cytokines description

1. M.Prasad Naidu
MSc Medical Biochemistry,
Ph.D.Research Scholar

2. CYTOKINES
CYTOKINES
Cytokines are small secreted proteins which mediate and
Cytokines are small secreted proteins which mediate and
regulate immunity, inflammation, and hematopoiesis. They are
regulate immunity, inflammation, and hematopoiesis. They are
produced in response to an immune stimulus.
produced in response to an immune stimulus.
Cytokine is the general term for a large group of molecules
Cytokine is the general term for a large group of molecules
involved in signaling between cells during immune responses.
involved in signaling between cells during immune responses.
All cytokines are proteins, some with sugar molecules
All cytokines are proteins, some with sugar molecules
attached (glycoproteines).
attached (glycoproteines).
They are synthesized and released by white blood cells and
They are synthesized and released by white blood cells and
tissue macrophages.
tissue macrophages.

3.  They are proteins, peptides or glycoproteins in nature.
They are proteins, peptides or glycoproteins in nature.
 Cytokines stimulate or suppress the functional activity of
Cytokines stimulate or suppress the functional activity of
lymphocytes, monocytes, neutrophils, fibroblast and
lymphocytes, monocytes, neutrophils, fibroblast and
endothelial cells.
endothelial cells.
 They modulate the function of other cell types. Long
They modulate the function of other cell types. Long
known to be involved in cellular immune response, these
known to be involved in cellular immune response, these
products have additional effects that play important roles
products have additional effects that play important roles
in both acute and chronic inflammation.
in both acute and chronic inflammation.
 200 different human cytokines was have been identified
200 different human cytokines was have been identified

4. TERMS AND DEFINITIONS
TERMS AND DEFINITIONS:
:
 Cytokines generated by mononuclear phagocytes
Cytokines generated by mononuclear phagocytes
are often called ‘Monokines’ and those by activated
are often called ‘Monokines’ and those by activated
lymphocytes are reffered to as ‘Lymphokines’.
lymphocytes are reffered to as ‘Lymphokines’.
 Additionally, both monocytes and macrophages
Additionally, both monocytes and macrophages
produce cytokines such as CSF’s, which stimulate
produce cytokines such as CSF’s, which stimulate
the growth of immature leukocytes in the bone
the growth of immature leukocytes in the bone
marrow.
marrow.

5. GENERAL PROPERTIES
GENERAL PROPERTIES
 Cytokines are produced during immune and inflammatory
Cytokines are produced during immune and inflammatory
responses and secretion of these mediators is transient and
responses and secretion of these mediators is transient and
closely regulated.
closely regulated.
 Cytokine effects are often redundant and these proteins can
Cytokine effects are often redundant and these proteins can
influence the synthesis or action of other cytokines.
influence the synthesis or action of other cytokines.
 Cytokines mediate their effects by binding to specific
Cytokines mediate their effects by binding to specific
receptors on target cells and the expression of cytokine
receptors on target cells and the expression of cytokine
receptors can be regulated by a variety of exogenous and
receptors can be regulated by a variety of exogenous and
endogenous signals.
endogenous signals.

6. Cytokines induce their effects in two ways
Cytokines induce their effects in two ways
1) they act on the same cell that produces them (autocrine
1) they act on the same cell that produces them (autocrine
effect)
effect)
e.g: IL-2 produced by activated T cells promotes T- cell
e.g: IL-2 produced by activated T cells promotes T- cell
growth
growth
2) they affect other cells in their vicinity (paracrine effect)
2) they affect other cells in their vicinity (paracrine effect)
e.g: IL-7 produced by marrow stromal cells promotes the
e.g: IL-7 produced by marrow stromal cells promotes the
differentiation of B- cell progenitors in the marrow
differentiation of B- cell progenitors in the marrow
 Many classic growth factors act as cytokines and
Many classic growth factors act as cytokines and
conversely many cytokines have growth promoting
conversely many cytokines have growth promoting
properties.
properties.

7. The main sets of cytokines are
The main sets of cytokines are
Interleukins
Interleukins
Interferons
Interferons
Tumour necrosis factors
Tumour necrosis factors
Growth factors
Growth factors
Colony stimulating factors
Colony stimulating factors
Chemokines
Chemokines

8. INTERFERONS (IFNs)
INTERFERONS (IFNs)
 Interferons
Interferons (
(IFN
IFNs) are proteins made and released by
s) are proteins made and released by
helper CD4+ T lymphocytes, as well as through
helper CD4+ T lymphocytes, as well as through
monocytes, macrophages, and endothelial cells in
monocytes, macrophages, and endothelial cells in
response to the presence of pathogens — such as
response to the presence of pathogens — such as
viruses, bacteria or parasites — or tumor cells.
viruses, bacteria or parasites — or tumor cells.
 IFNs belong to the large class of glycoproteins known as
IFNs belong to the large class of glycoproteins known as
cytokines. Although they are named after their ability to
cytokines. Although they are named after their ability to
"interfere" with viral replication within host cells
"interfere" with viral replication within host cells

9.  They are produced very early in infection
They are produced very early in infection
and are the first line of resistance to a
and are the first line of resistance to a
great many viruses
great many viruses
 These are particularly important in
These are particularly important in
limiting the spread of certain viral
limiting the spread of certain viral
infections. One group of interferons
infections. One group of interferons
(IFNα and IFNβ) is produced by cells
(IFNα and IFNβ) is produced by cells
which have become virally infected
which have become virally infected

10. Types of interferon
Types of interferon
Based on the type of receptor human interferons have been
Based on the type of receptor human interferons have been
classified into two major types.
classified into two major types.
Interferon type I:
Interferon type I:
 All type I IFNs bind to a specific cell surface receptor
All type I IFNs bind to a specific cell surface receptor
complex known as the IFN-α receptor. The type I
complex known as the IFN-α receptor. The type I
interferons present in humans are IFN-α, IFN-β and IFN-
interferons present in humans are IFN-α, IFN-β and IFN-
ω
ω.
.
Interferon type II:
Interferon type II:
 In humans this is IFN-γ
In humans this is IFN-γ

11. FUNCTIONS
FUNCTIONS
 they activate immune cells, such as natural killer cells
they activate immune cells, such as natural killer cells
and macrophages
and macrophages
 they increase recognition of infection or tumor cells by
they increase recognition of infection or tumor cells by
up-regulating antigen presentation to T lymphocytes
up-regulating antigen presentation to T lymphocytes
and
and
 they increase the ability of uninfected host cells to
they increase the ability of uninfected host cells to
resist new infection by virus. Certain host symptoms,
resist new infection by virus. Certain host symptoms,
such as aching muscles and fever, are related to the
such as aching muscles and fever, are related to the
production of IFNs during infection.
production of IFNs during infection.

13. INTERLEUKINS (ILs)
INTERLEUKINS (ILs)
 These are a large group of cytokines produced mainly by T
These are a large group of cytokines produced mainly by T
cells, although some are also produced by mononuclear
cells, although some are also produced by mononuclear
phagocytes (or) by tissue cells.
phagocytes (or) by tissue cells.
 The interleukins were first described as signals for
The interleukins were first described as signals for
communication between white blood cells (leuk- from
communication between white blood cells (leuk- from
leukocytes).
leukocytes).
 Currently, it is well-known that these molecules are
Currently, it is well-known that these molecules are
produced and used as signalling molecules in many cells
produced and used as signalling molecules in many cells
of the body, in addition to immune cells.
of the body, in addition to immune cells.

14.  They have a variety of functions, but most of them are
They have a variety of functions, but most of them are
involved in directing there cells to divide and differentiate
involved in directing there cells to divide and differentiate
 Interleukins represent a broad family of cytokines that are
Interleukins represent a broad family of cytokines that are
made by hematopoietic cells and act primarily on
made by hematopoietic cells and act primarily on
leukocytes
leukocytes
 There are currently 35 well-known interleukins, however,
There are currently 35 well-known interleukins, however,
there are many more to be found and characterized.
there are many more to be found and characterized.

15. TUMOUR NECROSIS FACTORS (TNF)
TUMOUR NECROSIS FACTORS (TNF)
Tumor necrosis factors
Tumor necrosis factors (or the
(or the TNF-family
TNF-family) refers to a
) refers to a
group of cytokines family that can cause cell death.
group of cytokines family that can cause cell death.
 TNF acts via the TNF Receptor (TNF-R) and is part of the
TNF acts via the TNF Receptor (TNF-R) and is part of the
extrinsic pathway for triggering apoptosis.
extrinsic pathway for triggering apoptosis.
 TNF interacts with tumor cells to trigger cytolysis or cell
TNF interacts with tumor cells to trigger cytolysis or cell
death.
death.

16. Types:
Types:
 Tumor necrosis factor-alpha (TNF-α) is the most
Tumor necrosis factor-alpha (TNF-α) is the most
well-known member of this class, and
well-known member of this class, and
sometimes referred to when the term "tumor
sometimes referred to when the term "tumor
necrosis factor" is used.
necrosis factor" is used.
 Tumor necrosis factor-beta (TNF-β), also known
Tumor necrosis factor-beta (TNF-β), also known
as lymphotoxin is a cytokine that is induced by
as lymphotoxin is a cytokine that is induced by
interleukin 10
interleukin 10

17. COLONY STIMULATING FACTORS
COLONY STIMULATING FACTORS
(CSFs)
(CSFs)
 Colony-stimulating factors
Colony-stimulating factors (CSFs) are secreted
(CSFs) are secreted
glycoproteins which bind to receptor proteins on the
glycoproteins which bind to receptor proteins on the
surfaces of hemopoietic stem cells and thereby activate
surfaces of hemopoietic stem cells and thereby activate
intracellular signaling pathways which can cause the cells
intracellular signaling pathways which can cause the cells
to proliferate and differentiate into a specific kind of blood
to proliferate and differentiate into a specific kind of blood
cell
cell
 These are primarily involved in directing the division and
These are primarily involved in directing the division and
differentiation of bone marrow stem cells, and the
differentiation of bone marrow stem cells, and the
precursors of blood leucocytes
precursors of blood leucocytes

18. TYPES:
TYPES:
 CSF1
CSF1 - macrophage colony-stimulating factor
- macrophage colony-stimulating factor
 CSF2
CSF2 - Granulocyte macrophage colony-
- Granulocyte macrophage colony-
stimulating factors (also called GM-CSF and
stimulating factors (also called GM-CSF and
sargramostim)
sargramostim)
 CSF3
CSF3 - Granulocyte colony-stimulating factors
- Granulocyte colony-stimulating factors
(also called G-CSF and filgrastim)
(also called G-CSF and filgrastim)

19. GROWTH FACTROS (GF)
GROWTH FACTROS (GF)
 A
A growth factor
growth factor is a naturally occurring substance
is a naturally occurring substance
capable of stimulating cellular growth, proliferation and
capable of stimulating cellular growth, proliferation and
cellular differentiation.
cellular differentiation.
 Growth factors typically act as signaling molecules
Growth factors typically act as signaling molecules
between cells and they are important for regulating a
between cells and they are important for regulating a
variety of cellular processes.
variety of cellular processes.
e.g:
e.g:
Epidermal growth factor (EGF)
Epidermal growth factor (EGF)
Fibroblast growth factor (FGF)
Fibroblast growth factor (FGF)
Granulocyte-colony stimulating factor (G-CSF)
Granulocyte-colony stimulating factor (G-CSF)
Nerve growth factor (NGF)
Nerve growth factor (NGF)

20. CHEMOKINES:
CHEMOKINES:
 This large group of chemotactic cytokines direct
This large group of chemotactic cytokines direct
movement of cells around the body, from the
movement of cells around the body, from the
blood stream into tissues and to the appropriate
blood stream into tissues and to the appropriate
location within each tissue.
location within each tissue.
 Some of the chemokines also activate cells to
Some of the chemokines also activate cells to
carry out particular functions.
carry out particular functions.
 Chemokines are cytokines that share the ability
Chemokines are cytokines that share the ability
to stimulate leukocyte movement (chemokinesis)
to stimulate leukocyte movement (chemokinesis)
and directed movement (chemotaxis) and are
and directed movement (chemotaxis) and are
particularly important in inflammation.
particularly important in inflammation.

21. CYTOKINE RECEPTORS
CYTOKINE RECEPTORS
Cytokine receptors fall into four families
Cytokine receptors fall into four families
1) Type I receptors
1) Type I receptors
2) Type II receptors
2) Type II receptors
3) Type III receptors
3) Type III receptors
4) Type IV receptors
4) Type IV receptors

22. TYPE I RECEPTORS:
TYPE I RECEPTORS:
 The largest family of cytokine receptors is Type I
The largest family of cytokine receptors is Type I
receptor superfamily. It is characterized by an
receptor superfamily. It is characterized by an
extracellular region of structural homology
extracellular region of structural homology
approximately 200 amino acids long.
approximately 200 amino acids long.
 Receptors for cytokines such as IL-2, IL-3, IL-4,
Receptors for cytokines such as IL-2, IL-3, IL-4,
IL-5, IL-6, IL-7, IL-9, IL-12, G-CSF and GM-CSF
IL-5, IL-6, IL-7, IL-9, IL-12, G-CSF and GM-CSF
belong to this family.
belong to this family.

23. TYPE II RECEPTORS:
TYPE II RECEPTORS:
 The Type II family of related cytokine receptors
The Type II family of related cytokine receptors
can be considered part of the immunoglobulin
can be considered part of the immunoglobulin
superfamily and contains receptors for all IFN
superfamily and contains receptors for all IFN
types as well as IL-10 and M-CSF
types as well as IL-10 and M-CSF
TYPE III RECEPTORS:
TYPE III RECEPTORS:
 TNF family cytokines bind to Type III cytokine
TNF family cytokines bind to Type III cytokine
receptors which all have multiple cysteine-rich
receptors which all have multiple cysteine-rich
repeats of about 40 amino acids in the
repeats of about 40 amino acids in the
extracellular domain
extracellular domain.
.

24. TYPE IV:
TYPE IV:
 Receptors for IL-1α and β are representative of
Receptors for IL-1α and β are representative of
the Type IV cytokine receptor family.
the Type IV cytokine receptor family.
Regardless of these subtypes, cytokine
Regardless of these subtypes, cytokine
receptors have several common characteristics.
receptors have several common characteristics.
They usually consist of two or more subunits, and
They usually consist of two or more subunits, and
receptors for different cytokines may even share
receptors for different cytokines may even share
common subunits.
common subunits.

26. MECHANISMS OF CELL ACTIVATION
MECHANISMS OF CELL ACTIVATION
 The binding of a cytokine to its appropriate receptor sets
The binding of a cytokine to its appropriate receptor sets
off a cascade that leads to induction or inhibition of
off a cascade that leads to induction or inhibition of
transcription of a number of cytokine regulated genes.
transcription of a number of cytokine regulated genes.
 This occurs via a chain of protein-protein recognition
This occurs via a chain of protein-protein recognition
events leading to binding of diverse trancription factors to
events leading to binding of diverse trancription factors to
DNA .
DNA .
 Cytokines initiate intracellular signals through ligand-
Cytokines initiate intracellular signals through ligand-
induced aggregation of receptor components.
induced aggregation of receptor components.
 Cytokine binding can cause hetero or homo-dimerization
Cytokine binding can cause hetero or homo-dimerization
of receptors or trimerization depend on particular family.
of receptors or trimerization depend on particular family.

29. Rheumatoid Arthritis
Rheumatoid Arthritis
 RA is a chronic systemic inflammatory disorder that may
RA is a chronic systemic inflammatory disorder that may
affect many tissues and organs but principally attacks the
affect many tissues and organs but principally attacks the
joints.
joints.
 An auto immune reaction in which T cells play the pivotal
An auto immune reaction in which T cells play the pivotal
role is widely held to be responsible for the chronic
role is widely held to be responsible for the chronic
destructive nature of RA.
destructive nature of RA.
 Once an inflammatory synovitis has been initiated by an
Once an inflammatory synovitis has been initiated by an
exogenous agent.
exogenous agent.

30. T- cells, mainly CD4+ memory cells appear within the
T- cells, mainly CD4+ memory cells appear within the
affected joints early early in the development of RA
affected joints early early in the development of RA
Soon the endothelial cells of synovial capillaries are activated
Soon the endothelial cells of synovial capillaries are activated
with the expression of ICAM-1
with the expression of ICAM-1
Leading to further attachment and transmigration of other
Leading to further attachment and transmigration of other
inflammatory cells
inflammatory cells
This sequence is further enhanced by release of IL-1, TNF-
This sequence is further enhanced by release of IL-1, TNF-α
α
and IFN-
and IFN-γ
γ
Activated CD4+ cells simultaneously activate monocytes,
Activated CD4+ cells simultaneously activate monocytes,
macrophages and promote the release of monokines and
macrophages and promote the release of monokines and
activated B cells with antibody production in affected joints
activated B cells with antibody production in affected joints

31.  TNF
TNF-
- α
α and have induces resorption of cartilage and
and have induces resorption of cartilage and
bone bystimulating release of collagenases from synovial
bone bystimulating release of collagenases from synovial
cells.
cells.
 Up regulates expression of adhesion molecules
Up regulates expression of adhesion molecules
(ICAM-1) which inhibits synthesis of proteoglycans in
(ICAM-1) which inhibits synthesis of proteoglycans in
cartilage
cartilage
 Stimulates fibroblasts via platelet derived growth factor.
Stimulates fibroblasts via platelet derived growth factor.

32. MULTIPLE MYELOMA
MULTIPLE MYELOMA
Multiple myeloma is a plasma cell cancer that originates
Multiple myeloma is a plasma cell cancer that originates
in the bone marrow and is characterized by involvement of
in the bone marrow and is characterized by involvement of
the skeleton at multiple sites.
the skeleton at multiple sites.
 The proliferation and differentiation of myeloma cells
The proliferation and differentiation of myeloma cells
seem to be dependent on several cytokines most notably
seem to be dependent on several cytokines most notably
‘IL-6’
‘IL-6’
 Serum levels of this cytokine are increased in patients
Serum levels of this cytokine are increased in patients
with active disease.
with active disease.

33.  IL-6 seems to be produced by tumorous plasma cells
IL-6 seems to be produced by tumorous plasma cells
themselves as well as by fibroblasts and macrophages in
themselves as well as by fibroblasts and macrophages in
the surrounding stroma.
the surrounding stroma.
 In addition to causing the growth of myeloma cells,
In addition to causing the growth of myeloma cells,
cytokines also mediate bone destruction by acting as
cytokines also mediate bone destruction by acting as
osteoclast activating factors.
osteoclast activating factors.
(TNF-
(TNF-β
β, IL-1, IL-6 and M-CSF)
, IL-1, IL-6 and M-CSF)

34. CYTOKINE THERAPY
CYTOKINE THERAPY

35.  Non specific stimulation or inhibition of particular
Non specific stimulation or inhibition of particular
components of the immune system may sometimes be of
components of the immune system may sometimes be of
benefit.
benefit.
 The best results have been obtained with cytokines and
The best results have been obtained with cytokines and
among these interferon-
among these interferon-α
α (IFN-
(IFN- α
α) is the most widely used
) is the most widely used
mainly for it’s antiviral properties.
mainly for it’s antiviral properties.
 The most striking clinical effect of a cytokine has been that
The most striking clinical effect of a cytokine has been that
of G-CSF in restoring bone marrow function after anti
of G-CSF in restoring bone marrow function after anti
cancer therapy.
cancer therapy.

36.  Interferon beta-1a and interferon beta-1b are used to treat
Interferon beta-1a and interferon beta-1b are used to treat
and control multiple sclerosis, an autoimmune disorder.
and control multiple sclerosis, an autoimmune disorder.
 Interferon therapy is used (in combination with
Interferon therapy is used (in combination with
chemotherapy and radiation) as a treatment for many
chemotherapy and radiation) as a treatment for many
cancers. This treatment is most effective for treating
cancers. This treatment is most effective for treating
hematological malignancy; leukemia and lymphomas
hematological malignancy; leukemia and lymphomas
including hairy cell leukemia, chronic myeloid leukemia,
including hairy cell leukemia, chronic myeloid leukemia,
nodular lymphoma, cutaneous T-cell lymphoma.
nodular lymphoma, cutaneous T-cell lymphoma.
 Both hepatitis B and hepatitis C are treated with IFN-α,
Both hepatitis B and hepatitis C are treated with IFN-α,
often in combination with other antiviral drugs
often in combination with other antiviral drugs

37.  Administered intranasally in very low doses, interferon is
Administered intranasally in very low doses, interferon is
extensively used in Eastern Europe and Russia as a
extensively used in Eastern Europe and Russia as a
method to prevent and treat viral respiratory diseases
method to prevent and treat viral respiratory diseases
such as cold and flu.
such as cold and flu.
 IFN therapy causes immunosuppression, in particular
IFN therapy causes immunosuppression, in particular
through neutropenia and can result in some infections
through neutropenia and can result in some infections
manifesting in unusual ways.
manifesting in unusual ways.
 The discovery that the β chemokines RANTES, MIP
The discovery that the β chemokines RANTES, MIP
(macrophage inflammatory proteins) suppress HIV-1.
(macrophage inflammatory proteins) suppress HIV-1.

38. CYTOKINE INHIBITORS
CYTOKINE INHIBITORS
 Cytokine inhibitors can be used for severe
Cytokine inhibitors can be used for severe
or chronic inflammatory conditions.
or chronic inflammatory conditions.
 Various ways of inhibiting TNF and IL-1
Various ways of inhibiting TNF and IL-1
have proved valuable in rheumatoid
have proved valuable in rheumatoid
arthritis and more controversially in septic
arthritis and more controversially in septic
shock and severe malaria.
shock and severe malaria.
e.g:
e.g:
Cyclosporin A; Pentamidine.
Cyclosporin A; Pentamidine.