11-Cytokines new A - Copy yara

8/8/2019 11-Cytokines new A - Copy yara

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CytokinesCytokines


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Definition

Cytokines are a large group of molecules

involved in signaling between cells during

immune response.They are proteins (usually

glycoproteins of low molecular weight.

a)Lymphokines;produced by lymphocytes

b)Monokines;produced by monocytes&macrophages


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Cytokines (Greek cyto-, cell; and -kinos, movement) are any of a

number of small proteins that are secreted by specific cells of the

immune system and glial cells, which carry signals locally between

They are a category]1[cells, and thus have an effect on other cells.

cellularthat are used extensively inmoleculessignalingof

. Theglycoproteins, orpeptides,proteins. They arecommunication

term cytokine encompasses a large and diverse family ofpolypeptide regulators that are produced widely throughout the body

by cells of diverse embryological origin


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Nomenclature

Cytokines have been classed as

,

andinterleukins,

lymphokines, based on their presumedchemokines

function, cell of secretion, or target of

action. Because cytokines are

characterised by considerable redundancy

, such distinctions,pleiotropismand

allowing for exceptions, are obsolete.


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The term interleukin was initially used by

researchers for those cytokines whose presumed

. It is now usedleukocytestargets are principally

largely for designation of newer cytokinemolecules discovered every day and bears little

relation to their presumed function. The vast

.helper cells-Tmajority of these are produced by

The term chemokine refers to a specific class ofcytokines that mediates chemoattraction

) between cells.chemotaxis(


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Actions:

cytokines regulate all important biological

processes as;cell growth,

cellactivation,immunity,tissue repair&wound

healing,fibrosis,haematopoiesis and other

biological functions.some are

chemotactic,named chemokines(asIL8)


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Mode of action:

Cytokines are secreted by certain cells in

response to specific stimuli and they bindto specific receptors on target cells

exerting their effect on these cells.


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Range of action:

Cytokines are produced throughout thebody.in localized areas as joint spaces orlymphoid tissue,they either act on thesame cell,which produced them(autocrineeffect).or on other types of adjacent

cells(paracrine effect).they may gainaccess to circulation,affecting distantcells(endocrine effect).


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Cytokines include theCytokines include the

followings:followings:

(1)Interferons(IFNs)

(2)Interleukins(ILs)

(3)Colony stimulating factors(CSFs) (4)Tumour necrosis factors and

(TNF- and )

(5)Transforming growth factors(TGF )


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Interferons:

They are particularly important in limiting

the spread of certain infections. They include the following types:

Type I IFNs:(IFN- and)

They are structurally related,

and areproduced in response to viruses or nucleic

acids.They have antiviral activity.


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Owing to theiranti proliferative effect

(inhibition of cell growth),they could be

used in rare cancers e.g.renal cancer &hairy cell leukaemia.

In addition they have some immunological

properties.


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Type IIIFN:(IFN- or immune IFN)

It's structurally distinct from type 1,and is

produced by activated T- cells & natural killer

cells(NK).

IFN- has important regulatory functions.It's

the most inducer ofmacrophage activation

&increase antigen presenting cell function. In addition,it has weak antiviral and anti-

proliferative effects


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Interleukins:

This is a large group of cytokines(more than

30)which are produced mainly by T-cells,but

also by mononuclear phagocytes or bytissue cells.Most are involved in directing

other cells to divide and differentiate.

EachIL act on a specific limited group ofcells which express the correct receptors for

that IL.Examples are the following:


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IL-1:

It's produced by many cells,but mostly by

macrophages in response to injury,infection

or antigen.It is the primary mediator of acutephase responses and can induce

inflammatory responses,sleep,fever and

increase(ACTH) release.IL-1 can stimulate

T&B-cells,macrophages,neutrophils and NK

cells.Almost all cells of the body have

receptors forIL-1 and can respond to it.


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IL-2:

The most powerful activator and growth

factor for T-cells,

and stimulate the releaseof IFN-.


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Colony stimulating factors:(CSFs)

They play role in hematopoiesis.

Examples are CSF for granulocytes andmacrophages,platelet generating factor

and erythropoietin.


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Tumour necrosis factors:(TNFs)

TNF-(cachectin) is produced by activated

macrophages,

Th 1,

2 and other somaticcells.whileTNF-(lymphotoxin) is produced

by activated lymphocytes andTh 1.They

have inflammatory,immuno-enhancing and

tumoricidal effect.


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Transforming growth factor :(TGF-)

It's produced by T& B lymphocytes,

macrophages,

platelets and other cells. It acts as growth factor for fibroblasts and

promote wound healing.It has an anti

proliferative effect on many cells and it

dampens immunologically mediated

inflammatory reactions.


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Clinical uses of cytokines:Clinical uses of cytokines:

1- Antiviral: as in the treatment of viral

hepatitis caused by HBV or HCV by IFN-.

2- Antitumour: as antiproliferative intreatment of certain leukaemias&

lymphomas.

3- Antiautoimmune(immunomodulatory):

as in treatment of rheumatoid arthritis by

TNF- inhibitors.


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4- Anti bacterial:

Treatment of resistant tuberculous in

conjunction with antibiotics.

5- Antifungal:

Treatment of resistant fungal

infections in conjunction with antifungal

therapy.


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General characteristics ofGeneral characteristics of

cytokinescytokines

1) Definition:

Molecules involved in signaling betweencells during immune response.

2) Classification:

A-lymphokines. B-monokines.


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3) Mechanism of action:(3 theories)

a-signal transduction &2nd messengerhypothesis;

The receptor for cytokine is a transmembrane protein,on the cytoplasmicaspect, this protein is attatched to anothercomplex protein named G protein.

Cytokine + receptor activation of G protein

transforming ATP to cAMP That inturn activate protein kinase

phosphorylation of cell proteins response.


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b-JAK-STAT system;

JAK: Janus Kinase (named after 2-headed Roman God due to 2 symmetrical

kinase Domains,they associate with

cytoplasmic tails of cytokine receptors


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STAT :Signal Transduction &ActivatedTranscription protein.

Cytokine + receptordimerization of the

receptoractivate JAK-STATactivation ofJAK receptor associated tyrosine kinasephosphorylate STAT.

phosphorylated STAT form multimeric

complexes,activated STAT are transcriptionfactors that translocate to the nucleus toactivate gene transcription.


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c-Caspases pathway;

They are multiple protease enzymescausing intra cellular destruction

Apoptosis


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4)Pleitropy;

They act on wide range of cells.

5)Redundency; More than one cytokine carry on the same

function(overlap effect on target cell).

6)Synergy; they potentiate each other


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7)Intracellular action.

8)act as 1st line of defence.

9)Not Ag specific nor dependent on Ag inits action.

10)They may have autocrine,paracrine or

endocrine effect.


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Assay of cytokinesAssay of cytokines::

1-Bio assay.

2-Ligand bind assay(ELISA &RIA).

3-HPLC chromatography. 4- Immunoaffinity purification.

5-Genocloning :Southern blot of the gene

cloning cytokines. 6-PCR .


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Lymphokines affecting theLymphokines affecting the

function of phagocytesfunction of phagocytes

* MIF :factor that inhibits migration of

macrophages,thus retaining them at the

site of inflammation.

* MAF :factor that activates

macrophage,receptor expression

&increase in microbicidal factors {oxygen

dependent & independent}as well aslysosomal enzymes.


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* chemotactic factor:for many cells

macrophages,PMNL,eosinophils,basophils

& lymphoid chemotactic factor, that bring

them to the site of inflammatory response.


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Lymphokines affecting otherLymphokines affecting other

cells include :cells include :

* Mitogenic factor(lymphocyte

transformation factor) :that recruits

additional lymphocytes &initiates

lymphocytes proliferation.

* B-cell growth &differentiation

factors(BCGF &BCDF):

With other factors,promote B-cell

differentiation Ab production.


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Interferons :Interferons :

They are * antiviral

* antiproliferative

* immunomodulatory

They affect many cells:

macrophages(MAF),

T-cytotoxic,

NK cells &B-cells.


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**TNF ( ,)TNF ( ,)

*Inflammatory by

a) IL-1 &IFN ,

b)fever induction

c) PMNL,macrophages chemotaxis& cytotoxicity

d)acute phase proteins

e)prostaglandins,collagenase


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*immunomodulatory

* tumoricidalby a)vascular thrombosis

b)tumour necrosis

c)caspases(proteases)


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Interleukins:Interleukins:

IL-1;

* Pan inflammatory;

-PMNL (chemotactic ,microbicidal)

-Macrophages (cytocidal,monokines)

-T cells (lymphokines,proliferation) -B cells (lymphokines,Ab production)


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-bone marrow(CSF,haematopoietin)

*act on non lymphoid cells;

-brain fever,anorexia

-liveracute phase proteins

-adrenalsglucocorticoids

-osteoclasts bone resorption

-adipocytes lipolysis

-fibroblasts proliferation .


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,macrophages are produced by1- and IL1-Both IL

. They form ancellsdendriticandfibroblasts,monocytes

of the bodyinflammatory responseimportant part of the

. These cytokines increase the expression ofinfectionagainst

cells to enable transmigrationendothelialonadhesion factors, to sites ofpathogens, the cells that fightleukocytesof

thermoregulatoryhypothalamusset the-infection and re

center, leading to an increased body temperature which

is therefore called an1-. ILfeverexpresses itself as

is also important in the regulation1-. ILpyrogenendogenous production in peripheral tissue has1-. ILhematopoiesisof

(increased sensitivityhyperalgesiaalso been associated with

to pain) associated with fever.


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Clinical significance

) has beenRA1ILantagonist (1-The IL

rheumatoid arthritisapproved for treatment of


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IL-2:

It's not species specific.secreted by T

cells,

& act upon B&T cells -Stimulate proliferation of both B&T cells.

-Induce secretion of other lymphokines.


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IL-3:

A product of T cells &monocytes- Act upon bone marrow stem

cells,simulating CSF.


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IL-4:

-produced by Th2 cells

-act as B-cell stimulating factor

-enhances expression of( MHC classII )Ag

-T cell growth factor

- Ag presenting ability of macrophages

-Augments immune response initiated by Tcells


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IL-5:

Induces growth &differentiation ofactivated B cells.

IL-6:

-stimulates hepatocytes to produce ARP.

-known as B cell differentiation factor 2

-enhances Tc-cells

-potent growth factor for myeloid cells


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IL-7:

act as CSF & proliferation of mature T cells

IL-8:

-mainly chemotactic for PMNL& T cells

-regulate lymphocytic homing&neutrophilic

infiltration

IL-9: -haemopoietic &thymopoietic effect


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IL-10:

-enhances B cell mediated immunity

-inhibit certain T cell responses

-inhibits cytokines production by NK

&macrophages

IL-11:

Arises from bone marrow stromal cells Has synergistic effect on hematopoiesis&

thrombopoiesis


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IL-12:

-arises from B cells & macrophages.

-stimulates Th 1,&supresses Th 2lymphocytes

-enhances production of TNF by T & NKcells

-induces production of IL-6 &synergisewith IL-2,promoting NK activity

-stimulates nieve T cells *


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IL-13:

-arises from Th 2 cells

-similar,but additive to IL-4 effect (humoralIR)

IL-15:

-arises from epithelial cells&monocytes(nonlymphocytic)

-enhances proliferation of activated T cells

-essential forNK survival,development &activation.

-promotes Th 1 responses.


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IL-16:-poduced by CD8 &some CD4

lymphocytes.

- suggested role in T cells anergy IL-17:

-produced by activated memory cells

-targets resting T cellsIL 6

,

IL 8,

G-CSF -stimulates T cell growth & proliferation

,&PMNL differentiation.


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IL-18:

-produced constitutively by keratinocytes&macrophages

-structuraly &functionaly related to IL 1 -induces IFN- production &other

inflammatory mediators

-synergistic with IL-12Th 1 differentiation

(cellularIR) -synergistic with IL-2IL-13 production

(humoral IR)


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SummarySummary

IL-1 &IL-18----------> Pan inflammatory

IL-2,

12,

15,

23-----------> Cell mediatedimmunity.

IL-4,

5,

6,

10,

13 ---------------> Humoralimmunity.

IL-8 -----------------> Chemotaxis .


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IL-3 ,7 ,9 ,11 --------------------->CSF

IL-21 + TNF- ----------------->Anti tumour.

IL-28,29,31 ---------------------->Anti viral

IL-10,35, TGF Suppression


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A cytokine storm, or hypercytokinemia is a

potentially fatal immune reaction consistingcytokinesbetweenpositive feedback loopof a

, with highly elevated levelsimmune cellsand

of various cytokines

SymptomsThe primary symptoms of a

, swelling andfevercytokine storm are high

. In somenauseaandfatigueredness, extreme

cases the immune reaction may be fatal.


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is fightingimmune systemWhen theCause:

, cytokines signal immune cells suchpathogens

to travel to themacrophagesandcells-Tas

site of infection. In addition, cytokines

activate those cells, stimulating them to

produce more cytokines Normally, thisfeedback loop is kept in check by the body.

However, in some instances, the reaction

becomes uncontrolled, and too many immune

cells are activated in a single place.


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. The precise reason for this is not entirely

understood but may be caused by an

exaggerated response when the immunesystem encounters a new and highly

pathogenic invader. Cytokine storms have

potential to do significant damage to body

tissues and organs. If a cytokine storm occurs

, for example, fluids and immunelungsin the

cells such as macrophages may accumulate

and eventually block off the airways,potentially resulting in death


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The cytokine storm (hypercytokinemia) is the

systemic expression of a healthy and vigorous

immune system resulting in the release of

mediatorsinflammatoryknown150more than

, andoxygen free radicals(cytokines,

).coagulation factors


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Both pro-inflammatory cytokines (such as

,1-Interleukin,alpha-Tumor necrosis factor

and Interleukin-6) and anti-inflammatory

and10interleukincytokines (such as

) are elevatedreceptor antagonist1interleukin

of patients experiencing aserumin the

cytokine storm.


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Cytokine storms can occur in a number of

infectious and non-infectious diseases

(GVHD),graft versus host diseaseincluding

(ARDS),acute respiratory distress syndrome

systemic, andsmallpox,avian influenza,sepsis]3[(SIRS).inflammatory response syndrome

Cytokine storm may also be induced bycertain medications.

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11-Cytokines new A - Copy yara