Cytokine PPT

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    IRAM KHALIQ

    SARA HINA SIDRA

    Pharmacology Therapeutics-III

    SIR IMRAN ARSHAD

    Semester:1

    M PHIL

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    CHEMICAL MEDIATORS

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    These are endogenous chemicalsubstances that are released from cells orplasma or the damaged tissue itself, to

    mediate & partake in various processes ofacute inflammation like vasodilatation,increased vascular permeability, PMN

    chemotaxis, fever, pain, tissue damage

    etc

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    DEFINITION

    The term "cytokine" is derived from a

    combination of two Greek words - "cyto"

    meaning cell and "kinos" meaning

    movement.Cytokines are cell signalling molecules

    that aid cell to cell communication in

    immune responses and stimulate themovement of cells towards sites of

    inflammation, infection and trauma.

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    Cytokines exist in peptide, proteinand

    glycoprotein (proteins with a sugar

    attached) forms.

    The cytokines are a large family of

    molecules that are classified in various

    different ways due to an absence of aunified classification system.

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    Functions of cytokines

    Stimulation

    Inhibition

    Differentiation

    Cell death

    chemoattract

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    Cytokine actions may be characterizedas:

    Autocrine(self modulating)

    Paracrine(modulating cells in theimmediate surroundings)

    Endocrine(modulating cells throughcirculation in the distant area)

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    Properties of cytokines

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    Names of Cytokines

    Source

    e.g.,Lymphokines

    Funct ion

    e.g.,Chemokines

    In tercel lular act ion

    e.g., Interleukins

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    Chain of Cytokine Action

    Stimulus>Cytokine-

    producing cell>

    Cytokine>Target

    cel l>Receptor>

    B iolog ical effect(s)

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    Cytokine-generating Cells

    A Variety Of Cells AreCapable Of MakingCytokines

    However The BiggestProducers: Mand

    TH

    Innate immunity Macrophages

    Endothelial cells

    Fibroblasts

    Adaptive immunity T lymphocytes

    Macrophages

    NK cellsTHI TH2

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    FUNCTIONAL CLASSES OFCYTOKINESCytokines classified according to their biologic

    actions into three groups:

    1) Mediators and regulators of innate immunity

    - Produced by activatedmacrophages andNKcells in response to microbial infection

    - they act mainly on endothelial cellsandleukocytesto stimulate the early

    inflammatory response to microbes

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    2) Mediators and regulators of acquiredimmunity

    - Produced mainly by T lymphocytesinresponse tospecific recognition of foreign antigens

    - They include IL-2, IL-4, IL-5,, IL-13, IFN,Transforming growth factor-(TGF-) andlymphotoxin (TNF- )

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    3) Stimulators of haematopoiesis

    - Produced by bone marrow, stormal cells,

    leukocytes- Stimulate growth and differentiation ofleukocytes- Stem cell factor, IL-3, IL-7, GM-CSF

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    1) Interferons (IFNs)

    * Interferons (IFNs):are proteins secreted inresponse to viral infections or other stimuli

    * They include:

    - INF-produced by leucocytesinduced by virus infected

    cells

    -INF-produced by fibroblasts

    -INF-produced by NK cells,TH1 cells, CD8T-cells

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    Action of INF- and IFN-:- Preventviral replication

    - IncreaseMHC-I expression on viralinfected cells helping their recognitionby CD8 T-cells

    -Increasecytotoxic action of Nk cells

    -Inhibitcell proliferation and tumorgrowth

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    Action of IFN-:

    -ActivateMacrophages

    - Increaseexpression of MHC-I and II onAPCs

    -Enhancecytotoxic actions of Nk cells

    -Promoteproduction of TH1 and inhibitsproliferation of TH2

    http://localhost/var/www/apps/conversion/tmp/Videos/RealPlayer%20Downloads/Cytokines/Interferon%20and%20how%20it%20works%20in%20the%20body.%20-%20YouTube.flvhttp://localhost/var/www/apps/conversion/tmp/Videos/RealPlayer%20Downloads/Cytokines/Interferon%20and%20how%20it%20works%20in%20the%20body.%20-%20YouTube.flv
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    2) Interleukins

    Group of cytokines(secreted proteins/signallingmolecules) that were first seen to be expressedby white blood cells (leukocytes).

    The function of the immune systemdepends in alarge part on interleukins. The majority ofinterleukins are synthesized by helper CD4+ Tlymphocytes, as well as through monocytes,macrophages, and endothelial cells.

    They promote the development anddifferentiation of T, B, and hematopoietic cells.

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    3)Tumor necrosis factors(TNF) Group of cytokines which can cause cell

    death (Apoptosis).

    Family members :- 19 cytokines are

    identified as part of the TNF family on thebasis of sequence, functional & structuresimilarities.

    The first two members of the family to beidentified were;

    TNF- TNF-

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    4) Transforming growthfactor (TGF) Sometimes referred to as Tumor Growth

    Factor.

    Two classes of polypeptide growth factors,

    TGF - & TGF .

    The two classes of TGFs are not structurallyor genetically related to one another & theyact through different receptor mechanisms.

    They dont always inducecellulartransformation, and are not the only growthfactors that induce cellular transformation.

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    5) Colony stimulating factors(CSFs) colony-stimulating factors are soluble,

    membrane-bound substances ofthe hematopoietic microenvironment.

    secreted glycoproteins that bind toreceptor proteins on the surfaces

    of hemopoietic stem cells.

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    6) Growth factor

    A naturally occurring substance capableof stimulating cellular growth,proliferation & cellular differentiation.

    Usually it is a protein or a steroidhormone.

    Growth factors are important forregulating a variety of cellular processes.

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    CHEMOKINES

    Family of chemoattractants forinflammatory cells & include;

    IL-8 chemotactic for neutrophils

    Platelet factor 4 chemotactic forneutrophils, monocytes & eosinophils

    MCP 1 chemotactic for monocytes

    Eotaxin chemotactic for eosinophils

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    Cytokine Receptors

    5 Major Families

    Immunoglobulin Superfamily

    Hematopoietin Receptor Family (Class I)

    Interferon Receptor Family (Class II) TNF Receptor Family

    Chemokine Receptor Family

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    Cytokine Receptors

    Multimeric receptors

    Common signal-transducing subunits

    Unique high affinity subunits

    High affinity subunits associated with

    activation of target cell

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    Seven-transmembrane-domain receptorssignal by coupling with trimeric GTP-

    binding proteins

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    Signal Transduction

    Initiated by cytokine binding

    Activates JAK (Janus kinase)

    Phosphorylation of tyrosine

    Binding of STAT(Signal transducers and

    activators of transcription)

    Translocation of STAT to cells DNA

    Transcription of specific target genes

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    Ligand Binds Subunit Ligand Binding Causes

    Dimerization of Receptor

    JAKs Get Activated Phosphorylation of tyrosine residues

    on receptor Phosphorylation of JAKs themselves

    STATS Dock Receptor Phosphorylation of STATs by JAKs

    Dimerized STATs Translocate ToNucleus

    Gene Expression

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    Role of Cytokines in Hematopoiesis

    SCF (Stem cell factor)

    GM-CSF (Granulocyte-macrophage

    colony-stimulating factor)

    IL-3 (Interleukin 3)

    IL-5 (Interleukin 5)

    IL-7 (Interleukin 7)

    IL-11(Interleukin 11)

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    Therapeutic Uses of Cytokines

    1) Interferon in treatment of viral diseases,cancer.

    2) Several cytokines are used to enhance T-cell

    activation in immunofideficincy diseases, e.g.IL-2, IFN-,TNF-.

    3) IL-2 and lymphokin