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1. CYTOKINE

2. BY: MALIHA FIRDOUS
Table of Contents
1.Cytokines
2.Production of cytokines
3.Working of cytokines
4.Properties of cytokines
5.Resemblance to hormones
6.Nomenclature of cytokines
7.Types of Actions cytokines perform
8.Types of cytokine
9.Receptors on cytokines
10. Bio-Functions of cytokines
11. Therapeutic uses of cytokines
12. References

3. CYTOKINES
Cytokines is the general term for a large group of molecules involved in signaling
between cells during immune responses.
Cytokines or immune-cytokines
were initially used to separate the
immune-modulatory proteins, also
called immune-transmitters, from
other growth factors that modulate
proliferation and bioactivities of
non-immune cells.
Cytokines are basically a diverse group of non antibody, low molecular weight,
small, soluble, secreted proteins that are produced in response to an antigen and
function as chemical messengers for regulating the innate and adaptive immune
systems.

4. PRODUCTION OF CYTOKINES
Cytokines are produced by virtually all cells
involved in both natural and specific immunity
innate and adaptive immunity, but especially they
are produced by T- helper lymphocytes. They are
synthesized and released by WBC’s and tissue
macrophages. The activation of cytokine-
producing cells triggers them to synthesize and
secrete their cytokines. They are produced during immune and inflammatory
responses and secretion of these mediators is transient and closely regulated.
WORKINGOF CYTOKINES
Cytokines are released by cytokine
producing cells either into the blood
circulation or directly into tissues as
they get a stimulus of the presence of
target cell. These cytokines locate
target cells and interact with receptors
on the target cells by binding to them.
This interaction triggers or stimulated
specific responses by the target cells.
PROPERTIES OF
CYTOKINES
1) Cytokines are small secreted proteins
which mediate and regulate immunity,

5. inflammation, and hematopoiesis.
2) They generally (although not always) act over short distances and short time
spans and at very low concentration.
3) They are pleiotropic means that a particular cytokine can act on a number of
different type of cells rather than a single type.
4) They are redundant means that they have the ability that a number of
different cytokines can carry out same functions.
5) They are multifunctional means that the same cytokine can regulate a
number of different functions.
6) Some of the cytokines are antagonistic in the way that one cytokine
stimulates a particular function whereas another cytokine inhibits that same
function.
7) Some are synergistic where in two different cytokines have greater effects in
combination than either of the two would by themselves.
8) The affinity between cytokines ad their receptor is very high. Because of
high affinity, cytokines can mediate biological effects at Pico-molar
concentration.
RESEMBLANCE TO HORMONES
Cytokines resemble hormones in their biological activity & systemic level, for
example, inflammation, systemic inflammatory responsesyndrome, acutephase
reaction, wound healing, and the neuroimmune network.
Cytokines act on a wider spectrumof target cells than hormones. The major
feature distinguishing cytokines fromhormones is the fact that cytokines are not
produced by specialized cells organized in specialized glands. Cytokines area
secreted protein which means that their expression site does not predict where
they exert their biological function. Several cytokines primary structure was found
to be identical with enzymes. Cytokines do not possessenzymatic activities
although there is a growing list of exceptions. Other cytokines require proteolytic
activation.
NOMENCLATURE OF CYTOKINES

6. Cytokines have been classified on the basis of their presumed function, cell of
secretion or their target of action because cytokines are characterized by
considerable redundancy and pleiotropism.
 Interleukin was previously used for those cytokines whose presumed targets
are white blood cells (leukocytes). It is now used for designation of newer
cytokine molecules and bears little relation to their presumed function. The
majority of these cytokines are produced by T-helper cells.
 Lymphokines: They are produced by activated T-cells, primarily bt T-helper
lymphocytes.
 Monokines:They are produced exclusively by mononuclear phagocytes or
monocytes.
 Interferon: They are involved in antiviral responses.
 Colony stimulating factors:They supportthe growth of cells in semisolid
media.
 Chemokines: They mediate chemo-attraction (chemo taxis) between cells.
They are those cytokines which have chemo-tactic activities i.e. are related with
chemical based activities.
ACTIONS OF CYTOKINES
• AUTOCRINE:
In it cytokine binds to receptoron the same
cell that had secreted it that means its target
cell is that same cell from which it had been
secreted.
• PARACRINE:
In it cytokine binds to receptors on nearby cells.
• ENDOCRINE:
In it cytokine binds to receptors on cells
present in distant parts of the body by
moving through blood circulation.

7. TYPES OF CYTOKINES
 INTERLEUKINS:
Produced by suchleukocytes as lymphocytes and monocytes, interleukins are
glycol-proteins involved in the activation and differentiation of immune cells. They
also play an important role in the proliferation, migration, maturation, pro- and
anti-inflammatory activities, as well as adhesion of these cells.
Together with interleukin receptors, interleukins belong to a super family (IL super
family) that is made up of proteins. While it's easy to generalize the functions of
these cytokines, this is largely dependent on the type of interleukins. Currently,
over 43 members of this super family have been identified (IL-1 to IL-43).
Like some of the other cytokines, interleukins are made up of proteins. Typically,
this is in responseto invading pathogens/antigens. While high volumes may be
produced depending on the type of interleukins and the invading organism, a small
quantity of the molecule is required to activate biological effects.
While a good number of interleukins elicit an action on the same cells that
produced them, some can enter the bloodstream which allows them to be
transported and elicit biological effects on distant cells in the body. For instance,
while IL-2 elicits biological effects on T cells (which produced them), IL-1 can
enter the bloodstream and reach the central nervous system.
Some of the other properties of interleukins include:
 Synthesis is a self-limited process
 Stimulate up-regulatory and down-regulatory mechanisms
 Have redundant functions in the body - Given interleukins can cause
different effects on various types of cells
 Can influence the synthesis and functioning of other interleukins
As already mentioned, different types of interleukins have different
functions. The following are some of the functions of a few of these
molecules:
· IL-1 - Indirectly stimulates immune responses via various effector proteins and
other cytokines.

8. · IL- 2- Interleukin 2 plays an important role in growth regulation of T cells.
· IL-3 - Stimulates the production of myeloid progenitor cells by
hematopoietic stem cells. However, an interaction between IL-3 and IL-7 results in
the production of lymphoid progenitor cells from hematopoietic stem cells.
· IL-4 - Interleukin 4 is involved in a number of biological processes ranging
from the proliferation of T cells and B cell stimulation to humoral and adaptive
immunity. Moreover, it contributes to the production of a number of cells
including dendritic cells, Th1 cells as well as Interferon Gamma cells.
· IL-5 - Like Il-4 and IL-13, interleukin 5 is also involved in stimulating the
growth of B-cells. However, it is also involved in increased secretion of
immunoglobin as well as activation of eosinophils.
· IL-6 - In addition to being the primary mediator in such illnesses as fever,
interleukin 6 has also been shown to overcome the blood-brain barrier in activating
the expression of Prostaglandin E2 in the hypothalamus which results in body
temperature change.
Some of the other common interleukins include:
 IL-8 - involved in the induction of chemo taxis
 IL-10 - involved in inflammation as well as regulation of the immune
responses
 IL-18 - involved in both immune responses in the body(innate and adaptive
responses)
 IL-33 - involved in immune responses of Th2 (e.g. parasitic infections)
 INTERFERONS (IFNS)
Interferon is a family consisting of widely expressed signaling proteins. Like the
other cytokines, interferons are also released by cells of the host's immune system
in responseto such invading organisms as bacteria and viruses.
They are also released to respond to tumor cells in some organisms. Currently,
three types of interferons have been identified. These include Type I IFNs, Type II
IFN, and Type III IFNs.
Type I IFNs (Type I Interferons)

9. Type I interferons are divided into two major groups that include IFN-α and IFN-β
as well as a number of additional isotopes that include, among others, IFN-κ, IFN-
ω, and IFN-δ. While only one type of IFN-β exists, IFN-α is further divided into
several subtypes including IFN-α1, IFN-α2, IFN-α3, IFN-α4, IFN-α5, and IFN-α6
among others.
In the body, the productionof Type I IFNs is dependent on the presence of
various microorganisms. For instance, following a viral infection, a signaling
pathway that causes phosphorylation, dimerization as well as passage of the
interferon responsefactor 3 (IRF3) to the nucleus is activated.
Along with a number of other transcription factors, IRF3 activates that synthesis of
IFN-β gene that binds to the interferon receptors located on the surface of an
infected cell which ultimately results in interferon response.
Through these responses, interferons help in the recruitment of effector molecules
that protectthe cells against infections (bacterial and viral infections). For instance,
by activating the production of natural killer cells and macrophages, interferons
contribute to the destruction of both the viruses and infected cells.
* Cells responsible for the productionof IFN-α and IFN-β are collectively known
as interferon-producing cells (IPCs) or natural interferon-producing cells.
IFN productionmay be presented as follows:
Functions of Type I interferons (IFN-α and IFN-β) are generally divided into three
main categories that include:
· Influence resistance to viral replication in cells - This is achieved through the
destruction of viral mRNA required for viral replication as well as inhibiting the
translation of viral proteins.
· Promote Ligand increase - Type I interferons promote an increase in ligands to
the receptors of NK cells which in turn stimulates them to attack and lyses infected
cells.
· Activate the destruction of infected cells by NK cells and macrophages.
* Given that Type 1 interferons also plan a role in immunosuppressive activities,
they are also used for the purposes oftreating autoimmune diseases.
Type II Interferon

10. Type II interferon is made up of a single cytokine known as IFN-y. This cytokine
is largely produced byTHI T cells, activated Natural Killer cells as well as CD8+
T cells. Unlike cytokines of Type I interferons, the gene responsible for encoding
the Type II cytokine is located in chromosome12 in human beings.
Moreover, IFN-y has been shown to be different from the other interferons in that
it does not producea potent antiviral effect. Rather, it largely serves to activate
effector cells.
While it's produced byT cells in adaptive immunity (following an increase in
antigen), IFN-y is produced bynatural killer cells in the innate immune system and
acts as a mediator. In the adaptive immune system, increased productionof IFN-y
is promoted by IL-12 and IL-18.
On the other hand, IL-4 and IL-10 correspond to the negative regulators involved
in its production. Apart from T cells, B cells and professional antigen-presenting
cells have also been shown to play a role in the production of IFN-y.
Like cytokines of Type I interferons, IFN-y also contributes to cell responseto
viral infections. Forinstance, by activating and causing the induction of MHC
(major histocompatibility complex), IFN-y has been shown to play a role in long-
term controlof viral infections in cells. In the process, it also coordinates the
transition from innate to adaptive immunity.
Some of the other functions of IFN-y include:
· Macrophage activation - By promoting the activation of macrophages, IFN-y
contributes to phagocytic and pinocytic activities of these cells and thus contributes
to microbial destruction.
· Inhibiting cell growth - In the body, IFN-y has also been shown to inhibit cell
growth and thus promote apoptosis.
Type III interferons
Unlike Type II interferon that only consists of a single cytokine, Type III is divided
into three important cytokines that include IFN-λ1, IFN-λ2, and IFN-λ3. Also
known as IL-28 (a & b) and IL-29, Type III interferons are characterized by a
structure that is more similar to proteins of the family IL-10.
On the other hand, the signaling pathway of these cytokines has been shown to
resemble that of Type I interferons in that they are dependent on the actions of
IRFs and NF-kB. While these cytokines also regulate a number of similar functions
as Type I interferons, they primarily function in mucosal epithelial cells (as well as

11. liver cells in human beings) where they serve to protectthem from viral infections.
 CHEMOKINES
Chemokines are a type of protein cytokine that play an important role in chemo
taxis. As such, there may be signals that guide certain immune cells to the affected
site.
Currently, about 50 Chemokines have been identified. They are divided into four
families based on the location of N-terminal cysteine residues in their three-
dimensional structure.
These include:
CC Chemokines - CC Chemokines are characterized by two adjacent cysteine
(known as CC chemokine ligands) located near the N-terminus of the structure. Of
the 27 CC Chemokines (CCL-1 to CCL-28) that have been identified so far, only 6
have 6 cysteine while the rest are characterized by four of these molecules.
For the most part, CC Chemokines are chemo tactic for monocytes with a few
being chemo tactic for lymphocytes. As such, they promote the
movement/migration of these cells to the affected site.
CXC Chemokines - As compared to CC chemokine, CXC Chemokines are
generally characterized by two cysteine located at the N-terminus. Here, the
cysteine is separated by an amino acid. So far, seventeen of these cytokines have
been identified. They are chemo tactic for neutrophils and thus promote the
movement/migration of these cells to the affected site.
CXCL8 (also known as IL-8) is one of the most common CXC Chemokines. It is
responsible for the recruitment of neutrophils as well as maintaining inflammatory
reactions.
With regards to neutrophils recruitment, CXC Chemokines have to interact with
the appropriate receptors located on the surface of neutrophils. For instance, by
interacting with CXCRI and CXCR2 receptors located on the surface of
neutrophils, ELR-positive CXC Chemokines are able to recruit them to action.
C-Chemokines - Currently, only two of CC Chemokines have been identified.
These include the XCL1 and XCL2 chemokines which are characterized by two
cysteine, one of which is located at the N-terminus while the other is located
downstream.

12. CX3C chemokines - Like the other chemokines, the CX3C chemokines also
contain two cysteine at the N-terminus. However, the cysteine are separated by
three amino acids. CX3CL1, which is the only chemokine in this group, is not only
a chemo attractant, but also a cell adhesion molecule. To serve its function,
CXCL1 has to bind to CX3CR1, a receptor located on the cell that expresses it.
Chemokine receptors - These include the G-protein-coupled receptors (consisting
of 7-transmembrane α-helical segments) and atypical receptors are expressed on all
white cells involved in immunity. While each type of the receptors can bind to
different chemokines (within the same family), a single chemokine can also bind to
several receptorsubtypes. Regardless, according to studies, a majority of these
chemokines have been shown to display receptor specificity.
While regulating leukocytes through the peripheral lymphoid tissues is one of the
functions of chemokines, their primary role entails recruiting such cells as
neutrophils and T cells to the site of inflammation. Here, the migration of the
leukocytes to the affected site is achieved by the stimulation of actin filaments.
Some of the other important functions of chemokines include:
 Promoting angiogenesis (CXC chemokines)
 Wound healing (CXC chemokines)
 Development of various non-lymphoid organs
 Priming certain T cells
* For the most part chemokines are relatively small in size, ranging between 8 and
14 kDa.
* To achieve their functions, chemokines have to be released in large amounts so
as to establish a concentration gradient necessary to influence cell migration.
 TUMOR NECROSIS FACTOR
Tumor Necrosis Factor(TNF) consists of a group of proteins involved in a number
of physiological and pathological processes.Currently, about 40 members of the
super family (TNF) have been identified with TNF-α and TNF-β being the most
notable examples.
Some of the other members of TNF include:

13.  CD40 Ligand
 OX40 Ligand
 FAS Ligand
 GITR Ligand
TNF-alpha (TNF-α)
Also known as TNF or TNFSF2, TNF-α is a multifunctional cytokine involved in
such processesas apoptosis and coagulation among others. In human beings, TNF-
α gene are located on chromosome6. This allows the cytokine to be expressed and
produced by suchimmune cells as macrophages, monocytes and T cells in
responseto invading pathogens or the presence of cytokines like IFN-y.
Some of the main characteristics of TNF-α include:
· Following activation of macrophages and other cells, TNF-α is synthesized as a
26-kD nonglycosylated type II membrane protein.
· Two types of TNFα that include mTNFα and sTNFα.
· Due to adipose tissue expression, TNF-α is sometimes referred to as an adipostat.
Functions of TNF-α
As mentioned, TNF-α is a multifunctional cytokine that ranges from immune roles
to programmed cell death.
Immune function - Like the other cytokines, TNF-α plays an important role in
immunity. In particular, TNF-α attracts certain immune cells to the affected site by
stimulating the expression of adhesion molecules by vascular endothelial cells.
This makes it possible for immune cells to adhere to blood vessel walls and
successfully migrate to the infected site and destroy invading pathogens (bacteria
and viruses).
Induces the production of chemokines that are involved in inflammatory
responses - These cytokines guide immune cells to the affected site.
Apoptosis - TNF-α promotes the programmed cell death of tumor cells by
promoting the recruitment of proteins involved in death signaling.
Biological functions - When produced in large amounts, TNF-α has been shown to
induce reduced blood pressure or shockduring such events as severe infections. In

14. some cases, however, a high concentration of this cytokine results in low blood
sugar concentration as well as intravascular thrombosis.
TNFβ - Also known as Lymphotoxin, TNFβ is a type II transmembrane protein.
The expression of this cytokine is stimulated by activated lymphocytes. With
regards to functions, TNFβ is a potent mediator involved in various immune and
inflammatory responses that have similarities to those of TNF-α.
Like TNF-α, TNF-β is also involved in the following processes:
 Apoptosis
 Coagulation
 Cell proliferation and differentiation
CYTOKINE RECEPTORS
Cytokine receptors are cell surface receptors that bind specifically to
cytokines and transduce their signals, including chemokine
receptor, interleukin receptor, interferon receptor, tumor necrosis factor
receptor (TNF receptor), colony-stimulating factor receptor (CSF
receptor), growth factor receptors and TGF-beta super family receptors .
The patterns of expression of cytokine receptors are a product of
differentiation and provide for changes in physiological regulation. These
cytokine receptors enable cells to communicate with the extracellular
environment by responding to signals generated in the vicinity or in other
parts of the organism. Thus, the initial binding of cytokines to their receptors
is a key event that occurs rapidly, at very low cytokine concentrations, is
usually virtually irreversible, and leads to intracellular changes resulting in a
biologic response. The biologic response can vary between cytokine
receptors and from cell to cell but in general it involves gene expression,
changes in the cell cycle, and release of mediators such as cytokines
themselves.
The classification of cytokine receptors based on their three-dimensional structure
has been given:

15.  Immunoglobulin (Ig) super family, which are ubiquitously present throughout
several cells and tissues of the vertebrate body, and share structural
homology with immunoglobulin (antibodies), cell adhesion molecules, and
even some cytokines. Examples: IL-1 receptor types.
 Hemopoietic Growth Factor (type 1) family, whose members have certain
conserved motifs in their extracellular amino-acid domain. The IL-2 receptor
belongs to this chain, whose γ-chain (common to several other cytokines)
deficiency is directly responsible for the x-linked form of Severe Combined
Immunodeficiency (X-SCID).
 Interferon (type 2) family, whose members are receptors for IFN β and γ.
 Tumor necrosis factors (TNF) (type 3) family, whose members share
a cysteine-rich common extracellular binding domain, and includes several
other non-cytokine ligands like CD40, CD27 and CD30, besides the ligands on
which the family is named.
 Seven transmembrane helix family, the ubiquitous receptor type of the
animal kingdom. All G protein-coupled receptors (for hormones and
neurotransmitters) belong to this family. Chemokine receptors, two of which
act as binding proteins for HIV (CD4 and CCR5), also belong to this family.
 Interleukin-17 receptor (IL-17R) family, which shows little homology with
any other cytokine receptor family. Structural motifs conserved between
members of this family include: an extracellular fibronectin III-like domain, a
transmembrane domain and a cytoplasmic SERIF domain. The known members
of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-
17RE.
BIO-FUNCTIONS OF CYTOKINES
 They stimulate development of cellular and humeral immune response.
 They induce inflammatory response.
 They regulate hematopoiesis i.e. formation of blood cellular components.
 They control cellular proliferation and differentiation.
 They help in Healing wounds, tissue maintenance and repair.
 Embryogenesis and organ development involves important mediators called
Cytokines.
 Cytokines play a key role in neuro-immunological, neuro-endocrinological,
and neuro-regulatory processes.

16.  Cytokines also regulate cell cycle, differentiation, migration, cell survival &
cell death, and cell transformation.
THERAPEUTICUSES OF CYTOKINES
I. Interferons are used in the treatment of viral diseases and cancer.
II. Several cytokines are used to enhance T-cell activation in
immunodeficiency diseases, e.g. IL-2, IFN-y etc.
III. IL-2 and Lymphokines activating killer cells are used in the treatment
of cancer.
IV. Anti-TNF antibodies are used in treating septic shocks.
V. Anti-IL-2R𝛼 is used in treatment of adult T-cell leukemia.
REFERENCES
• https://www.slideshare.net/MMASSY/lecture-cytokines
• https://www.verywellhealth.com/what-are-cytokines-189894
• https://www.onlinebiologynotes.com/cytokines-properties-receptors/
• https://www.sinobiological.com/research/receptors/cytokine-receptors
• https://en.wikipedia.org/wiki/Cytokine