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Cytokines
Xiaojian Wang
Institute of Immunology
Zhejiang University
[email protected]
Introduction to cytokines
Cytokines are small soluble
proteins that mediate immune and
inflammatory reactions and are
responsible for communications
between leukocytes or between
leukocytes and other cells via
binding the receptor.
是除免疫球蛋白和补体的另一类特
异性免疫效应物质
• Cytokines work by binding to
a target cell. Therefore, for
a cytokine to have an effect,
two things have to occur:
– The cytokine needs to be
present there
– The target cell needs to
have a receptor on its
surface
• Therefore, regulation can
occur at either step.
Nomenclature

According to their source
1) Lymphokine
2) Monokine

According to their function
1) Colony stimulating factor
2) Interleukin
3) Interferon
4) Tumor necrosis factor
5) Growth factor
6) Chemokine
Manner of action
1) Autocrine: IL-2
Th
2) Paracrine : IL-12 DC
3) Endocrine: IL-1, TNF-
Th
Th
Under certain circumstances (e.g. septic shock), large
amounts of CKs (such as TNF-) are produced, they
may be active distant from their site of secretion.
Manner of action
Cytokines
1. General Properties of Cytokines
2. Functional Categories of cytokines
3.
4.
5.
6.
Cytokine receptors
Biologic function of Cytokines
Cytokine related diseases
Therapeutic Use of cytokines
1. General Properties
1.1. The actions of cytokines are often pleiotropic and
redundant;
1.2. Cytokines often influence the synthesis and actions
of other cytokines ;
1.3. Cytokine actions may be local and systemic ;
1.4. Cytokines initiate their actions by binding to
specific membrane receptors on target cells;
1.5. The cellular responses to most cytokines consist of
changes in gene expression in target cells, resulting
in the expression of new functional protein in the
target cells.
1.1 The actions of cytokines are often
pleiotropic and redundant
One cytokine can target different target cells
1.1 The actions of cytokines are often
pleiotropic and redundant
Different cytokines can exert similar effect
Cytokine
Network
1.2 Cytokines often influence the actions of
and synthesis of other cytokines;
Cytokines can work together or against each other
1.2 Cytokines
often influence
the actions and
the synthesis of
other cytokines
(Cascade effect)
One cytokine can
induce another
cytokine and so
on…….
1.3 Cytokine actions may be local and/or systemic
1.4
Cytokines initiate their
actions by binding to
specific
membrane
receptors on target cells.
1.5 The cellular responses to
most cytokines consist of
changes in gene expression
in target cells, resulting in
the expression of new
functional protein in the
target cells
General Properties
1.Pleiotropism
2.Redundancy
3.Synergy
4.Antagonism
5.Network
2. Functional Categories of cytokines
CKs are classified into 6 functional categories
2.1
2.2
2.3
2.4
2.5
2.6
Interleukines
Interferons
Colony Stimulating Factors
TNF family
Chemokines
Transforming Growth Factors
2.1 Interleukins (IL)
1.Cytokines produced by leukocytes and act on leukocytes
The term interleukine, (inter-) as a means of communication,
(-leukin) deriving from the fact that many of these proteins
are produced by leukocytes and act on leukocytes.
2. The interleukins are produced by a wide variety of body cells.
The function of the immune system depends in a large part on
interleukins,
The majority of interleukins are synthesized by helper CD4+ T
lymphocytes, as well as through monocytes, macrophages, and
endothelial cells. They promote the development and
differentiation of T, B, and hematopoietic cells. And rare
deficiencies of a number of them have been described, all
featuring autoimmune diseases or immune deficiency.
Interleukin, IL
IL 1～38
IL-2（T cell growth factor）
IL-4（ B cell growth factor ,Th2 type）
IL-6（ Th2 type ）
IL-8（belongs to chemokine）
IL-10（Th2 type）
IL-11（stimulator of platelet）
IL-12（Th2 type）
IL-2
IL-4
2.2 Interferons (IFNs)
Interferons (IFNs) are natural cell-signaling proteins produced by the
cells of the immune system to challenges such as viruses, parasites and
tumor cells.
Groups
Type I IFN: IFN- and IFN-
The major source is leukocytes (PDC), fibroblasts and virus
infected cells.
Help prevent the spread of virus to uninfected cells.
Type II IFN: IFN-
IFN- is produced by activated T cells and NK cells. Its main
function is immune regulation.
IFN-
的 抗 病 毒 作 用
病毒
抑制病
毒复制
病毒复制
IFN-诱导蛋白
诱导刺激
信号转导
胞核
胞核
IFN-
2.3 Colony-stimulating factor
Colony-stimulating factors (CSFs) are secreted glycoproteins which
bind to receptor proteins on the surfaces of hemopoietic stem cells
and thereby activate intracellular signaling pathways which can cause
the cells to proliferate and differentiate into a specific kind of blood
cell (usually white blood cells）。
2.3 Colony-stimulating factor
The name “colony-stimulating factors” comes from the method by which
they were discovered. Hemopoietic stem cells were cultured in semi solid
matrix which prevents cells from moving around, so that if a single cell starts
proliferating, all of the cells derived from it will remain clustered around the
spot in the matrix where the first cell was originally located, and these are
referred to as "colonies." It was therefore possible to add various substances
to cultures of hemopoietic stem cells
and then examine which kinds of
colonies (if any) were "stimulated" by them.
The substance which was found to stimulate formation of colonies of
macrophages, for instance, was called macrophage colony-stimulating factor,
for granulocytes, granulocyte colony-stimulating factor, and so on.
2.4 Tumor necrosis factors
• TNF was originally identified (and was so named) as a substance
that can cause the necrosis of tumors in vivo.
• TNF- and TNF-
TNF- is produced by LPS-stimulated mononuclear phagocytes
and activated T cells. Involved in inflammation.
TNF- is also termed lymphotoxin (LT), and is produced mainly
by activated T cells.
2.5 Chemokines
Chemokines are a family of small cytokines,
or proteins secreted by cells. Their name is
derived from their ability to induce
directed chemotaxis in nearby responsive
cells; they are chemotactic cytokines.
Chemokines
share
structural
characteristics such as small size (all of
them are all about 8-10 kilodaltons in size),
and all of them have four cysteine residues
in conserved locations that are key to
forming their 3-dimensional shape.
2.5 Chemokines
About 50 different members.
2
lymphotactin
28
1
17
2.6 Transforming growth factor
(TGF)
Transforming growth factor (sometimes referred to as Tumor
growth factor, or TGF) is used to describe two classes of
polypeptide growth factors, TGFα and TGFβ.
TGFα is upregulated in some human cancers. It is produced in
macrophages, brain cells, and induces epithelial development.
TGFβ exists in three known subtypes in humans, TGFβ1, TGFβ2,
and TGFβ3. These are upregulated in Marfan's syndrome and
some
human
cancers,
and
play
crucial
roles
in
tissue
regeneration, cell differentiation, embryonic development, and
regulation of the immune system.
Pleiotropic effects of TGF-β on leukocytes. All leukocytes produce and
respond to TGF-β. The yin-yang symbol illustrates the fact that TGF-β
exerts both stimulatory and inhibitory effects on immune cells
3. Cytokine Receptors
3.1
Five families
Immunoglobin domain Receptors in this family has the
immunoglobin domain named after the immunoglobulin
molecules
This receptor family have conserved amino acid sequence motifs in the
extracellular domain consisting of four positionally conserved cysteine
residues (CCCC) and a conserved sequence of tryptophan-serine-( any
amino acid)- tryptophan-serine (WSXWS,where X is the nonconserved
amino acid). The receptors for all the cytokines classified as
hematopoietins belong to the class I cytokine receptor family, which
also is called the hematopoietin receptor family.
The class II cytokine receptors possess the conserved CCCC motifs, but lack
the WSXWS motif which is present in class I cytokine receptors. Initially only
the three interferons, were thought to be ligands for these receptors.
However, recent work has shown that receptors for the IL-10 ,IL19 are also
members of this group.
Tumor necrosis factor receptors (TNFRs) are cytokine receptors that
binds TNFs (TNF).
They were also called death receptors since they can transduce signals
lead to cell death,
Chemokine receptors are receptors of chemokines. There have been 19 distinct
chemokine receptors described in mammals. They each have a 7 transmembrane
(7TM) structure and couple to G-Protein for signal transduction within a cell,
making this kind of receptor belong to a large protein family of G protein-coupled
receptors. Following interaction with their specific chemokine ligands, chemokine
receptors trigger a flux in intracellular calcium (Ca2+) ions (calcium signaling). This
causes cell responses, including the onset of a process known as chemotaxis that
traffic the cell to a desired location within the organism.
3.2 Multi-subunit receptor and common
receptor subunit
• Multi-subunit receptor
one for cytokine binding
another for cytokine signaling
• Common receptor subunit
There is same receptor subunit for cytokine
signaling among the different cytokine receptors. e.g.
IL-2R
The same receptor subunit for cytokine signaling among the
different cytokine receptors. e.g. IL-2R
Another feature common to most of the hematopoietin (class I cytokine)
is multiple subunits, often including one subunit that binds specific
cytokine molecules and another that mediates signal transduction.
3.3 Soluble cytokine receptors
• Is the extracellular part of the receptor
• Functions
1) antagonist of CKs: competitively bind to CK
2) delivery tools of CKs
3) index of diagnosis and prognosis of diseases: sIL2R
4. Cytokines have numerous functions.
Mediators and regulators of Innate Immunity
Mediators and regulators of adaptive immunity
Stimulators of hematopoiesis
The innate immunity comprises the cells and mechanisms that defend the
host from infection, in a non-specific manner. Innate immune systems
provide immediate defense against infection, but does not confer longlasting or protective immunity to the host.
The adaptive immune system is composed of highly specialized, systemic
cells and processes that eliminate or prevent pathogenic challenges. It can
recognize and remember specific pathogens and confer long-lasting or
protective immunity to the host. It is adaptive immunity because the
body's immune system prepares itself for future challenges.
4.1 Main Cytokines in innate immunity
抗细菌作用： TNF, IL-1,IL-6, IL-8
抗病毒作用： IFNa/b IFN-Y, IL-12, MCP
TNF
Interleukin-1
Interleukin-12
Type I interferons
Interleukin-10
Interferon-γ (IFN-γ):
TNF
Mediator of acute inflammatory response to gramnegative bacteria and other infectious microbes.
Mainly produced by mononuclear phagocytes
(Macrophage stimulated with LPS);
Can be membrane protein or
released (trimer)
Biological Actions of TNF
In the low quantities, TNF
recruit
neutrophils
and
monocytes to sites of infection
and activate these cells to
eradicate microbes;
Large amount of TNF can cause
systemic
clinical
and
pathological abnormalities such
as Septic shock (endotoxin
shock): vascular collapse.
Interleukin-1 (IL-1):
Mediator of inflammatory response to infectious microbes.
Mainly produced by activated mononuclear phagocytes;
Two forms IL-1α and IL-1β
(30% homologous), IL-1 β
need to be cleaved to be
active
Similar effect as TNF
Interleukin-12
Produced by activated
mononuclear phagocytes and
dendritic cells
Stimulate IFN production by
NK and T lymphoctyes.
Enhance cytolytic functions
of activated NK and CTL
cells.
Is a link between innate and
adaptive immunity.
Type I interferons: IFN-α (20) and
IFN-β
Stimulated by viral infection, mediate early
innate immune response to viral infectionsestablishment of “antiviral state”
Biological Actions:
Inhibits viral replication
Stimulate the development of Th1 cells
Interleukin-10:
IL10:
produced
by
activated
macrophages, is an inhibitor of
activated macrophages and dendritic
cells and inhibits the production of
IL12;
IL10 is thus involved in the control of
innate immune reactions and cellmediated immunity.
IL-10 inhibitroy factor
.
Interferon-γ (IFN-γ):
IFN-γ is the principal macrophage-activating cytokine, T
lymphocytes and NK cells produced the IFN-γ and activated
macrophages to kill phagocytosed microbes.
4.2 Cytokines mediate and regulate adaptive
immunity
Interleukin-2
Interleukin-4
Interferon-γ
Transforming Growth Factor-β
Interleukin-2:
IL-2 is a growth factor for antigen-stimulated T-lymphocytes and is
responsible for T cell clonal expansion after antigen recognition.
Promote proliferation of antigen-specific T cells;
Promote the proliferation and differentiation of other immune
cells;
Interleukin-4 (IL4):
IL4 is the major stimulus for the production of IgE antibodies and
for the development of Th2 cells from naïve CD4+ helper T cells.
Biological Actions:
Stimulate B cell Ig heavy chain class switching to IgE isotype
Stimulate Th2 cells
Inhibit Th1 differentiation and cell-mediate immune response
Interferon-γ (IFN-γ):
The role of IFN-γ in adaptive immunity is to promote the
differentiation of Th1 helper cell and cell-mediated immune reaction.
IFN- γ can also inhibit the development of Th2 helper cells
IFN-γ stimulates the expression of MHC I and MHC II molecules
and costimulators on APCs.
Transforming Growth Factor-β (TGF-β):
Produced by Ts, macrophages, and other cell types
It inhibits the proliferation of T cells and the activation of
macrophages.
Acts on PMNs and endothelial cells to block pro-inflammatory
cytokine effects
Inhibitory factor: IL-10 ,TGF-β
4.3 Cytokines in
hematopoiesis
5.Cytokine and disease
Cytokine-related diseases
1. 细胞因子风暴： Bacterial septic shock
endotoxins (cell walls) stimulate production
of IL-1 and TNF-
2. 致热与炎症病理损害： IL-1, IL-6
3. 肿瘤的发生与逃逸
Cancers of lymphoid system- overproduction
of cytokines such as IL-6 (B-cell) or IL-5
(Hodgkin’s disease) or IL-2 (adult T-cell
leukemia). IL-10, TGF-B 抑制机体的免疫功能。
4. 免疫系统相关疾病
1.）超敏反应 IL-4。 2.)自身免疫病：类风湿关节炎，TNF-a
3.） 免疫缺陷病 Chagas ’ disease (parasitic)- suppression of
-subunit of IL-2 receptor 4.）器官移植排斥反应：
IL-1, IL-2,TNF-a
6. Cytokine therapies
Interferons
IFN-- certain types of tumors
IFN-- multiple sclerosis
these are antiviral
IFN-- chronic granulomatous disease
IL-2- certain types of cancer
infusion
LAK (lymphokine-activated killer) cells
TILs (tumor-infiltrating lymphocytes)
GM-CSF- immune deficiencies
TNF (tumor necrosis factors)
TNF- and 
In some cases inhibit proliferation of tumor
cells but not normal cells
May damage vascular endothelial cells in
tumors, thus inhibiting blood supply
to the tumor
Anti-TNF-a antibody
Considerations when Considering
Therapeutic Applications
• Normally, cytokines are transferred from one cell to
another over a very short distance.
– Probably yields very high doses in that local environment
that are difficult to mimic clinically
• Interactions with other cytokines are undoubtedly important.
• Cytokines have a short half-life and are degraded quickly.
Requires continual administration.
• Cytokines
have
many
different
effects
(pleiotropy);
therefore, often see unexpected and undesirable sideeffects.
Sample question
•
A.
B.
C.
D.
Which of the following cytokines plays an inhibitory effect
on macrophages and dendritic cells terminating
inflammatory response?
IL-2
IL-4
IFN-
IL-10
Answer=D
Sample question
• Which of the following cytokines promote the
differentiation of Th1 helper and inhibit the development of
Th2 helper cells ?
A. IFN-γ
B. IL-4
C. IFN-
D. IL-2
Answer=A
Characteristic of cytokine to perform their biological functions?
Thanks for your attention!