Lecture 17Lecture 17CytokinesCytokines

What are cytokines?What are cytokines?

A collection of polypeptides used for A collection of polypeptides used for communicationscommunications between cellsbetween cells

Play role similar to hormones (messengers of the endocrine Play role similar to hormones (messengers of the endocrine system)system) Hormones usually act at a Hormones usually act at a distancedistance Cytokines act Cytokines act locallylocally

Differ from growth factors that are produced Differ from growth factors that are produced constitutivelyconstitutively, , while cytokine production is carefully while cytokine production is carefully regulatedregulated

Play an important role in both innate and adaptive immunityPlay an important role in both innate and adaptive immunity

Cytokine nomenclatureCytokine nomenclature

Interleukins (1-18)Interleukins (1-18) Interferons (Interferons ()) Others (common names)Others (common names)

Cytokine -mediated effectsCytokine -mediated effects Cell growthCell growth Cell differentiationCell differentiation Cell deathCell death Induce non-responsiveness to other Induce non-responsiveness to other

cytokines/cellscytokines/cells Induce responsiveness to other Induce responsiveness to other

cytokines/cellscytokines/cells Induce secretion of other cytokinesInduce secretion of other cytokines

How do cytokines tell cells what How do cytokines tell cells what to do?to do?

Produced by cells as part of normal cellular Produced by cells as part of normal cellular activity and/or the result of environmental triggeractivity and/or the result of environmental trigger

Bind to receptors on cellsBind to receptors on cells Trigger signal transduction pathwaysTrigger signal transduction pathways Initiate synthesis of new proteins Initiate synthesis of new proteins

Properties of cytokinesProperties of cytokines

ProteinsProteins Low molecular weightLow molecular weight Bind to receptor on either cell which produced Bind to receptor on either cell which produced

it or another cellit or another cell Receptor binding triggers a signalReceptor binding triggers a signal Signal results in altered pattern of gene Signal results in altered pattern of gene

expressionexpression

Cytokines can act in three Cytokines can act in three different mannersdifferent manners

AutocrineAutocrine Cytokine binds to receptor on cell that secreted itCytokine binds to receptor on cell that secreted it

ParacrineParacrine Cytokine binds to receptors on near by cellsCytokine binds to receptors on near by cells

EndocrineEndocrine Cytokine binds cells in distant parts of the bodyCytokine binds cells in distant parts of the body

Cytokine ActionsCytokine Actions PleiotropyPleiotropy

Act on more than one cell type (INFAct on more than one cell type (INF)) RedundancyRedundancy

More than one cytokine can do the same thing (IFNMore than one cytokine can do the same thing (IFN and IFNand IFN))

SynergySynergy Two or more cytokines cooperate to produce an effect Two or more cytokines cooperate to produce an effect

that is different or greater than the combined effect of that is different or greater than the combined effect of the two cytokines when functioning separately (IL-12 the two cytokines when functioning separately (IL-12 and IL-8) and IL-8)

AntagonismAntagonism Two or more cytokines work against each other (IL-4 Two or more cytokines work against each other (IL-4

and IL-12)and IL-12)

How can non-specific How can non-specific cytokines act specifically?cytokines act specifically?

Only cells expressing receptors for specific Only cells expressing receptors for specific cytokines can be activated by themcytokines can be activated by them

Many cytokines have very short half-livesMany cytokines have very short half-lives Only cells in close proximity will be activatedOnly cells in close proximity will be activated

High concentrations of cytokines are needed for High concentrations of cytokines are needed for activationactivation Only cells in close proximity will be activatedOnly cells in close proximity will be activated May require cell-to cell contactMay require cell-to cell contact

Five cytokine receptor familiesFive cytokine receptor families

Immunoglobulin superfamily receptorsImmunoglobulin superfamily receptors Class I cytokine receptor family Class I cytokine receptor family

(hematopoietin receptors)(hematopoietin receptors) Binds most of the cytokines in the immune Binds most of the cytokines in the immune

and hematopoietin systemsand hematopoietin systems Class II cytokine receptor familyClass II cytokine receptor family TNF receptor familyTNF receptor family Chemokine receptor familyChemokine receptor family

Cytokines regulate the immune Cytokines regulate the immune responseresponse

Cells with the appropriate Cells with the appropriate receptors become activatedreceptors become activated To differentiateTo differentiate To express receptors which will To express receptors which will

make them receptive to other make them receptive to other cytokinescytokines

To secrete other cytokinesTo secrete other cytokines

Signal Transduction by cytokine Signal Transduction by cytokine receptorsreceptors

Cytokine receptors on different cell types Cytokine receptors on different cell types trigger different eventstrigger different events

How do you get the message from the outside How do you get the message from the outside of the cell to the machinery inside?of the cell to the machinery inside?

Cytokines, growth factors and hormone Cytokines, growth factors and hormone signal transduction pathwayssignal transduction pathways

The Jak/Stat Signaling PathwayThe Jak/Stat Signaling Pathway

Involvement of cytokines in the Involvement of cytokines in the immune responseimmune response

Alert to Alert to infection.tumor/etc.infection.tumor/etc.

Recruit cells to siteRecruit cells to site Specify type of Specify type of

immune responseimmune response Immune effector Immune effector

phasephase Immune down-Immune down-

regulationregulation Immune memory Immune memory

and resetting the and resetting the systemsystem

Early mediators Early mediators (IFN(IFN))

Chemokines (MIP-Chemokines (MIP-11))

Early & late Early & late mediators (IL-2, mediators (IL-2, IFNIFN, IL-4, IL-5), IL-4, IL-5)

Down-regulators Down-regulators (IL-10, TNF(IL-10, TNF))

Maintenance of Maintenance of cytokines, etc. (GM-cytokines, etc. (GM-CSF, IL-3, IL-7, etc.)CSF, IL-3, IL-7, etc.)

Early mediatorsEarly mediators

Interferons Interferons Induced by dsRNA, etc.Induced by dsRNA, etc. Induced by CD40/CD40L pathwayInduced by CD40/CD40L pathway IFNs can induce more of themselvesIFNs can induce more of themselves Directly interferes with viral replicationDirectly interferes with viral replication Activation of T and NK cellsActivation of T and NK cells

ChemokinesChemokines

Recruit to sites of infectionRecruit to sites of infection MIP-1MIP-1 (NK and T cells) (NK and T cells) MIG, RANTES (CD4MIG, RANTES (CD4++T cells)T cells) IL-8 (neutrophils)IL-8 (neutrophils) Eotaxin (eosinophils)Eotaxin (eosinophils)

Early mediatorsEarly mediators

IL-12, IL-15, 1l-18, IFN-IL-12, IL-15, 1l-18, IFN- (from NK cells), IL-10 (from NK cells), IL-10 Proinflammatory mediatorsProinflammatory mediators Produced by cell associated with innate immunity Produced by cell associated with innate immunity

(macrophages, NK, etc.)(macrophages, NK, etc.) Mediate direct effectsMediate direct effects Promote inflammationPromote inflammation Shape downstream responsesShape downstream responses

Late mediatorsLate mediators

IL-2, IL-4, IL-5, IFN-IL-2, IL-4, IL-5, IFN-, TNF, IL-6, IL-10, TNF, IL-6, IL-10 Produced by cells of the adaptive immune Produced by cells of the adaptive immune

response (T and B cells)response (T and B cells) Direct effectsDirect effects More immunoregulatory functionsMore immunoregulatory functions

Cytokine secretion and Cytokine secretion and biological activities of Tbiological activities of THH1 and 1 and

TTHH2 Subsets2 Subsets

Type 1Type 1 Type 2Type 2

IL-2IL-2IFN-IFN-TNFTNF

IL-4IL-4IL-5IL-5

Cell-mediatedCell-mediatedImmune responseImmune response(intracellular(intracellularOrganisms)Organisms)

Humoral Humoral responseresponse(parasites)(parasites)

T cellT cell

Down regulatorsDown regulators

IL-10, IL-11, TGF-IL-10, IL-11, TGF- Inhibit proliferation, cytokine Inhibit proliferation, cytokine

productionproduction Produced by both innate and adaptive Produced by both innate and adaptive

cellscells

Maintenance cytokinesMaintenance cytokines

GM-CSF, IL-3, IL-7, IL-9, etc.GM-CSF, IL-3, IL-7, IL-9, etc. Induce cell differentiation, cell growthInduce cell differentiation, cell growth

Cytokine cross-regulationCytokine cross-regulation

In a a given immune response, either In a a given immune response, either TTHH1 or T1 or THH2 response dominates2 response dominates

Cytokines of one response tend to Cytokines of one response tend to down-regulate the other type of down-regulate the other type of responseresponse

Example: TExample: THH1 cells secrete IFN-1 cells secrete IFN-, , which inhibits proliferation of Twhich inhibits proliferation of THH2 2 subsetsubset

Role of TRole of THH1/T1/THH2 balance in 2 balance in

determining disease outcomes determining disease outcomes

Balance of two subset determines Balance of two subset determines response to diseaseresponse to disease

LeprosyLeprosy Tuberculoid (TTuberculoid (THH1, CMI response, patient 1, CMI response, patient

lives)lives) Lepromatous (TLepromatous (THH2, humoral response, 2, humoral response,

patient dies)patient dies)

Cytokine-related diseasesCytokine-related diseases

Bacterial septic shockBacterial septic shock Blood pressure drops, clots form, hypoglycemia ensues, patient diesBlood pressure drops, clots form, hypoglycemia ensues, patient dies LPS triggers results in TNF releaseLPS triggers results in TNF release TNF induces IL-1 which induces IL-6 and IL-8TNF induces IL-1 which induces IL-6 and IL-8

Bacterial toxic shock and related diseasesBacterial toxic shock and related diseases Superantigens trigger large numbers of T cells which release massive Superantigens trigger large numbers of T cells which release massive

amounts of cytokines amounts of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell (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)receptors and the MHC class II molecules on APC’s, bypassing the need for antigen)

Lymphoid and myeloid cancersLymphoid and myeloid cancers Some cancer cells secrete cytokinesSome cancer cells secrete cytokines

Chagas’ diseaseChagas’ disease Trypanosoma cruzi infection results in sever immune suppressionTrypanosoma cruzi infection results in sever immune suppression Depression of IL-2 receptor productionDepression of IL-2 receptor production

Components of the immune Components of the immune systemsystem

Intra- and Extracellular Inflammatory Intra- and Extracellular Inflammatory Mechanisms to Destroy or Inactivate Mechanisms to Destroy or Inactivate PathogensPathogens

T cellT cell

T cellT cellCD8CD8

T cellT cellCD4CD4

B cellB cell

??Cytotoxic Cytotoxic

T cellsT cells

InflammatoryInflammatorycytokinescytokines

HelpHelp

AntibodyAntibody

Macro-Macro-phagesphages

Granulo-Granulo-cytescytes

Interferon &Interferon &Non-lymphoidNon-lymphoid

CytokinesCytokines

ComplementComplement

Adapted from Marrack and Kappler, 1994Adapted from Marrack and Kappler, 1994

Infectious agents that target cytokinesInfectious agents that target cytokines

Epstein-Barr virus foster the generation of T helper cells Epstein-Barr virus foster the generation of T helper cells that do not produce IL-2. that do not produce IL-2.

EBV produces an analog of IL-10 that favors TEBV produces an analog of IL-10 that favors THH2 cells, 2 cells,

rather than Trather than THH1.1. Parasites such as tape worms induce high levels of IgE, an Parasites such as tape worms induce high levels of IgE, an

immunoglobulin induced by Timmunoglobulin induced by THH2 cells. 2 cells.

Since TSince THH1 cells mediate inflammation, this may be a 1 cells mediate inflammation, this may be a

protective ploy to avoid destructive inflammatory protective ploy to avoid destructive inflammatory processes.processes.

Immunosuppressive effects of oral Immunosuppressive effects of oral bacteria on immune functionbacteria on immune function

Impairment of B and T cell function (Impairment of B and T cell function (P. intermedia, P. intermedia, P. asaccharolytica, P. endodontalis, P. P. asaccharolytica, P. endodontalis, P. melaninogenicamelaninogenica))

Production of specific toxins that kill monocytes (Production of specific toxins that kill monocytes (A. A. actinomycetemcomitansactinomycetemcomitans))

Provoke the release of peroxide, prostaglandins and Provoke the release of peroxide, prostaglandins and other mediators capable of inhibiting lymphocyte other mediators capable of inhibiting lymphocyte function (function (T. denticolaT. denticola))

Modulate expression of cytokinesModulate expression of cytokines

Cytokine-inducing components of Cytokine-inducing components of PeriodontopathogensPeriodontopathogens

Taken from Wilson, M., Reddi, K., Henderson, B. 1996. Taken from Wilson, M., Reddi, K., Henderson, B. 1996. Cytokine-inducing components of periodontopathogenic Cytokine-inducing components of periodontopathogenic bacteria. bacteria. J. Periodont. Res.J. Periodont. Res. 3131:393-407.:393-407.

Pro-inflammatory cytokines such as interleukin (IL)-1, Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF) are believed IL-6, IL-8 and tumor necrosis factor (TNF) are believed to be the major pathological mediators of inflammatory to be the major pathological mediators of inflammatory diseases ranging from arthritis to periodontal diseases.diseases ranging from arthritis to periodontal diseases.

It is believed that components of microorganisms have It is believed that components of microorganisms have the capacity to induce cytokine synthesis in host cells.the capacity to induce cytokine synthesis in host cells.

Cytokine-inducing components of Cytokine-inducing components of Gram-positive bacteriaGram-positive bacteria

Cytokine-inducing components of Cytokine-inducing components of Gram-negative bacteriaGram-negative bacteria

Cytokine-induction by LPS from Cytokine-induction by LPS from periodontopathogens other than periodontopathogens other than P. P.

gingivalisgingivalis

Cytokines produced by host cells in response to Cytokines produced by host cells in response to components/products from components/products from

periodontopathogensperiodontopathogens

Interferon ActionInterferon Action

Viral replication stimulates the infected host cell Viral replication stimulates the infected host cell to produce interferon. to produce interferon.

Interferon induces uninfected cells to Interferon induces uninfected cells to produce antiviral proteins that prevent translation of produce antiviral proteins that prevent translation of

viral mRNAviral mRNA degrade viral nucleic aciddegrade viral nucleic acid

Viral replication is blocked in uninfected cellsViral replication is blocked in uninfected cells

Therapeutic uses of cytokinesTherapeutic uses of cytokines

Modulation of TModulation of THH activation activation Interfere with receptor functionInterfere with receptor function Interfere with cytokineInterfere with cytokine

Make it unable to bind to receptorMake it unable to bind to receptor Make it unable to actMake it unable to act

Examples of therapeutic usesExamples of therapeutic uses Soluble T-cell receptorSoluble T-cell receptor Anti-IL-2RAnti-IL-2R Interleukin analogs which bind receptor, but do Interleukin analogs which bind receptor, but do

not trigger activation (ties up receptor)not trigger activation (ties up receptor) Toxins conjugated to cytokines which kill Toxins conjugated to cytokines which kill

activated T-cellsactivated T-cells Administration of cytokines to enhance immunity Administration of cytokines to enhance immunity

(side effects/ short half lives)(side effects/ short half lives) AllergiesAllergies