Lymphokines &

Cytokines

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Immunology & Disease

Edward H Sugita

Wednesay 11/4/12 Lecture 8

Introduction

Concepts:

Macrophage : Il-1, Il-6. Il-12, TNF-IFN-TH1 : IL-2, IFN-, Lt (TNF-)

TH2 : IL-4, IL-5, IL-9, IL-10, IL-13

GFs : IL-3, IL-7, IL-11, IL-14, IL-15, G-CSF, M-CSF, GM-CSF, TGF-

1. T cells secrete many proteins and glycoproteins in response to appropriate stimulation.2. The proteins secreted by lymphocytes are called lymphokines. The most important of

these lymphokines are interleukins (ILs) .3. The ILs either enhance interactions between lymphocytes or act as cell growth stimulants.

The most important of these are IL-2, secreteed by TH1 cells, and IL-2 secreted by MOs. 4. TH1 and TH2 cells secrete 2 distinct patterns of cytokines that result in occurrence of a

very different IR. 5. The IFNs are antiviral or regulatory proteins. IFN- secreted by T cells. It has complex

effects, including blockage of viral replication, activqtion of MOs, and inhibition of tumor cell growth.

6. Lymphotoxins (LTs) and tumor necrosis factors (TNFs) are proteins from MOs or T cellsthat have the ability to kill some tumor cells or other abnormal cells.

7. Lymphocytes also secrete a mixture of GFs that promote development of many types of cells in the BM.

Main classes of cytokine

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Lymphokines and their activities

There may be overlap between these lymphokines, eg MAF activity is partly due to IFN-. There may also be heterogeneity within a category, eg TRF is a mixture of lymphokines causing B cell proliferation and maturation to the Ab-forming plasma cells. Only CSF, IFN- and IL-2 are available in a pure form.

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2. Regulation of othe lymphocytes (Ag-specific factors)

1. Regulation of othe lymphocytes (non-Ag specific factors)

3. Induction of inflammation and MMN cell infiltration

4. Modulation of the function of phagocytes

6. Destruction of non-leucocytes target cells

5. Regulation of other tissues

Interleukin-2 (IL-2)

Interferon & (IFN)Interleukin-3 (IL-3)

lymphotoxins (heterogenous) (LT)

Soluble IR suppressor (SIRS)Inhibitor of DNA synthesis (IDS)allogeneic effector factor (AEF)T cell replacing factot (TRF)

absorbed Ag specific helper factors (THF)absorbed Ag specific duppressor factors (TSF)

migration inhibitor factor (MIF) macrophage activation factor (MAF)leuucocyte migration inhibition factor (LIF)chemotasctic factor (CF)interferon ( & ) (IFN)colony stimulating factor (CSF)macrophage fusion factor (MFF)

skin reaction factor (SRF)

colony stimulating factor (CSF)osteoclast activating factor ( OAF)

Cytokines secreted by each cellCytokines = Lymphokines

= secreted protein by immune system’s cells

. .. .

TH1 TH2 TC Other cells

Cytokines (lymphokines)

Cytokine’s Receptors ( 4 groups)

HGFRTNFRIgR superfam.OthersProduction of inter-cell mediator proteins

Control of Immune response

+ 90 activity reactions

... . ... ... ....

Macrophag

- Cytokines = Hormones

- 1 cell can produces > 1 Cytokine

- many has identical activity

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Cytokines

3. Cytokines mainly secreted by T cells:

4. Growth Factors secreted by lymphocytes:

1. Main cytokines:

2. Cytokines secreted by Macrophage:

TH1: -IL-2, IFN-, TNF-TH2: -IL-4, IL-5, IL-9, IL-10, IL-13

- IL-7, IL-11, IL-14, IL-15, G-CSF (Granulocytes Colony

-Interleukin (IL), Interferon (IFN), Tumor Necrosis

-IL-1, IL-6, IL-12, TNF-

Factor (TNF), Growth Factor (GF), Chemokine

Stimulating Factor), M-CSF (Macrophage Colony Stimu-lating Factor), GM-CSF (Granulocyte Monocyte ColonyStimulating Factor), TGF- (Transforming Growth Fac-tor-)

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InterleukinRegulator of inter-lympgocytes and leukocytes’ inter-actions.

Interleukin

Target cellProducer

IL-1 Macrophage TH2 cell, B cellIL-1 Macrophage TH2 cell, B cell

IL-2 Sel TH1 cell, NK cell T cell, B cell

IL-3 T cell Hematopoetic cell , Stem cellIL-4 TH2 cell T cell, B cell , mast cellIL-5 TH2 cell B cell, T cellIL-6 Fibroblast, T cell B cellIL-7 Stroma cell Lymphocyte (young)IL-8 Macrophage T cell, Neutrophile

IL-9 TH2 cell T cellIL-10 TH2 cell, B cell TH1 cell

IL-11 Stroma cell B cell

IL-12 Macrophage, B cell TH1 cell, NK cell

IL-13 TH2 cell B cell

IL-14 B cell B cell

IL-15 MonoMorphoNuclear cell T cell

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Interferon

Interferon Producer Target cell

IFN- Macrophage Many kinds of cellsIFN Fibroblast Many kinds od cellsIFN TH1 cell, NK cell Macrrophage, Many kinds of cellsIFN Trophoblast Uterus’ cell

TNF

TNF Producer Target cell

TNF- Macrophage Tumor cell

TNF- T cell Tumor cell

GF

= glucoprotein synthesied as a respons of viral infection/ immuneor chemical stimulation

Able to kill tumor cells

Stimulates cells to grow; to guarantee enough cells to survive

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Chemokine

C-X-C C-X-C (eg MIP-1 a & b, MCP, RANTES)(eg IL-8 )

IL-8

Chemotaxis

endothel

fibroblast

hepatocyte

PMN

T cell

Basophile

Chemoattractant

endotoxin

ds RNA virus

IL-1

TNF-

Macrophage

MMN

Lymphocyte

keratinocyte

PMCPRANTES

Chemotaxis

.. ....

...

.. ..

...

..

.......

.....

...

.. ..

...

..

.. ....

...

.. ..

...

..

. .. . ....

.. ... .

. .. . ....

.. ... .

. .. . ....

.. ... .

TNF--

TNF--

IL-1

IL-1

IL-8

IL-8

IL-8

14 proteins acting on inflammation

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Chemokine

IL-8

o Ekspressed CD11a/CD18o Release of granuleo Ourburst of respirationo Release of leukotrien

RIL-8

MIP-1a & MIP-1b

B cell TC cell TCD4+cell

attractattract

IL-1, TNF-a

o Stimulation of respiratory

Note: RANTES = Regulated upon Activation Normal T Expressed & Secreted

MCP

T cell

Activation

RANTES

.. ...

......

.. ..... ....

Chemotaxis

B cell

Mast cellT activated

MO

FibroblastNeutrophile

Monocyte

T cell

Monocyte Fibroblast

Endothel

MonocyteT cell

Eosi-

. .. . ....

.. ... .

IL-8

cell

o Attract & activate monocyte

nophyle

outburst

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IL-1, IL-6, IL-12, TNF-

IL-1

. ..

T cell

MO

Ag-MHC-TCRIL-1

secretion

.T cell

.T cell

IL-1

Ag

PK activated

ceramide Sphingomyelin pathway

jun & NF- activated

Ag

Other transcription factors

IL-4 gen activated

IL-1

IL-1

IL-1

IL-1

IL-2

IL-4

B cell

IL-1 IL-6 IL12 TNF-TNF

. .. . ....

.. ... . . .. . ..

...

. ... .

. .. . ....

.. ... .

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IL-1 systemic effect

Pro-inflammation effect

Cytotoxic effect Metabolic effect

Cell growth effectEfect to leucocyte

Effect on tissue

*Increase of -Collagen synthesis -Chondrocyte’s protease synthesis -Chondrocyte’s plasminogen activator -Bone resorption -PGE2 ‘s fibroblast synthesis

* on -Tumor cell -Pancreatic -cell

*Increase of -Intestine mucous production -Lipoprotein lipase -Transcription of liver metallothionine -Syntheis of Acute Phase Protein

*Increase of -T and B cells chemotactic -Thromboxane’s neutrophile synthesis -Basophile histamine secretion -Eosinophilic degranulation -Chemoattractant -IL-2 production

*Increase of -Fibroblast -Keratinocyte -Mesangial cell -Glia cell *Increase of

-IFN- synthesis -Adherencee molecule expression -Proliferation of vascular plain muscle

IL-1

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IL-6

Differentiation

Differentiation, Proliferation, Aktivation, Production of IL-2

Proliferation

Acute Phase Protein syntheis (assist by IL-1 )

Growth & differentiation.....

+ IL-1 : IgM

+ IL-5 : IgA

+ IL-1 T cell differentiation IL-2 production

IL-2-R

T cell more responsive to IL-2

Sel CD8+

Stimulates haematopoetic colony in bone marrow

Causes febris

IL-6

B cell

T cell

MO

Stroma cell

Liver cell

Fibroblast

Neuron

Keratinocyte

Endothel

IL-2

IL-2

IL-1

IL-1

IL-5

. .. . ....

.. ... .

Diffeerentiation & syntheis of Ig

T cell G0 G1phase induction CD4+ cell proliferation

IL-6-R (CD126/Cw130;dimer glycoprotein one acts as a receptor and the other one as a transducer). Found on resting B cell and recent activated adult B cell.

IL-2

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IL-12

Ag processor

Expression of IL-2-R

Lymphokine Activated Killer

IL12

IL12

MO

B cell

Dendrite cellIL-2

IL-4

IL-2

TNF--

. .. . ....

.. ... .

IFN--

Secretion stimulator ( = feed-back loop)

TH1 cell (G0 G1 ) differentiation

Secretion costimulator &

Inhibitor of TH2 cell function ( eg IgE production by B cell with the help of )

Increaase proliferation of T & NK cells

Increase cytotoxicity associated with

Production inductor of LAK associated with

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TNF-Inflammation mediator

Growth factor

NK cell

Macrophage T cell

Tumor cell Adipocyte B cell Endothel cellOsteoclast

Muscle cell Neutrophile Fibroblast

Hepatocyte

*Destruction *Inhibition lipo- protein lipase

*Growth differentiation

*CD54 expression IL-1 production

*Activation

*increase in catabolisme

*increase in phagocytosis

*proliferation *increase in catabolisme

GenIL-1 IL-6

stimulation

kolagenase

Collagen I inhibition

expression

CD11b/CD18

productionfos myc jun

Transcription factor

Growth of fibroblast

Anti-viral (synergetic with IFN)

TNF- recombinant can expressed MHCcl. II

TNF-

TNF--

TNF--

TNF--

. .. . ....

.. ... .

membrane soluble

Origin, target dan role of TNF-

. .. . ....

.. ... .

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TNF-

Gram negativeVirusTumor cell Microbe toxinC5a

FungusParasiteIL-2IFN-

Steroid

TNF- membrane protein

Soluble TNF-

CD120a(=TNFR-I) TNF-

CD120b(=TNFR-II) TNF-

TNFR-III TNF-

Common cellHepatocyte

Soluble TNF-R

Sol. TNF-R

Sol. TNF-

Activity modulation

CD120a(=TNFR-I)

cytotoxicityanti-viral activityFibroblast proliferation

CD120b(=TNFR-II

Thymocyte proliferation

TNF--

TNF--

TNF-- TNF--

TNF-- TNF--

. .. . ....

.. ... . . .. . ..

...

. ... .TNF--

Signal transduction Receptor through sphingomyelin pathway 1c

TNF-

endotoxin

Septic shock

MalignancyParasite infect.Bacterial infect.

dose <proliferation

production

Ig

Tc cell

activity

proliferation

GM-CSF

M-CSFproduction inflammation

chemotactic

fagocytic

cytolytic

secretion

SO

production

Expression of leucocyte adhesion mol.Expression of pro-coagulantExpression of MHC Class I

. .. . ....

.. ... .

. .. . ....

.. ... .

TNF--

TNF--

TNF--

TNF--

TNF--

TNF--

IL-1

IL-1

IL-1

IL-1TNF--

IL-2

IL-2

IL-2

Sunthesis inhibition for lipid uptake by pre-adipocyte cells

Loss of lipid & body weight, anaemia, protein depletion

IL-1 & IFN- in-crease the cyto-toxic effect of TNF-

The mechanisme of cell lysis induced by TNF- is considered as a command for apoptosis

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(TH1 ><TH2)IL-2 (by TH1)

IL-12IFN-

Ag IL-12activation

B

NK TH

TC

IL-2R

IFN-

function

Ag IL-12

activation

TH1

IL-2R proliferation

B

growth

IgG2a product.

proliferationcytotoxicty

Lymphokine Activated Killer

IFN-

IL-5production

expression

IL-1 secretionIL-6 secretionTNF-secretion

Increased Cytotoxicity

. .. . ....

.. ... .

. .. . ....

.. ... .

IL-2

IL-2

IL-2

IL-2

IL-2

IL-2

IL-2

IL-2

TNF--

TNF--

TNF-

IL12

IL12

IL-5

IFN--

IFN--

IFN--

TNF-

Origin & target of IL-2-2

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IL-2

TH1 cell activated

active T cell B cell

NK cell Macrophage *Proliferation Differentiaiton Increased Ig synthesis

*Proliferation Lymphokines production Increases cytotoxic activity (LAK)

* Activation (LAK)

* Increased cytotoxicity Increased IL-1 secretion

IL-2R

(CD25)CD122)

IL4R & IL7R)

heterotrimer

1) CD122)IL4R & IL7R)

Combination

Signal transduction

2) (CD25) High affinity

3) CD122)IL4R & IL7R)

Low affinity

CD122)IL4R & IL7R)

High affinity4) (CD25)

1000R high affinity / 1000R low affinity

Only high affinity R activation

Soluble Reseptor= sIL-2RCD122)

TK activation

IL-2

=indication of T cell activated

IL-2 Origin & target of IL-2-2 NK cell

. .. . ....

.. ... .

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IFN- (by TH1)

IL-2 T CD8+

TH1 cell

NK cellIFN-

IFN-R =CDw119 (found on many kinds of cell)

IgG2a productionIgG3. IgG1, IgG2a, IgE suppression

IL-4 stimulation of IgG1 & IgE

Suppression of IgM, IgG3, IgG2a, IgG2b

IFN-

T cell MHC Cl. I production IL-2 & IL-2R ( cell)production TH1

IFN-

IL-2

Tc

Proliferationendurance to not lysed, tumor, viral

TH1 cell

Inhibition of IL-4 production

IgE production blocked

IFN-function is para- dox al

IFN-

Ag

loop +

IFN- IFN-

IFN-RFagocytosis increased ADCC

. .. . ....

.. ... .

IL-2

IL-2

IL-4

IFN--

IFN--

IFN--

IFN--

IFN--

IFN--IFN--

IFN--

Immunosuppression increased cell’s

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Origin & target IFN-

NK cell T cell

B cell Macrophage NK cell T cell Viral infected cell *Increased: IgG2a production*Decreased: -proliferation -CD23 expression*Depressed: IgE & IgG1 production*Adverse: IL-4 effect

*Increased: -MHC class I & II ex- pression -Antimicrobe activity -Antitumor activity -TNF- -FcR expression -inhibition- migration

*Increased: -activity

*Induced IL-2 & IL-2R production*Increased or suppressed -delayed type hypersensi- tivity reaction -graft rejection*Increased: -supressor activity -cytotoxicity

*Depressed -viral growth

IFN-

IFN-

. .. . ....

.. ... .

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IFN-

• function

• inhibition

growth

Syncronization of cells in division

• TNF-aR expression

• MHC Cl I expression

...... ....... .. ......

.. ...

..

..

. ..

.

..... ....

..

.IFN-

virus IFN-

MHC cl I MHC cl II

Expression’s regulation

• Ag recognition

Transplantation

T cell

IFN-

Induction ofi MHC kcl II

Rejection activity

transplant

T cell

MMNIFN-

MHC cl IIIGM-CSF

IFN-

GM-CSFIL-3

IFN-

IFN-

IFN-R

Gut’s epithelial secretory component

. .. . ....

.. ... .

. .. . ....

.. ... .

IFN--

IFN--

IFN--

IFN--

IFN--

IFN--

IFN-- IFN--

IFN--IFN-

Prolonged G1 & S+G2 phase

• MHC Cl II expression’s inhibited

• Cell destruction

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TNF-by TH1 = LimfotoksinTc (CD8+) & TH1 (CD4+) cells

TNF- TNF- homolog

Activated TH1 cell

Neutrophile

Tumor cell

B cell

Virus

*Increased activity

* Apoptosis

* Increased -Proliferation -Ig secretion

* Growth inhibition

solubleMembrane’s surface

transformed normal

more susceptibelgrowth ecpression of

active

• SO production

• fagocytosis• cytotoxicity

febris

• leucocyte’s adhesion• procoagulant activation antiviral

IFN-

synergetic

AT

P2’-5’ A synthetase 2-5 A (Adenine trinukleotide)

Cellular Activase Rnase L

Viral mRNA broken

Protein synthesis inhibition

• proliferation• Ig IL-2 induced secretion

TNF--TNF--

TNF-

IFN--

TNF--

TNF-- TNF--

TNF--

TN

F--

TNF--

TNF--

TNF--

TNF--

TNF-

certain Ag

Origin & target TNF-

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IL-4, IL-5, IL-6, IL-10, IL-13 by TH2 cell

TH2 cell

IL-1 Mixed Limphokines

B cell

Ig

IL-4

Active TH2 cell

IL-4

T cellB cell Macrophage

Stem cell

*Increased -Proliferation -Cytotoxic Activity (LAK) -Giant cell formation

*Increased - Proliferation - MHC cl II expression - CD23 expression -IgG1, IgE, IgA secretion

*Increased - Ag presentation - MHC expression - Tumoricidal activity

* Activation

Origin & target of IL-4

. .. . ....

.. ... .

IL-4

IL-4

IL-4

IL-1

Active TH2 cell

. .. . ...... ....

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IL-4

IL-4

B cell

o Growth & differeentiation

G1 S phase

-Thy-1-FcR-CD23

o IgG1, IgA, IgE synthesis

o IgG2b , IgG3 synthesis suppression

IL-4 gen

breakageo IL-5, IL-9, IL-10 not produced

TH2 cell

Tc cell

IL-4

development

Fetal thymocyteIL-4

growth

IL-4o MHC cl II expressiono Ag presentation abilityo Cytotoxic activity

o induction of giant cell formationo stimulator of macrophage deriva-

Thy-1 expression

T cell

o IgR synthesisB cell

o proliferation

o IL-1 secretiono TNF-secretiono IL-6 secretion

><

IFN-

CDw24

R IL-2 & IL-7

(ligand’s binder)

expression. .. . ....

.. ... .

. .. . ....

.. ... .

IL-4

IL-4

IL-4IL-4

IL-4

IL-4

IL-4

IL-4

IL-4

IFN--

IFN--

IFN--

IFN--

IFN--

o Increased expression: - MHC cl II tives

o MHC cl II

components

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IL-5

Stimulation

IL-5 - growth- differentiation IL-5

Active TH2 cell

Eosinophile B cell T cell*Increased -Differentiation -Chemotaxis

*Increased -Proliferation -IgM, IgG, IgA secretion -IL-2R expression & differentiation

*Increased -Cyotoxicity

TH2 cell

B cell

Origin & target of IL-5

IL-5

B cell IgG, IgM, IgA sinthesis

IgE synthesis

IL-5

IL-4

Fce R expression

CD44 R homing

Fc R

CD44

IL-5

IL-2 Tc cell

IL-2R

active

IL-5

Eosinophile precursor

growth differentiation

IL-5

peptide IL-3R

GM-CSFR

IL-5

IL-5

IL-5

IL-5

IL-5

IL-5

IL-5

IL-2

IL-4

* Increased

. .. . ....

.. ... .

*Increased

1c

IL-9

Stimulation

TH2 cell

TH2 cell

TH1 cell

IL-9

growth

IL-9

mast cellIL-3

proliferation

IL-9

B cellIL-4

IgE production

IL-10

TH2 cell

IL-10 =CSIF

Cytokine Synthesis Inhibiting Factor

TH1 cell TH2 cell

Regulation of Cytokines pro-

o IL-1 secretiono IL-12 secretiono TNF- secretion o Reactive O radicals

o Ag presentation through MHC cl II

IL-10

. .. . ....

.. ... .

. .. . ....

.. ... .

IL-9 IL10

IL-9

IL-9

IL-9

IL10

IL10

IL10

IL10

IL-4

IL-3

Stimulation

duction

IL-10 * Supression of

IL-10

o Stmulates IL-IRA production

1c

IL-10

TH1 cell

IL-10

...

..IL-12

inhibits IFN- production

IL-4IL-3

= secundair effect

mast cellproliferation

synergic

B cell

induction of MHC cl II expression increased growth

B cell

TH1 cell

Active Macrophage

IL-10

*Increased - MHC cl II expression - Growth

*Supression - IL-1, IL-12, TNF- , MHC cl. II*Increased - IL-1RA

*Proliferation

*Supressed function

TH1

TH2

1) = function regulation

1)

1)

2) = inhibition

2)IL-4

IgE synthesis

IL-10R structural asso-ciated with IFN--R

IL-10 suppressed proinflammation and immunomodulator cytokines secretion

. .. . ....

.. ....

. .. . ....

.. ... .

IL-3

IL-10

IL-4

IL-4

IL12

IL-2

IFN--

IL10

IL10

IL10

IL10

IL10

IL-2inhibits production

IL-10

Origin & target of IL-10

. .. . ....

.. ... .

. .. . ....

.. ... .

B cell mast cell

Macrophage

2)

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IL-13

TH2 cell

B7

CD28ligation

activated

IL-13

(from active presenting cell)

activated TH2 cell

proliferation IgG4 & IgE differentiation increased secretion

MMN

B cell

NK cell

IL-13

IL-13

IL--2

regulates

IFN-

IL13

IL13

IL13

IL13

IL-2

IFN--

MHC cl II expression CD28 expression FcR suppression

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Growth Factors

fibroblast macrophage T cell Other cellsStroma cell

Stem cell

Monocyte

Hematopoetic cell

young lympho-B cell

M-CSF G-CSF

IL-3 GM-CSF IL-7IL-11

IL-7

proliferation

pre-B cell

thymocyte

T cell proliferation

T CD4+ cell

T CD8+ cell

o induced IL-2 expression

o induced IL-2Ro induced CD71

thymocyte

LAK T cell

inhibitsTGF-

B cellT ell

CDw127CDw127

Monocyte

CDw127 chain is identical with the one found in IL-2R & IL-4R

. .. . ....

.. ... .

IL-3

IL-7

IL-7

IL-7

IL-7

IL-7

IL-7

IL-7

IL-7

IL11

IL-2

cyte

IL-7

IL-7

IL-7

IL-7

IL-7 IL-7

1c

IL-11

IL-11IL-6

growth

B cell

megakaryocyte

thrombocytes

IL-3

hepatocyteAcute phase prot.

IL-14

B cell

Malignant Bcell

T cell

IL-15CD4+ (Sel TH) T cell proliferationCD8+ (Sel Tc) T cell proliferation

MMN LAK

G-CSF

M-CSF

GM-CSF

TNF-IL-1

IL-1

TNF-proliferation

LPS; Fibronektin

PMN/MO/Eos.

Cytotoxicity ADCC

Adhesion & segregation

PMN mobilization & accu-

Fc R,CD11b/18 expression

TumoricidalMHC cl II excretion Macrophage suppression

. .. . ....

.. ... .

. .. . ....

.. ... .

. .. . ....

.. ... .

. .. . ....

.. ... .

IL11

IL11

IL-3

IL14

IL14

IL15IL15

IL-1

IL-1

TNF--

IL-6

TNF--

IL-14

proliferation

Selective multyiplica-

inhibits Ig secretion

tion

IL15binds (CD 122)IL-2R chain

TNF-

G-CSF

pro-genitor granulocyte maturation neutro- phile stimulates SO product-

ion Increased ADCC neu-

trophile

M-CSF

differentiation

cytotoxicity

GM-CSF

Phagocytosis SO,C4,IL-1,IFN-, E2, IL-

IRA production

mulation

SO,CIRA

IL-15IL-15

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TGF-= Glycogen-S-S-protein; Embryonal development; tumorigenesis, wound healing, fibrosis, immune

regulation

T cell B cell

ThrombocyteActive macrophage

T cell

B cell Macrophage *Inhibits -Proliferration -Differentiation -Ig Production*Increases -IgA Production

*Inhibits -Proliferation -Differentiation -IFN-production -Cytotoxicity -MHC cl II expression

*Inhibits -IL-1 Release -Cytotoxicity -Maturation*Increases -Chemotaxis -Activation

thrombocyteMO B cell T cell

TGF-

protease

activeTGF-

binding

secretion

TGF-R1 TGF-R2 TGF-R3 TGF-R4 TGF-R5

Stimulation / Inhibition

. .. . ....

.. ... .

TGF-

Origin & target of TGF-

. .. . ....

.. ... .

. .. . ....

.. ... .

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TGF-

o proliferation

o chemotaxis

o chemotaxis

o chemotaxis

o IL-1 secretiono TNF-secretiono increasez TH cell function

o inhibits IL-1R expression

o inhibits differentiation

o inhibits respiration outbursto inhibits cytotoxicity

o inhibits proliferation

o inhibits proliferation

o inhibits immune function(on chronic diseases)o inhibits Tc cell development

o inhibits LAK cell productiono inhibits NK cell production

GM-CSF IFN- TNF-muc IL-2RMHC cl II

inhibits

o inhibits differentiation

IL--2

o inhibits differentiationo inhibits proliferation

o blocks Ig Light chaino blocks IgG1 & IgM productiono terminates differentiation

LPSo IgA expression

o increases IgA’s Hc changing

IL-5TGF-

IgA Response

o regulates growth

o regulates collagen production

o regulates growth

o regulates fibronectin productiono supresses collagenase poduction

o adherence inhibiti- on to endothel

. .. . ....

.. ... .

IL-2

IL-5TNF--IFN--

TGF-

TGF-

TGF-

TGF-

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Cytokines Receptor

Membrane’s Receptor

LigandTransducer

cell

Groups: HGFR (Haematopeotic Growth Factor Receptor) TNFR (Tumor Necrosis Factor Receptor) Ig R Superfamily Other Receptors

HGFR (Haematopeotic Growth Factor Receptor)

Receptor IL-2 IL-3 IL-5 IL-7 IL-9

GM-CSFG-CSF

IL-3 IL-5 IL-2 IL-4 IL-7Rantai Rantai

Domain ekstraselnya > & ada residu X-Tr-S; Domain membran & domain

IL-4

Binds only 1 ligand

The extracellular domain is big and contains X-Tr-S residue; membranic & cytoplasmic domains are also big and do not contain TK or enzymatic activity

1c

TNFR (Tumor Necrosis Factor Receptor)= transmembran protein type II protein peptide chain & multi-ligands

CD120a, CD120b, CD40, CD27, CD30, fas

B cellT cell

Apoptosis signal

The repertoire domain is rich in Cysteine

Ig R Superfamily

R CDw121 untuk IL-1 & R CD126 untuk IL-6 IL-6IL-1

= its structure is specific R IL2Ra (CD25), R IL-8, R TGF-b dan R IFN-g (CDw119)

On binding, the trimer form aggregates the receptor

= the domain is identical with Ig and many have intrinsic TK activity

Some are proto-oncogen products ( eg fms, kit)

Some contain Ig domain besides HGFR domain

Other Receptors

1c