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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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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
slide6
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

slide7
(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
slide11
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

slide12
T lymphocytes in response to Ags are the principal sources of cytokine in adaptive immunity .
  • The function of T helper cells is mediated by cytokines
slide13
What are cytokines?
  • 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
Autocrineaction

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

slide16
pleiotropism
  • redundancy
  • synergy
  • antagonism
cytokines3
Cytokines
  • General Properties
  • Functional Categories of Cytokines
  • Cytokine Receptors
  • Biologic Actions
functional categories of cytokines
Functional Categories of Cytokines
  • 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
  • General Properties
  • Functional Categories of Cytokines
  • Cytokine Receptors
  • Biologic Actions
cytokine receptors
Cytokine Receptors
  • 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.

slide21
-S-S-

-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

slide22
IL-2R IL-4R IL-7R IL-9R IL-15R

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

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

cytokines5
Cytokines
  • General Properties
  • Functional Categories of Cytokines
  • Cytokine Receptors
  • Biologic Actions
biologic actions
Biologic Actions
  • 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 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

slide27
Active recruitment of the cells to the sites of infectionrecognition of microbes phagocytosis destruction
slide28
TNF

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 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
slide30
directing migration of leukocytes

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

slide31
X: any amino acid

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

slide32
CXCL8/IL-8

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

cytokines and inflammation
Cytokines and Inflammation
  • 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
slide36
directing migration of leukocytes

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 tissuesSegregation 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 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
  • 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

slide40
type I IFN inhibits viral replication

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 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
slide42
Microbes

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

biologic actions1
Biologic Actions
  • Cytokines That Mediate and Regulate Innate Immunity
  • Cytokines That Mediate and Regulate Adaptive Immunity
  • Cytokines That Stimulate Hematopoiesis
slide45
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

function of t cell derived cytokines
Function of T cell derived Cytokines
  • 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
slide47
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
slide49
IL-2
  • 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
  • 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
slide51
IFN-:A principal macrophage-activating cytokine

Leukocyte recruitment (inflammation)

Neutrophil activation (killing of phagocytosed microbes)

slide53
A more detailed introduction of functions of cytokines in adaptive immune response are in charpter 13 (Effector Mechanisms of Cell-Mediated Immunity)
biologic actions2
Biologic Actions
  • Cytokines That Mediate and Regulate Innate Immunity
  • Cytokines That Mediate and Regulate Adaptive Immunity
  • Cytokines That Stimulate Hematopoiesis
in summary
In summary
  • What are cytokines?
  • Cytokines that mediate innate immunity
  • Cytokines that mediate adaptive immunity
  • Cytokines That Stimulate Hematopoiesis
slide58
Colony stimulating factor, CSF
  • 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

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