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Cytok

ines
Ishaque PK
PondichErry university

Introduction

The immune system recognizes the presence of


pathogens by several proteins that bind to
molecules secreted by the pathogen or carried on
their surface.

The cells responsible for these immune responses


include:
a)
c)
e)
g)

B-Cells
b) T-Cells
Macrophages
d) Neutrophils
Basophils
f) Eosinophils
Endothelial cells
h) Mast cells

These cells have distinct roles in the immune


system and communicate with other immune
cells by cytokines, which control proliferation,

Overview

The development of an effective immune response


involves lymphoid cells, inflammatory cells, and
hematopoietic cells.

The complex interactions among these cells are


mediated by a group of proteins collectively designated
cytokines
to
denote
their
role
in
cell-to-cell
communication.

Cytokines / immunocytokines (Greek, cyto =cell &


kinos =movement) are low molecular weight regulatory
proteins or glycoproteins secreted by white blood cells
and various other cells in the body in response to a
number of stimuli.

Properties

Cytokines bind to specific receptors


on the membrane of target cells,
triggering
signal-transduction
pathways that ultimately alter gene
expression in the target cells.
The cytokines and their fully
assembled receptors exhibit very
high affinity for each other and
deliver intracellular signals.
The cytokines and their receptors
exhibit very high affinity for each
other, with dissociation constants
ranging from
10 10 to 10 12 M.
Because their affinities are so high,
cytokines can mediate biological
effects at picomolar concentrations.

A particular cytokine may


bind to receptors on the
membrane of the same
cell that secreted it,
exerting autocrine action.

It may bind to receptors


on a target cell in close
proximity to the producer
cell, exerting paracrine
action.

In a few cases, it may


bind to target cells in
distant parts of the body,
exerting endocrine action

Cytokines
exhibit
the
attributes of:
Pleiotropy,
Redundancy,
Synergy,
Antagonism,
cascade
induction,
which permit
them
to
regulate
cellular
activity in a
coordinated,

Two or more cytokines that mediate similar functions are said


to be redundant.
Cytokine synergism occurs when the combined effect of two
cytokines on cellular activity.
antagonism that is, the effects of one cytokine inhibit or offset

Nomenclature

Interleukins - that act as mediators between


leukocytes. The vast majority of these are produced
byT-helper cells.

Lymphokines- produced by lymphocytes.

Monokines- produced exclusively by monocytes.

Interferons- involved in antiviral responses.

Colony Stimulating Factors- support the growth of


cells blood cell .

Chemokines

mediate

chemoattraction

Classification

Cytokines have been classified on the basis of their


biological responses into pro or anti-inflammatory
cytokines, depending on their effects on
immunocytes .

Major cytokines include:

Lymphokines
Interleukins (IL)
Monokines
Interferons (IFN)
colony stimulating factors (CSF)
Tumor Necrosis Factors-Alpha and Beta (TNF)

Other.
# Type-1 & Type-2
Type-1 cytokines are cytokines produced by Th1 T-helper
cells.
Include IL-2 (IL2), IFN-gamma (IFN-G), IL-12 (IL12) & TNFbeta (TNF-b).
Type-2 cytokines are those produced by Th2 T-helper
cells.
Include IL-4 (IL4), IL-5 (IL5), IL-6 (IL6), IL-10(IL10), and IL13 (IL13).
# Mediators of natural immunity:
TNF-, IL-1, IL-10, IL-12, type I interferons (IFN- and IFN), IFN-, and chemokines.
# Mediators of adaptive immunity:
IL-2, IL-4, IL-5, TGF-, IL-10 and IFN-.

# Classified into family groups according to the


types of secondary and tertiary structure.

IL-6 (IL6), IL-11 (IL11), CNTF (C-NTF), LIF, OSM


(Oncostatin-M), EPO (Erythropoietin), G-CSF (GCSF), GH
(Growth Hormone), PRL (Prolactin), IL-10 (IL10), IFNalpha (IFN-A), IFN-beta (IFN-B) form long chain 4 helix
bundles.
IL-2 (IL2), IL-4 (IL4), IL-7 (IL7), IL-9 (IL9), IL-13 (IL13), IL3 (IL3), IL-5 (IL5), GM-CSF (GMCSF), M-CSF (MCSF), SCF,
IFN-gamma (IFNG) form short chain 4 helix bundles.
Beta foil structures are formed by IL1-alpha (IL1A), IL1beta (IL1B), aFGF (FGF-acidic), bFGF (FGF-basic), INT-2
(INT2), KGF (FGF7).
EGF, TGF-alpha (TGF-A), Betacellulin (BTC), SCDGF,
Amphiregulin, HB-EGF, form EGF-like antiparallel betasheets.

Lymphokines

Lymphokinesare a subset ofcytokinesthat are


produced by a type ofimmune cellknown as
alymphocyte.
They are protein mediators typically produced byT
cellsto direct the immune system response by
signalling between its cells.
Lymphokines have many roles, including the
attraction
of
other
immune
cells,
includingmacrophagesand other lymphocytes, to
an infected site and their subsequent activation to
prepare them to mount an immune response.
Circulating lymphocytes can detect a very small
concentration of lymphokine and then move up the
concentration gradient towards where the immune

Lymphokinesinclude:

Colony-stimulating factors(csfs), includingGM-CSF.


Interferons(ifns) IFN.
InterleukinsIL-1toIL-8,IL-10, IL-13.
Macrophage inflammatory protein-1 beta (mip-1).
Neuroleukin (lymphokine product of lectinstimulated T cells).
Osteoclast-activating factor.
Platelet-derived growth factor (PDGF).
Transforming growth factor beta (tgf).
Tumour necrosis factor-alpha (cachectin) (TNF).
Tumour necrosis factor-beta (tnf,lymphotoxin
,LT).

Actions of lymphokinesinclude:
Activates B cells, inhibitsmacrophagefunction :IL10.
Activationofneutrophils,eosinophils, andmonocyte
/macrophages:GM-CSF.
Bone resorption : osteoclast activating factor
Bone marrowgrowthanddifferentiationof
immune cells :IL-3
B cellgrowthanddifferentiation:IL-4.
B
celldifferentiation,activatessomemicrophages(pm
n) :IL-5
Co-stimulatorofT cells, inducesgrowthinB
cells:IL-6
Inflammation, fever,catabolismand
cachexia,activationof somemicrophages:TNF

Monokine

Amonokineis
a
type
ofcytokineproduced
primarily bymonocytesandmacrophages.

Examples
includeinterleukin
necrosis factor-alpha.

Other
monokines
include
alpha
and
betainterferon, andcolony stimulating factors.

1andtumor

Interleukeins

avarietyof naturally occuringpolypeptidesthat


are
thefamilyofcytokineswhichaffectfunctionsofsp
ecificcell typesand are found insmallquantities.
They are secreted regulatoryproteinsproduced
bylymphocytes,monocytesand
various
othercelltypesand
are
released
bycellsinresponsetoantigenicand
nonantigenicstimuli. Consist of IL1 to IL37.
IL-1 activates Antigen Presenting Cells and CD4+
lymphocytes; affects the differentiation of the BCells and T-Cells and other immunocompetent cells
and takes part in the regulation of production of
other cytokines and GM-CSF (GranulocyteMacrophage Colony-Stimulating Factor).

IL-3 is a potent activator of hemopoietic cells. It


stimulates NK-Cells and acts as a synergist with IL-4
during the induction of CD4+ lymphocyte activation
process.
IL-5 stimulates the production and maturation of
eosinophils during inflammation.
IL-7 is known as the growth factor of the immature
B-Cells and T-Cells. It induces apoptosis of tumor
cells and causes differentiation of cells from a
subgroup of acute myeloblastic leukemia.
IL-8 acts as a chemotactic factor that attracts
neutrophils, basophils and T-Cells to sites of
inflammation.
IL-9 stimulates the excretion of IL-2, IL-4, IL-6, IL-11,
and takes part in a stimulation of cytotoxicity of Tkillers and NK-Cells, inducing apoptosis.
IL-10 acts to repress secretion of pro-inflammatory

IL-11 is a pro-inflammative factor, which regulates


the functions of B-Cells and T-Cells. It also takes part
in the induction of various killer cells activities and
acts as an autocrine factor for the proliferation of
megacaryocytes.
IL-12 is a critical linker between the innate immunity
and adaptive immunity, capable of TH1 (T Helper
Type-1) differentiation and IFN-Gamma release by TCells and NK cells.
IL-13 is very sensitive to monocytes and B-Cells. IL13 does not act on T-Cells but inhibits the
proliferation of leukemic pro-B-Cells.
IL-14 is a BCGF (B-Cell Growth Factor) and the hyper
production
of
this
interleukin
enables
the
progression of NHL-B (B-cell Type Non Hodgkin's
lymphoma).
IL-15 is analogous to IL-2 and increases the anti-

IL-17 is principally produced by CD4+ T-Cells, which


induces granulopoiesis via GMCSF. It takes part in
the regulation of many cytokines and can reinforce
the antibody dependant tumor cell destruction.
IL-18 acts as a synergist with IL-12, especially in the
induction of IFN-Gamma production and inhibition of
angiogenesis.
IL-19 is produced mainly by monocytes and is
similar to IL-10 in its function. It is stimulated by
GM-CSF
and
regulates
the
functions
of
macrophages, and also suppresses the activities of
TH1 and TH2.
IL-21 executes an important role in the regulation of
hematopoiesis and immune response. It promotes a
high production of T-Cells, fast growth and
maturation of NK-Cells and B-Cells population.
IL-22 is produced by activated T-Cells in acute

Interferons
Interferons play an important role in the first
line of defense against viral infections.
They are part of thenon specific immune
systemand are induced at an early stage in
viral infection before the specific immune
system has had time to respond.
Interferons are made by cells in response to
an appropriate stimulus, and are released into
the surrounding medium; they then bind to
receptors on target cells and induce
transcription ofapproximately 20-30 genes in
the target cells, and this results in an antiviral state in the target cells.

Types of interferon

Based on the type of receptor through which they


signal, human interferons have been classified into
three major types.
1. Interferon type I:
All type I IFNs bind to a specific cell surface
receptor complex known as theIFN receptor
(IFNAR) that consists
ofIFNAR1andIFNAR2chains. The type I
interferons present in humans areIFN-,IFNandIFN-.
2. Interferon type II:
Binds toIFNGRthat consists
ofIFNGR1andIFNGR2chains. In humans this
isIFN-.
3. Interferon type III:

Chemokines

Chemokines are a family of smallcytokines,


orSignaling proteinssecreted bycells.
Their name is derived from their ability to induce
directed chemotaxisin nearby responsive cells; they
arechemotactic cytokines.
Proteins are classified as chemokines according to
shared structural characteristics such as small size
(they are all approximately 8-10kilodaltonsin size),
and the presence of fourcysteineresidues in
conserved locations that are key to forming their 3dimensional shape.

Classification

Chemokines have been classified into four main


subfamilies:
1.
2.
3.
4.

CXC Chemokines (contain CXL1 to CXL17)


CC Chemokines (contain CCL1 to CCL28)
CX3C Chemokines (contain CX3CL1)
XC Chemokines (contain XCL1 & XCL2)

All of these proteins exert their biological effects by


interacting
withG
protein-linkedtransmembrane
receptorscalledchemokine
receptors,
that are
selectively found on the surfaces of their target cells.

Colony Stimulating Factor

Colony-stimulating factors(CSFs) are secreted


glycoproteinsthat bind to receptor proteins on the
surfaces
ofhemopoietic
stem
cells,
thereby
activatingintracellular signalingpathways that can
cause the cells toproliferateanddifferentiateinto a
specific kind ofblood cell.
The colony-stimulating factors are soluble, in
contrast to other, membrane-bound substances of
thehematopoietic microenvironment.
They
transduce
byparacrine,endocrine,
orautocrinesignaling.
Colony-stimulating factors include:
CSF1-Macrophage
colony-stimulating
factor(MCSF)
CSF2-Granulocyte macrophage colony stimulating

Tumor necrosis factors

Tumor necrosis factors(or theTNF family) refer to a


group ofcytokinesthat can cause cell death
(apoptosis).
Nineteen cytokines have been identified as part of
the TNF family on the basis of sequence, functional,
and structural similarities.They include:
Tumor necrosis factor(TNF), formerly known as TNF
or TNF alpha, is the best-known member of this
class. TNF is amonocyte-derivedcytotoxin that has
been implicated in tumor regression,septic shock,
andcachexia.
Lymphotoxin-alpha,
formerly
known
asTumor
necrosis factor-beta(TNF-), is a cytokine that is
inhibited byinterleukin 10.
Lymphotoxin-alpha(LT-alpha)
andlymphotoxin-

T cell antigen gp39 (CD40L), a cytokine that seems


to be important in B-cell development and activation.
CD27L, a cytokine that plays a role in T-cell
activation. It induces the proliferation of costimulated T cells and enhances the generation of
cytolytic T cells.
CD30L, a cytokine that induces proliferation of T
cells.
FASL, a cytokine involved in cell death.
4-1BBL, an inducible T cell surface molecule that
contributes to T-cell stimulation.
OX40L, a cytokine that co-stimulates T cell
proliferation and cytokine production.
TNF-related apoptosis inducing ligand (TRAIL), a
cytokine that induces apoptosis.

Cytokine Receptors

Cytokine Receptors Fall Within Five Families


Receptors for the various cytokines are quite
diverse structurally, but almost all belong to one
of five families of receptor proteins:
Immunoglobulin super family receptors
Class I cytokine receptor family (also known as
the hematopoietin receptor family)
Class II cytokine receptor family (also known as
the interferon receptor family)
TNF receptor family.
Chemokine receptor family.

References

Immunology by Kuby

http://pathmicro.med.sc.edu/mobile/m.immuno13.htm

http://www.rndsystems.com/research_topic.aspx?
r=14

http://www.ebioscience.com/resources/pathways/cyto
kine-network.htm

http://www.prospecbio.com/Cytokines

http://en.wikipedia.org/wiki/Cytokine