 4 - 2 4 - 2  Cytokine ActionsPleiotropy Act on more than one cell type (INFa/b) Redundancy More than one cytokine can do the same thing (IFNa/b and IFNg) Synergy Two or more cytokines cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately (IL-12 and IL-8) Antagonism Two or more cytokines work against each other (IL-4 and IL-12) P(P P?PPP P?P # 1  ? 0How can non-specific cytokines act specifically?115Only cells expressing receptors for specific cytokines can be activated by them Many cytokines have very short half-lives Only cells in close proximity will be activated High concentrations of cytokines are needed for activation Only cells in close proximity will be activated May require cell-to cell contact\z0;Qz0;Q Five cytokine receptor families Immunoglobulin superfamily receptors Class I cytokine receptor family (hematopoietin receptors) Binds most of the cytokines in the immune and hematopoietin systems Class II cytokine receptor family TNF receptor family Chemokine receptor familyB`PDPPP`DP&Cytokines regulate the immune response''Cells with the appropriate receptors become activated To differentiate To express receptors which will make them receptive to other cytokines To secrete other cytokines26PsP6(s$)Signal Transduction by cytokine receptors**Cytokine receptors on different cell types trigger different events How do you get the message from the outside of the cell to the machinery inside?/Involvement of cytokines in the immune response00(Alert to infection.tumor/etc. Recruit cells to site Specify type of immune response Immune effector phase Immune down-regulation Immune memory and resetting the systemP Early mediators (IFNa/b) Chemokines (MIP-1a) Early & late mediators (IL-2, IFNg, IL-4, IL-5) Down-regulators (IL-10, TNFg) Maintenance of cytokines, etc. (GM-CSF, IL-3, IL-7, etc.)xP#)<u<Early mediators(Interferons a/b Induced by dsRNA, etc. Induced by CD40/CD40L pathway IFNs can induce more of themselves Directly interferes with viral replication Activation of T and NK cellsF $$$  Chemokines (xRecruit to sites of infection MIP-1a (NK and T cells) MIG, RANTES (CD4+T cells) IL-8 (neutrophils) Eotaxin (eosinophils)>y#" 2cEarly mediators(IL-12, IL-15, 1l-18, IFN-g (from NK cells), IL-10 Proinflammatory mediators Produced by cell associated with innate immunity (macrophages, NK, etc.) Mediate direct effects Promote inflammation Shape downstream responses0PLate mediators(IL-2, IL-4, IL-5, IFN-g, TNF, IL-6, IL-10 Produced by cells of the adaptive immune response (T and B cells) Direct effects More immunoregulatory functions. CCytokine secretion and biological activities of TH1 and TH2 Subsets@D1   Down regulatorsiIL-10, IL-11, TGF-b Inhibit proliferation, cytokine production Produced by both innate and adaptive cells(jWMaintenance cytokinesGGM-CSF, IL-3, IL-7, IL-9, etc. Induce cell differentiation, cell growthHH Cytokine cross-regulationIn a a given immune response, either TH1 or TH2 response dominates Cytokines of one response tend to down-regulate the other type of response Example: TH1 cells secrete IFN-g, which inhibits proliferation of TH2 subsetP&  k #  8Role of TH1/TH2 balance in determining disease outcomes @9   +Balance of two subset determines response to disease Leprosy Tuberculoid (TH1, CMI response, patient lives) Lepromatous (TH2, humoral response, patient dies)j=a=$   .   # ,= $ '  Cytokine-related diseasesBacterial septic shock Blood pressure drops, clots form, hypoglycemia ensues, patient dies LPS triggers results in TNF release TNF induces IL-1 which induces IL-6 and IL-8 Bacterial toxic shock and related diseases Superantigens trigger large numbers of T cells which release massive amounts of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell receptors and the MHC class II molecules on APC s, bypassing the need for antigen) Lymphoid and myeloid cancers Some cancer cells secrete cytokines Chagas disease Trypanosoma cruzi infection results in sever immune suppression Depression of IL-2 receptor productionPP+PPP$PPgP+Z$  gPc V Components of the immune system ( !'Infectious agents that target cytokines(($qEpstein-Barr virus foster the generation of T helper cells that do not produce IL-2. EBV produces an analog of IL-10 that favors TH2 cells, rather than TH1. Parasites such as tape worms induce high levels of IgE, an immunoglobulin induced by TH2 cells. Since TH1 cells mediate inflammation, this may be a protective ploy to avoid destructive inflammatory processes.~r  Y  i"=Immunosuppressive effects of oral bacteria on immune function>>$VImpairment of B and T cell function (P. intermedia, P. asaccharolytica, P. endodontalis, P. melaninogenica) Production of specific toxins that kill monocytes (A. actinomycetemcomitans) Provoke the release of peroxide, prostaglandins and other mediators capable of inhibiting lymphocyte function (T. denticola) Modulate expression of cytokinesfWP%E5q #>7 #3Cytokine-inducing components of Periodontopathogens44$Taken from Wilson, M., Reddi, K., Henderson, B. 1996. Cytokine-inducing components of periodontopathogenic bacteria. J. Periodont. Res. 31:393-407. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF) are believed to be the major pathological mediators of inflammatory diseases ranging from arthritis to periodontal diseases. It is believed that components of microorganisms have the capacity to induce cytokine synthesis in host cells.NxX,_ b%!6Cytokine-inducing components of Gram-positive bacteria77$ &"6Cytokine-inducing components of Gram-negative bacteria77$($KCytokine-induction by LPS from periodontopathogens other than P. gingivalis*L>    )%\Cytokines produced by host cells in response to components/products from periodontopathogens]] .*Interferon ActionViral replication stimulates the infected host cell to produce interferon. Interferon induces uninfected cells to produce antiviral proteins that prevent translation of viral mRNA degrade viral nucleic acid Viral replication is blocked in uninfected cellsBt]1t]1  Therapeutic uses of cytokinesModulation of TH activation Interfere with receptor function Interfere with cytokine Make it unable to bind to receptor Make it unable to act@U9 E9,(Examples of therapeutic usesSoluble T-cell receptor Anti-IL-2R Interleukin analogs which bind receptor, but do not trigger activation (ties up receptor) Toxins conjugated to cytokines which kill activated T-cells Administration of cytokines to enhance immunity (side effects/ short half lives) AllergiesP//03  ` fy`ff3` Mj*333FV*` ffNNt^X` ffNL|>rL` +T3f3f` MMMff3f` Lx[he2` {$$>?" dd@,?nAd@    @ `  n?" dd@   @@``PR    @ ` ` p>> @(    6 " `P  T Click to edit Master title style! !$  0 " `  RClick to edit Master text styles Second level Third level Fourth level Fifth level!     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S d 6 `P   P*   d 6d `   R*  H d 0޽h ? 3380___PPT10.UPL  0((  x  c $ `@   p  S 0A j0281081N H  0޽h ? 33  *( 8hD  x  c $ { P  { r  S 5pD  5 H  0޽h ? >gԟ  P0(  Px P c $5 `P  5 x P c $5l  5 H P 0޽h ? >gԟ  T$(  Tr T S y5  5 r T S ,x50 5 H T 0޽h ? >gԟ  X*(  Xx X c $̒5 `  5 r X S 50  5 H X 0޽h ? >gԟ  @0( UU @x @ c $5 `P  5 x @ c $|c5 ` 5 H @ 0޽h ? >gԟ  *(  x  c $ȥ5 `P  5 r  S $5@@pD  5 H  0޽h ? >gԟ  *( 8 v  x  c $5 `P  5 r  S 50 5 H  0޽h ? >gԟ  H$(  Hr H S  5  5 r H S 5` 5 H H 0޽h ? >gԟ  L*(  Lx L c $m5 `P  5 r L S 05| 5 H L 0޽h ? >gԟ    *(   x  c $`5 `P  5 r  S ``5|kp 5 H  0޽h ? >gԟ  0$0(  $x $ c $D  `P   x $ c $  `4    H $ 0޽h ? >gԟ* @lj(  lP l C (ASlide 9 0 l S     tBCytokines, growth factors and hormone signal transduction pathwaysCC H l 0޽h ? >gԟ* Ptj(  tR t C *ASlide 200p t S 5  5 rThe Jak/Stat Signaling Pathway(H t 0޽h ? ̙33d   (  x  c $  `P   r  S  `    r  S Ъ p    H  0޽h ? >gԟ  0(  x  c $  `P   x  c $\  `   H  0޽h ? >gԟ  0( 8Ƨ  x  c $  `P   x  c $8 Fvg    H  0޽h ? >gԟ  p0(  x  c $H9 `P   x  c $9 `  H  0޽h ? >gԟ  *(  x  c $ `P   r  S 8|pE  H  0޽h ? >gԟ  qi` (( `P (x ( c $P   X2 ( 0  X" ( 00  X ( 00 @  ( <U  >Type 1  ( <K >Type 2  ( <L]S FE  ZIL-2 IFN-g TNF0   ( <aS 8  ; IL-4 IL-5   ( <_pPB  k7Cell-mediated Immune response (intracellular Organisms)88  ( <ep \  QHumoral response (parasites) ( <g9 3  8T cellH ( 0޽h ? >gԟ  *( y k| x  c $p `P   r  S p p   H  0޽h ? >gԟ  0(  x  c $u `P   x  c $DF06   H  0޽h ? >gԟ   ,$(  ,r , S dC   r , S 8D|  H , 0޽h ? >gԟ  0$(  0r 0 S K   r 0 S |  H 0 0޽h ? >gԟ  4$( -? 4r 4 S     r 4 S P  H 4 0޽h ? >gԟ K0 y&'(    S ~ Complement  ~ " HG/*1?" % ~ # HG/*1?" d ~ $ HG/*1?" | ~ % HG/*1?"  , &  `Xwawa1?"C &Adapted from Marrack and Kappler, 1994'' , H  0޽h ? 3eX{IZ(a K0 TL(    S ~TQwawa1 ? P     S ~(Rwawa1 ?  H  0޽h ? 3eX{IZ(a K0 TL(    S ~<wawa1 ?tU     S ~wawa1 ?u `  H  0޽h ? 3eX{IZ(a   <(  ~  s *ؾK5   ~  s *p   H  0޽h ? 3eX{IZ(a  |t0 (  ~  s *Ω `P   N  c &UAPAp H  0޽h ? 3eX{IZ(a  z@( x<  ~  s *\ `P   T  s ,mdHAj@ H  0޽h ? 3eX{IZ(a  P( $4,x< $ ~  s *fP   Z  2 ~ hAAH  0޽h ? 3eX{IZ(a  0( d ~  s *dmUP   Z  2 +1A@pH  0޽h ? 3eX{IZ(a   *(  x  c $8s `P   r  S spp   H  0޽h ? >gԟ  p8$(  d;4` 8r 8 S ѩp@   r 8 S 0ҩ   H 8 0޽h ? >gԟ  p$(  g   r  S  ֩   r  S d  H  0޽h ? >gԟn 0 .&`p(   pR p 3 d   , p C ]d T  <4___PPT9  Cytokines, Growth Factors and Hormones Cytokines, growth factors (GF), and hormones are all chemical messengers that mediate intercellular communication. The regulation of cellular and nuclear functions by cytokines, growth factors, and peptide or protein hormones is initiated through the activation of cell surface receptors (Rc). All receptors have two main components: 1) a ligand-binding domain that ensures ligand specificity and 2) an effector domain that initiates the generation of the biological response upon ligand binding. The activated receptor may then interact with other cellular components to complete the signal transduction process. Many growth factors bind to receptors that are linked through G-proteins to membrane-bound phospholipase C (PLC). Activation of PLC cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to form diacylglycerols (DAG) and D-myo-inositol- 1, 4, 5-triphosphate (IP3). IP3 regulates intracellular Ca2+ by binding to the IP3 receptor on the endoplasmic reticulum (ER) and stimulating Ca2+ release from the ER. Free intracellular Ca2+ can bind to calmodulin, and this Ca2+ -calmodulin complex, in the presence of cyclic-AMP (cAMP), activates protein kinase A (PKA) by binding to the regulatory subunit of the enzyme. DAG binds to and activates protein kinase C (PKC). Other hormone receptors may be linked through G-proteins to adenylate cyclase (AC) instead of PLC. Activation of AC increases the cellular levels of cAMP and, in the presence of the Ca2+-calmodulin complex, will activate PKA. Additionally, some growth factor and cytokine receptors are protein tyrosine kinases (PTK) that are directly activated by ligand-receptor interaction. Activation of any of the protein kinases, PKA, PKC, or PTK, catalyzes the phosphorylation of other proteins within the cell. Enzymes that are activated or inhibited by phosphorylation may mediate functional processes within the cell, while others may be one step in a protein kinase cascade that regulates nuclear events. Steroid hormones (i.e. estrogen, glucocorticoids), thyroid hormone, vitamin D3, and retinoids are all small lipophilic molecules that easily penetrate both the cellular and nuclear membranes to enter the nucleus where they bind to their respective receptors that are ligand-dependent transcription factors. These ligand-receptor complexes bind to specific DNA response elements in the promoter region and regulate gene expression. References Luttrell, L.M., et al., G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors. Adv. Second Messenger Phosphoprotein Res. 31, 263-277 (1997). Marshall, C.J., Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 80,179-185 (1995). Kumar, R., Thompson, E.B., The structure of the nuclear hormone receptors. Steroids 64, 310-319 (1999) (0 " h 0 "  0 " 0 " &  L    > + $ } P a eI/M$     t i%7<#  '*sH p 0޽h ? 33  0   |- ( 0| |R | 3 d     | C d P0T  <4___PPT9 -The Jak/Stat Signaling Pathway A wide variety of extracellular signals activate the Stat (signal transducers and activators of transcription) class of transcription factors. Cytokines, lymphokines, and growth factors all signal through a related superfamily of cell surface receptors that are associated with and activate Janus kinases (Jaks). Ligand-induced dimerization of the receptor induces the reciprocal tyrosine phosphorylation of the associated Jaks, which, in turn, phosphorylates tyrosine residues on the cytoplasmic tail of the receptor. These phosphorylated tyrosines serve as docking sites for the Src Homology-2 (SH-2) domain of the Stat protein, and Jak catalyzes the tyrosine phosphorylation of the receptor-bound Stat. Phosphorylation of Stat at a conserved tyrosine residue induces SH-2-mediated homo- or heterodimerization, followed by translocation of the Stat dimer to the nucleus. Stat dimers bind to specific DNA response elements in the promoter region of target genes to activate gene expression. APS (adaptor molecule containing pleckstrin homology and SH-2 domains) can inhibit the Jak-Stat pathway by binding to the cytoplasmic domain of the receptor where it is phosphorylated (activated) by Jak. Activated APS binds to c-Cbl and blocks Stat activation. References Wakioka, T., et al., APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. Leukemia 13, 760-767 (1999). Schindler, C., Cytokines and JAK-STAT signaling. Exp. Cell Res. 253, 7-14 (1999). ` " 22 "    P   )z } R9 2( + #(0 PYH | 0޽h ? 33 0 tl(  R  3 d   r  # d @    H  0޽h ? 33 0 tl (   R   3 d   r   # d @    H   0޽h ? 33  0 (  X  C d   5  S 45d @  5  H  0޽h ? 3380___PPT10.S>r[]gi_oQq~Gekmm_acUIs{uwz| ~j[% ( u,3.`Uz60FO? 3 Oh+'0 hp    (0'Cytokines and Chemokines iDennis Lopatinh TexturedpatDennis Lopatinh71nMicrosoft PowerPointnes@e@tE@UGPICT @@ HH Z @  .**.HDDH*&&*D@@D*&((''&((&&((''&((&((&((&((&''((&''&((&((&((&((&*D@BBAA@BB@@BBAA@BB@BB@BB@BB@AABB@AA@BB@BB@BB@BB@D*&(())&((&&(())&((&((&((&((&))((&))&((&((&((&((&*D@BBCC@BB@@BBCC@BB@BB@BB@BB@CCBB@CC@BB@BB@BB@BB@D0,+--..--**,*--../-*,++,**--,.*())+-+))++(,*(++))++,-+--..,,)++--**)++,,++**((,,++..- **))++-+**++)++, ))++,,-+*,++,-1GC??@==?=??@@A?BDCC?==@@C>@B@AA>@=CAACCD?B@CCAACC?@C??@@DDACC@@==ACCDDCCFFDCC@@??@@==AACC@>==CCACC? 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%O =:Lecture 6 Cytokines6What are cytokines?(hA collection of polypeptides used for communications between cells Play role similar to hormones (messengers of the endocrine system) Hormones usually act at a distance Cytokines act locally Differ from growth factors that are produced constitutively, while cytokine production is carefully regulated Play an important role in both innate and adaptive immunity9&R-)FCytokine nomenclature=Interleukins (1-18) Interferons (a,b,g) Others (common names).>!$$$Cytokine -mediated effectsCell growth Cell differentiation Cell death Induce non-responsiveness to other cytokines/cells Induce responsiveness to other cytokines/cells Induce secretion of other cytokinesP(How do cytokines tell cells what to do?))Produced by cells as part of normal cellular activity and/or the result of environmental trigger Bind to receptors on cells Trigger signal transduction pathways Initiate synthesis of new proteins P$ Properties of cytokinesProteins Low molecular weight Bind to receptor on either cell which produced it or another cell Receptor binding triggers a signal Signal results in altered pattern of gene expressionP,Cytokines can act in three different manners--Autocrine Cytokine binds to receptor on cell that secreted it Paracrine Cytokine binds to receptors on near by cells Endocrine Cytokine binds cells in distant parts of the body 4 - 2 4 - 2  Cytokine ActionsPleiotropy Act on more than one cell type (INFa/b) Redundancy More than one cytokine can do the same thing (IFNa/b and IFNg) Synergy Two or more cytokines cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately (IL-12 and IL-8) Antagonism Two or more cytokines work against each other (IL-4 and IL-12) P(P P?PPP P?P # 1  ? 0How can non-specific cytokines act specifically?115Only cells expressing receptors for specific cytokines can be activated by them Many cytokines have very short half-lives Only cells in close proximity will be activated High concentrations of cytokines are needed for activation Only cells in close proximity will be activated May require cell-to cell contact\z0;Qz0;Q Five cytokine receptor families Immunoglobulin superfamily receptors Class I cytokine receptor family (hematopoietin receptors) Binds most of the cytokines in the immune and hematopoietin systems Class II cytokine receptor family TNF receptor family Chemokine receptor familyB`PDPPP`DP&Cytokines regulate the immune response''Cells with the appropriate receptors become activated To differentiate To express receptors which will make them receptive to other cytokines To secrete other cytokines26PsP6(s$)Signal Transduction by cytokine receptors**Cytokine receptors on different cell types trigger different events How do you get the message from the outside of the cell to the machinery inside?/Involvement of cytokines in the immune response00(Alert to infection.tumor/etc. Recruit cells to site Specify type of immune response Immune effector phase Immune down-regulation Immune memory and resetting the systemP Early mediators (IFNa/b) Chemokines (MIP-1a) Early & late mediators (IL-2, IFNg, IL-4, IL-5) Down-regulators (IL-10, TNFg) Maintenance of cytokines, etc. (GM-CSF, IL-3, IL-7, etc.)xP#)<u<Early mediators(Interferons a/b Induced by dsRNA, etc. Induced by CD40/CD40L pathway IFNs can induce more of themselves Directly interferes with viral replication Activation of T and NK cellsF $$$  Chemokines (xRecruit to sites of infection MIP-1a (NK and T cells) MIG, RANTES (CD4+T cells) IL-8 (neutrophils) Eotaxin (eosinophils)>y#" 2cEarly mediators(IL-12, IL-15, 1l-18, IFN-g (from NK cells), IL-10 Proinflammatory mediators Produced by cell associated with innate immunity (macrophages, NK, etc.) Mediate direct effects Promote inflammation Shape downstream responses0PLate mediators(IL-2, IL-4, IL-5, IFN-g, TNF, IL-6, IL-10 Produced by cells of the adaptive immune response (T and B cells) Direct effects More immunoregulatory functions. CCytokine secretion and biological activities of TH1 and TH2 Subsets@D1   Down regulatorsiIL-10, IL-11, TGF-b Inhibit proliferation, cytokine production Produced by both innate and adaptive cells(jWMaintenance cytokinesGGM-CSF, IL-3, IL-7, IL-9, etc. Induce cell differentiation, cell growthHH Cytokine cross-regulationIn a a given immune response, either TH1 or TH2 response dominates Cytokines of one response tend to down-regulate the other type of response Example: TH1 cells secrete IFN-g, which inhibits proliferation of TH2 subsetP&  k #  8Role of TH1/TH2 balance in determining disease outcomes J9 $ $$ $+$Balance of two subset determines response to disease Leprosy Tuberculoid (TH1, CMI response, patient lives) Lepromatous (TH2, humoral response, patient dies)j=a=$   .   # ,= $ '  Cytokine-related diseasesBacterial septic shock Blood pressure drops, clots form, hypoglycemia ensues, patient dies LPS triggers results in TNF release TNF induces IL-1 which induces IL-6 and IL-8 Bacterial toxic shock and related diseases Superantigens trigger large numbers of T cells which release massive amounts of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell receptors and the MHC class II molecules on APC s, bypassing the need for antigen) Lymphoid and myeloid cancers Some cancer cells secrete cytokines Chagas disease Trypanosoma cruzi infection results in sever immune suppression Depression of IL-2 receptor productionPP+PPP$PPgP+Z$  gPc V Components of the immune system ( !'Infectious agents that target cytokines(($qEpstein-Barr virus foster the generation of T helper cells that do not produce IL-2. EBV produces an analog of IL-10 that favors TH2 cells, rather than TH1. Parasites such as tape worms induce high levels of IgE, an immunoglobulin induced by TH2 cells. Since TH1 cells mediate inflammation, this may be a protective ploy to avoid destructive inflammatory processes.~r  Y  i"=Immunosuppressive effects of oral bacteria on immune function>>$VImpairment of B and T cell function (P. intermedia, P. asaccharolytica, P. endodontalis, P. melaninogenica) Production of specific toxins that kill monocytes (A. actinomycetemcomitans) Provoke the release of peroxide, prostaglandins and other mediators capable of inhibiting lymphocyte function (T. denticola) Modulate expression of cytokinesfWP%E5q #>7 #3Cytokine-inducing components of Periodontopathogens44$Taken from Wilson, M., Reddi, K., Henderson, B. 1996. Cytokine-inducing components of periodontopathogenic bacteria. J. Periodont. Res. 31:393-407. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF) are believed to be the major pathological mediators of inflammatory diseases ranging from arthritis to periodontal diseases. It is believed that components of microorganisms have the capacity to induce cytokine synthesis in host cells.NxX,_ b%!6Cytokine-inducing components of Gram-positive bacteria77$ &"6Cytokine-inducing components of Gram-negative bacteria77$($KCytokine-induction by LPS from periodontopathogens other than P. gingivalis*L>    )%@ pp0___PPT10 h___PPT2001D<4X0? %O =:Lecture 17 Cytokines6 What are cytokines?(hA collection \Cytokines produced by host cells in response to components/products from periodontopathogens]] .*Interferon ActionViral replication stimulates the infected host cell to produce interferon. Interferon induces uninfected cells to produce antiviral proteins that prevent translation of viral mRNA degrade viral nucleic acid Viral replication is blocked in uninfected cellsBt]1t]1  Therapeutic uses of cytokinesModulation of TH activation Interfere with receptor function Interfere with cytokine Make it unable to bind to receptor Make it unable to act@U9 E9,(Examples of therapeutic usesSoluble T-cell receptor Anti-IL-2R Interleukin analogs which bind receptor, but do not trigger activation (ties up receptor) Toxins conjugated to cytokines which kill activated T-cells Administration of cytokines to enhance immunity (side effects/ short half lives) AllergiesP//03 \ 0$(  0r 0 S 6;P    r 0 S 7;|  H 0 0޽h ? >gԟr ,2 -3F( 4/ 0`DTimesNew Romant V R0K RDTahomaew Romant V R0K R" DArialew Romant V R0K R"0DWingdingsRomant V R0K R@DHelveticaRomant V R0K R "                      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communications between cells Play role similar to hormones (messengers of the endocrine system) Hormones usually act at a distance Cytokines act locally Differ from growth factors that are produced constitutively, while cytokine production is carefully regulated Play an important role in both innate and adaptive immunity9&R-)FCytokine nomenclature=Interleukins (1-18) Interferons (a,b,g) Others (common names).>!$$$Cytokine -mediated effectsCell growth Cell differentiation Cell death Induce non-responsiveness to other cytokines/cells Induce responsiveness to other cytokines/cells Induce secretion of other cytokinesP(How do cytokines tell cells what to do?))Produced by cells as part of normal cellular activity and/or the result of environmental trigger Bind to receptors on cells Trigger signal transduction pathways Initiate synthesis of new proteins P$ Properties of cytokinesProteins Low molecular weight Bind to receptor on either cell which produced it or another cell Receptor binding triggers a signal Signal results in altered pattern of gene expressionP,Cytokines can act in three different manners--Autocrine Cytokine binds to receptor on cell that secreted it Paracrine Cytokine binds to receptors on near by cells Endocrine Cytokine binds cells in distant parts of the body 4 - 2 4 - 2  Cytokine ActionsPleiotropy Act on more than one cell type (INFa/b) Redundancy More than one cytokine can do the same thing (IFNa/b and IFNg) Synergy Two or more cytokines cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately (IL-12 and IL-8) Antagonism Two or more cytokines work against each other (IL-4 and IL-12) P(P P?PPP P?P # 1  ? 0How can non-specific cytokines act specifically?115Only cells expressing receptors for specific cytokines can be activated by them Many cytokines have very short half-lives Only cells in close proximity will be activated High concentrations of cytokines are needed for activation Only cells in close proximity will be activated May require cell-to cell contact\z0;Qz0;Q Five cytokine receptor families Immunoglobulin superfamily receptors Class I cytokine receptor family (hematopoietin receptors) Binds most of the cytokines in the immune and hematopoietin systems Class II cytokine receptor family TNF receptor family Chemokine receptor familyB`PDPPP`DP&Cytokines regulate the immune response''Cells with the appropriate receptors become activated To differentiate To express receptors which will make them receptive to other cytokines To secrete other cytokines26PsP6(s$)Signal Transduction by cytokine receptors**Cytokine receptors on different cell types trigger different events How do you get the message from the outside of the cell to the machinery inside?/Involvement of cytokines in the immune response00(Alert to infection.tumor/etc. Recruit cells to site Specify type of immune response Immune effector phase Immune down-regulation Immune memory and resetting the systemP Early mediators (IFNa/b) Chemokines (MIP-1a) Early & late mediators (IL-2, IFNg, IL-4, IL-5) Down-regulators (IL-10, TNFg) Maintenance of cytokines, etc. (GM-CSF, IL-3, IL-7, etc.)xP#)<u<Early mediators(Interferons a/b Induced by dsRNA, etc. Induced by CD40/CD40L pathway IFNs can induce more of themselves Directly interferes with viral replication Activation of T and NK cellsF $$$  Chemokines (xRecruit to sites of infection MIP-1a (NK and T cells) MIG, RANTES (CD4+T cells) IL-8 (neutrophils) Eotaxin (eosinophils)>y#" 2cEarly mediators(IL-12, IL-15, 1l-18, IFN-g (from NK cells), IL-10 Proinflammatory mediators Produced by cell associated with innate immunity (macrophages, NK, etc.) Mediate direct effects Promote inflammation Shape downstream responses0PLate mediators(IL-2, IL-4, IL-5, IFN-g, TNF, IL-6, IL-10 Produced by cells of the adaptive immune response (T and B cells) Direct effects More immunoregulatory functions. CCytokine secretion and biological activities of TH1 and TH2 Subsets@D1   Down regulatorsiIL-10, IL-11, TGF-b Inhibit proliferation, cytokine production Produced by both innate and adaptive cells(jWMaintenance cytokinesGGM-CSF, IL-3, IL-7, IL-9, etc. Induce cell differentiation, cell growthHH Cytokine cross-regulationIn a a given immune response, either TH1 or TH2 response dominates Cytokines of one response tend to down-regulate the other type of response Example: TH1 cells secrete IFN-g, which inhibits proliferation of TH2 subsetP&  k #  8Role of TH1/TH2 balance in determining disease outcomes J9 $ $$ $+$Balance of two subset determines response to disease Leprosy Tuberculoid (TH1, CMI response, patient lives) Lepromatous (TH2, humoral response, patient dies)j=a=$   .   # ,= $ '  Cytokine-related diseasesBacterial septic shock Blood pressure drops, clots form, hypoglycemia ensues, patient dies LPS triggers results in TNF release TNF induces IL-1 which induces IL-6 and IL-8 Bacterial toxic shock and related diseases Superantigens trigger large numbers of T cells which release massive amounts of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell receptors and the MHC class II molecules on APC s, bypassing the need for antigen) Lymphoid and myeloid cancers Some cancer cells secrete cytokines Chagas disease Trypanosoma cruzi infection results in sever immune suppression Depression of IL-2 receptor productionPP+PPP$PPgP+Z$  gPc V Components of the immune system ( !'Infectious agents that target cytokines(($qEpstein-Barr virus foster the generation of T helper cells that do not produce IL-2. EBV produces an analog of IL-10 that favors TH2 cells, rather than TH1. Parasites such as tape worms induce high levels of IgE, an immunoglobulin induced by TH2 cells. Since TH1 cells mediate inflammation, this may be a protective ploy to avoid destructive inflammatory processes.~r  Y  i"=Immunosuppressive effects of oral bacteria on immune function>>$VImpairment of B and T cell function (P. intermedia, P. asaccharolytica, P. endodontalis, P. melaninogenica) Production of specific toxins that kill monocytes (A. actinomycetemcomitans) Provoke the release of peroxide, prostaglandins and other mediators capable of inhibiting lymphocyte function (T. denticola) Modulate expression of cytokinesfWP%E5q #>7 #3Cytokine-inducing components of Periodontopathogens44$Taken from Wilson, M., Reddi, K., Henderson, B. 1996. Cytokine-inducing components of periodontopathogenic bacteria. J. Periodont. Res. 31:393-407. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF) are believed to be the major pathological mediators of inflammatory diseases ranging from arthritis to periodontal diseases. It is believed that components of microorganisms have the capacity to induce cytokine synthesis in host cells.NxX,_ b%!6Cytokine-inducing components of Gram-positive bacteria77$ &"6Cytokine-inducing components of Gram-negative bacteria77$($KCytokine-induction by LPS from periodontopathogens other than P. gingivalis*L>    )%\Cytokines produced by host cells in response to components/products from periodontopathogens]] .*Interferon ActionViral replication stimulates the infected host cell to produce interferon. Interferon induces uninfected cells to produce antiviral proteins that prevent translation of viral mRNA degrade viral nucleic acid Viral replication is blocked in uninfected cellsBt]1t]1  Therapeutic uses of cytokinesModulation of TH activation Interfere with receptor function Interfere with cytokine Make it unable to bind to receptor Make it unable to act@U9 E9,(Examples of therapeutic usesSoluble T-cell receptor Anti-IL-2R Interleukin analogs which bind receptor, but do not trigger activation (ties up receptor) Toxins conjugated to cytokines which kill activated T-cells Administration of cytokines to enhance immunity (side effects/ short half lives) AllergiesP//03 j @((  x  c $} `@   p  S 0A j0281081N H  0޽h ? 33r(.Mt2 .=v3