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Lu Qing, PhD , MD Department of Immunology School of Medicin, Fudan University Tel : 5423-7093 E-mail: [email protected] Cytokines. What are cytokines?.

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Cytokines

Lu Qing, PhD,MDDepartment of ImmunologySchool of Medicin, Fudan UniversityTel:5423-7093E-mail: [email protected]

Cytokines


What are cytokines
What are cytokines?

  • “Cytokines” are soluble protein secreted by the cells of innate and adaptive immunity and therefore mediate many of the functions of these cells

  • Based on their cellular sourcesmonokines (mononuclear phagocyte)lymphokines (lymphocytes)interlukins (leukocytes) (IL-1, IL-2, etc.)

  • A subfamily of cytokines primarily functions in directing migration of cells, these are called “chemotactic cytokines” or “chemokines”


Cytokines1
Cytokines

  • General Properties

  • Functional Categories of Cytokines

  • Cytokine Receptors

  • Biologic Actions


Cytokines2
Cytokines

  • General Properties

  • Functional Categories of Cytokines

  • Cytokine Receptors

  • Biologic Actions



Phagocytes-identify, ingest, and destroy microbes

  • Mononuclear phagocytes

  • Neutrophils (polymorphonuclear leukocytes)

Short-lived (6h); the most abundant population of circulating WBCs;mediate the earliest phase of inflammatory response


(b)

Bacterium becomes attached to membrane evaginations called pseudopodia

Bacterium is ingested, forming phagosome

Phagosome fuses with lysosome

Lysosomal enzymes digest captured material

(a)

Digestion products are released from cell


Nk cells kill infected cells and tumor cells
NK cells-kill infected cells and tumor cells

  • perforin/granzyme (cytolysis)

  • Fas/FasL

  • TNF-/TNFR-I

Cell apoptosis


Nk cells secret cytokine mainly ifn g to activate macrophage to destroy phagocytosed microbes

As a result of cellular activation:

NK cells secret cytokine, mainly IFN-g—to activate macrophage to destroy phagocytosed microbes.

Mononuclear phagocytes are the principal source of cytokines of innate immunity

  • Tumor necrosis factor (TNF)

  • IL-1

  • IL-12

  • Type I IFNs

  • IL-15

  • IL-18



Three elemental R‘s of T-cell biology: repertoire, recognition, response

Repertoire of clones

Recognition phase

Recognition of processed antigens: peptide-MHC

Cytokine production is one of the principal response of T cells to antigen recognition

Activation phase

Effector phase

ResponseClonal expansionFunctional differentiationMemoryTolerance to self

TH1(IFN-)TH2(IL-4,5, 13)TH17(IL-17)TR1(IL-10)Foxp3+TregCTL



What are cytokines? of cytokine in adaptive immunity .

  • Cytokines are polypeptides produced by the cells of innate and adaptive immunity in response to microbes and other antigens as a result of cellular activation.

  • Cytokines initiate their actions by binding to specific membrane receptors on target cells.

  • The cellular responses to most cytokines consist of gene activation, resulting in the expression of new functions and sometimes the proliferation of the target cells


Cytokine actions may be local and systemic

Autocrine of cytokine in adaptive immunity .action

act on cytokine-producing cell itself

Paracrine action

act on a nearby cell

circulation

Endocrine action

act at a distance from the site of infection

Cytokine actions may be local and systemic


T lymphocytes often secret cytokines at the site of contact with antigen presenting cells
T lymphocytes often secret cytokines at the site of contact with antigen-presenting cells .

Most cytokines act close to where they are produced


  • pleiotropism with antigen-presenting cells .

  • redundancy

  • synergy

  • antagonism


Cytokines3
Cytokines with antigen-presenting cells .

  • General Properties

  • Functional Categories of Cytokines

  • Cytokine Receptors

  • Biologic Actions


Functional categories of cytokines
Functional Categories of Cytokines with antigen-presenting cells .

  • Mediators and regulators of innate immunityTumor necrosis factor (TNF), IL-1, IL-6, IL-12, Type I IFNs, IL-15, IL-18,chemokines

  • Mediators and regulators of adptive immunityIL-2, IL-4, IL-5, IFN-g, TGF-, LT(TNF- ), IL-13,etc

  • Stimulators of hematopoiesisgranulocyte-CSF, G-CSF macrophage-CSF,M-CSF granulocyte-macrophage-CSF, GM-CSF) erythropoietin, EPO TPO stem cell factor, SCF


Cytokines4
Cytokines with antigen-presenting cells .

  • General Properties

  • Functional Categories of Cytokines

  • Cytokine Receptors

  • Biologic Actions


Cytokine receptors
Cytokine Receptors with antigen-presenting cells .

  • Type I cytokine receptors

  • Type II cytokine receptors

  • Ig superfamily

  • TNF receptors

  • Seven-transmembrane -helical receptors

*Classification of cytokine receptors based on structural homologies among the extracellular cytokine-binding domain.


-S-S- with antigen-presenting cells .

-S-S-

-S-S-

Cytokine receptor families and ligands

Ig superfamily

Type I cytokine-R

Type II cytokine-R

TNF-R

Chemokine-R

C1C3C2

C1C3C2

C1C3C2

Conserved cycteins

CC

C

C

C1C3C2

WSXWS

G protein

IL-2 IL-3 IL-4 IL-5 IL-6 IL-7

IL-9 IL-11 IL-12 IL-13 IL-15 OSM

GM-CSF G-CSF EPO

TNF-a TNF-b CD40L NGF FASL

IFN-a IFN-b IFN-g

IL-10

IL-1 M-CSF C-kit

IL-8 RANTES MIP-1 PF4


IL-2R IL-4R IL-7R IL-9R IL-15R with antigen-presenting cells .

common g chain

g–chain shared by IL-2 receptor family

a b g

a g

a b g

Cytokine receptors consist of unique ligand-binding chains and one or more signal-transducing chains,which are often shared by receptors for different cytokines


Cytokine receptors and signaling
Cytokine receptors and signaling with antigen-presenting cells .

Different cytokines binding to cytokine receptors activated distinct signal transduction pathways resulting in gene activation.


Cytokines5
Cytokines with antigen-presenting cells .

  • General Properties

  • Functional Categories of Cytokines

  • Cytokine Receptors

  • Biologic Actions


Biologic actions
Biologic Actions with antigen-presenting cells .

  • Cytokines That Mediate and Regulate Innate Immunity

  • Cytokines That Mediate and Regulate Adaptive Immunity

  • Cytokines That Stimulate Hematopoiesis *Cytokines have many functions, we’ll focus on a few central functions of a few key cytokines


Mononuclear phagocytes are the principal source of cytokines of innate immunity
*Mononuclear phagocytes with antigen-presenting cells . are the principal source of cytokines of innate immunity

Cytokines That Mediate and Regulate Innate Immunity

  • Tumor necrosis factor (TNF)

  • IL-1

  • IL-6

  • chemokines

  • Type I IFNs

  • IL-12

  • IL-15

  • IL-18

Proinflammatory cytokines


Active recruitment of the cells to the sites of infection with antigen-presenting cells .recognition of microbes phagocytosis destruction


TNF with antigen-presenting cells .

Low quantities

(plasma conc.<10-9M)

Moderate

quantities

High quantities

(plasma conc.10-7M)

Systemic effects

Septic shock

Local inflammation

Leukocyte

Fever

Low output

Activation

Thrombus

Adhesion molecule

IL-1,chemokines

Endothelial cell

Hypoglycemia


Mononuclear phagocytes are the principal source of cytokines of innate immunity1
*Mononuclear phagocytes with antigen-presenting cells . are the principal source of cytokines of innate immunity

Cytokines That Mediate and Regulate Innate Immunity

  • Tumor necrosis factor (TNF)

  • IL-1

  • IL-6

  • chemokines

  • IL-12

  • Type I IFNs

  • IL-15

  • IL-18


directing migration of leukocytes with antigen-presenting cells .

Chemokines

Tissue

Primary lymphoid organs

Secondary lymphoid organs

Blood

inflammation

Cellular sources

to inflammatory sites

  • inflammatory stimuli

  • Constitutively produced in lymphoid organs

Physiologic traffic of lymphocytes through the organs


X: any amino acid with antigen-presenting cells .

C: cyctein

Chemokine family and structure

Family Structure

The chemokines are classified into families based on the number and location of N-terminal of cyctein residues CXC、CC、C、CX3C


CXCL8/IL-8 with antigen-presenting cells .

CXCL1/GROα

CXCL4/PF4

CXCL10/IP-10

Microbesinflammatory cytokines

CXC chemokines

CC chemokines

CCL2/MCP-1

leukocytesendothelial cells epithelial cells fibroblasts

CCL3/MIP-1

CCL5/RANTES

CCL11/Eotaxin

lymphocytes

neutrophils

basophils

lymphocytes

eosinophils

Endothelial cells

Mononuclear phagocytes


The chemokine/chemokine-receptor family with antigen-presenting cells .



Cytokines and inflammation
Cytokines and Inflammation with antigen-presenting cells .

  • Macrophages or DCs stimulated via microbes make pro-inflammatory cytokines, especially TNF (Tumor necrosis factor), IL-1, and IL-6

  • TNF and IL-1 signal to endothelial cells to make them:

    • Leaky to fluid (influx of plasma; containing antibodies, complement components, etc.)

    • Sticky for leukocytes, leading to influx of neutrophils first, then monocytes, lymphocytes

  • Chemokines induce movement of leukocytes and their migration toward chemical gradient of the cytokine


directing migration of leukocytes with antigen-presenting cells .

Chemokines

Tissue

Primary lymphoid organs

Secondary lymphoid organs

Blood

inflammation

to inflammatory sites

  • inflammatory stimuli

  • Constitutively produced in lymphoid organs

Physiologic traffic of lymphocytes through the organs


Segregation of b cells and t cells in distinct areas of the lymph node is dependent on cytokines

Chemokines regulate the traffic of lymphocytes and other cells through peripheral lymphoid tissues

Segregation of B cells and T cells in distinct areas of the lymph node is dependent on cytokines.

CXCR5/CCR7


Mononuclear phagocytes are the principal source of cytokines of innate immunity2
*Mononuclear phagocytes cells through peripheral lymphoid tissues are the principal source of cytokines of innate immunity

Cytokines That Mediate and Regulate Innate Immunity

  • Tumor necrosis factor (TNF)

  • IL-1

  • IL-6

  • chemokines

  • Type I IFNs

  • IL-12

  • IL-15

  • IL-18


Type i ifns
Type I IFNs cells through peripheral lymphoid tissues

  • Major cellular sourcesIFN-: mononuclear phagocytes IFN-: fibroblasts

  • Potent stimulusviral infection

  • Functionmediate the early innate immune response to viral infections

Inhibits viral replication

Increase expression of class I MHC molecules

Stimulates the development of Th1 cells in human


type I IFN inhibits viral replication cells through peripheral lymphoid tissues

Induction of “antiviral state”

virus

Viral replication

Induction of enzymes that block viral replication

Potent stimulus

nucleus

nucleus

Virus infected cells

IFN-a

Nearby uninfected cell


Mononuclear phagocytes are the principal source of cytokines of innate immunity3
*Mononuclear phagocytes cells through peripheral lymphoid tissues are the principal source of cytokines of innate immunity

Cytokines That Mediate and Regulate Innate Immunity

  • Tumor necrosis factor (TNF)

  • IL-1

  • IL-6

  • chemokines

  • Type I IFNs

  • IL-12

  • IL-15

  • IL-18


Microbes cells through peripheral lymphoid tissues

Antigen presentation

Activation

Macrophage

Dendriticcell

Naïve CD4+T cell

CD40 CD40L

IL-12

CD8+ T cell

NK cell

NK cell

TH1 cell

IFN-

Increased cytolytic activity

Macrophage activation;killing of phagocytosed microbes

Killing of infected cell


Roles of cytokines in innate immunity and inflammation

0 1 3 6

Hours after LPS injection

Roles of cytokines in innate immunity and inflammation


Biologic actions1
Biologic Actions 6

  • Cytokines That Mediate and Regulate Innate Immunity

  • Cytokines That Mediate and Regulate Adaptive Immunity

  • Cytokines That Stimulate Hematopoiesis


Three elemental R‘s of T-cell biology: 6 repertoire, recognition, response

Repertoire of clones

Recognition phase

Recognition of processed antigens: peptide-MHC

Cytokine production is one of the principal response of T cells to antigen recognition

Activation phase

Effector phase

ResponseClonal expansionFunctional differentiationMemoryTolerance to self

TH1(IFN-)TH2(IL-4,5, 13)TH17(IL-17)TR1(IL-10)Foxp3+TregCTL


Function of t cell derived cytokines
Function of T cell derived Cytokines 6

  • In the activation phase of T cell-dependant immune response:Regulate the growth and differentiation of various lymphocyte population

  • In the effector phase of adaptive immune response:Recruit, activate, and regulate specialized effector cells, such as mononuclear phagocytes, neutrophils, and eosinophils, to eliminate antigens


Cytokine of adaptive immunity are produced mainly by T lymphocytes in response to specific recognition of protein Ags.

  • The function of T helper cells is mediated by cytokines


Figure 8 20
Figure 8-20 lymphocytes in response to specific recognition of protein Ags.


IL-2 lymphocytes in response to specific recognition of protein Ags.

  • a growth factor for antigen-stimulated T lymphocytes

  • responsible for T cell clonal expansion after antigen recognition


Function of t cell derived cytokines1
Function of T cell derived Cytokines lymphocytes in response to specific recognition of protein Ags.

  • In the activation phase of T cell-dependant immune response:Regulate the growth and differentiation of various lymphocyte population

  • In the effector phase of adaptive immune response:Recruit, activate, and regulate specialized effector cells, such as mononuclear phagocytes, neutrophils, and eosinophils, to eliminate antigens


IFN- lymphocytes in response to specific recognition of protein Ags.:A principal macrophage-activating cytokine

Leukocyte recruitment (inflammation)

Neutrophil activation (killing of phagocytosed microbes)


  • IFN- lymphocytes in response to specific recognition of protein Ags. treatment inhibits the propagation of Leishmania that survive within macrophages



Biologic actions2
Biologic Actions adaptive immune response are in charpter 13 (Effector Mechanisms of Cell-Mediated Immunity)

  • Cytokines That Mediate and Regulate Innate Immunity

  • Cytokines That Mediate and Regulate Adaptive Immunity

  • Cytokines That Stimulate Hematopoiesis


Pluripotent stem cells adaptive immune response are in charpter 13 (Effector Mechanisms of Cell-Mediated Immunity)


SCF and IL-7 adaptive immune response are in charpter 13 (Effector Mechanisms of Cell-Mediated Immunity)


In summary
In summary adaptive immune response are in charpter 13 (Effector Mechanisms of Cell-Mediated Immunity)

  • What are cytokines?

  • Cytokines that mediate innate immunity

  • Cytokines that mediate adaptive immunity

  • Cytokines That Stimulate Hematopoiesis


Colony stimulating factor, CSF adaptive immune response are in charpter 13 (Effector Mechanisms of Cell-Mediated Immunity)

  • Cellular sources:Bone marrow stromal cells, leukocytes

  • Function:stimulate the growth and differentiation of immature leukocytes

  • Members:granulocyte-CSF, G-CSF macrophage-CSF,M-CSF granulocyte-macrophage-CSF, GM-CSF)

    erythropoietin, EPO TPO stem cell factor, SCF


THANK YOU adaptive immune response are in charpter 13 (Effector Mechanisms of Cell-Mediated Immunity)


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