Cytokines

CYTOKINES

Definition:

• Cytokines are a diverse group of non-antibody proteins that act as

mediators between cells. ( they are chemical molecules).

• They were initially identified as products of immune cells that act as

mediators and regulators of immune processes but many cytokines

are now known to be produced by cells other than immune cells and

they can have effects on non-immune cells as well.

• Cytokines are currently being used clinically as biological response

modifiers for the treatment of various disorders.

CYTOKINES• The term cytokine is a general term used to describe a large

group of proteins but there are other terms that are commonly used to describe particular kinds of cytokines.

• These include:

1. Monokines (cytokines produced by mononuclear phagocytic cells).

2. Lymphokines (cytokines produced by activated lymphocytes, especially Th cells).

3. Interleukins (cytokines that acts as mediators between leukocytes).

4. Chemokines (small cytokines primarily responsible for leukocyte migration).

• Cytokines are not typically stored as preformed proteins.

Rather their synthesis is initiated by gene transcription

and their mRNAs are short lived.

• They are produced as needed in immune responses.

• Cytokines regulate the intensity and duration of the immune response by stimulating or inhibiting the activation, proliferation, and/or differentiation of various cells, by regulating the secretion of other cytokines or of antibodies, or in some cases by actually inducing programmed cell death in the target cell.

Chemical signaling

Cytokines bind to specific receptors on target cells with high

affinity and the cells that respond to a cytokine are either:

1. The same cell that secreted cytokine (autocrine).

2.A nearby cell (paracrine) or

3.A distant cell reached through the circulation (endocrine).

Cellular responses to cytokines are generally slow (hours)

because they require new mRNA and protein synthesis.

The Functions of Cytokines

• Cytokine signaling is very flexible and can induce both

protective and damaging responses.

• One cytokine often influences the synthesis of other

cytokines.

Action of Cytokines

Pleiotropy Affects multiple cell types

Redundancy Multiple cytokines affects cells of the same type

Synergy Cytokines acting in concert on the same cell

Antagonism Competing actions

Cascading Cytokines acting sequentially

Types of Cytokines’ receptors

• Receptors for cytokines are heterodimers (sometimes heterotrimers) many of which can be grouped into families based on common structural features; one subunit is common to all members of a given family.

• Different cytokine receptors have specific cytokine-binding chains usually associated with a common signaling chain.

Types of Cytokines’ receptors

• According to the extracellular cytokine-binding domain, cytokine receptors are divided into 5 families:1. Class I cytokine receptors(hematopoietin family):heterodimers2. Class II cytokine receptors (interferon family): heterodimers3. TNF receptor family4. Immunoglobulin(Ig) superfamily receptors(IL-1)rare5. Chemokine receptors(seven-transmembrane a-helical receptors)

Cytokine networks• Cytokines function as part of a larger inter-related

system of proteins and signaling cascades, the cytokine network.

• These are complex interactions in which different cells can respond differently to the same cytokine depending upon other signals received by the cell.

Although the focus of most research has been on the

production and action of cytokines on cells of the

immune system, it is important to remember that many

of them have effects on other cells and organ systems.

A schematic diagram showing some of the interactions in the cytokine network

Figure 5A

A schematic diagram showing some of the interactions in the cytokine network

Figure 5B

A schematic diagram showing some of the interactions in the cytokine network

Figure 5C

Cytokine networks (Cont)

In fact, the cytokine network is quite complex and represents a

series of overlapping and inter-related connections amongst

cytokines.

Within this network:

1.One cytokine may induce or suppress its own synthesis,

2. Induce or suppress the synthesis of other cytokines,

3. Induce or suppress synthesis of cytokine receptors (both its own

and other cytokine Rs),

4. Antagonize or synergize with other cytokines.

Categories of cytokines

Cytokines can be grouped into different

categories based on their functions or their

source but it is important to remember that

because they can be produced by many

different cells and act on many different cells,

any attempt to categorize them will be subject

to limitations.

Categories of cytokines

Categories of cytokines

Interleukin 1 family:

Cytokines of the interleukin 1 (IL-1) family are typically

secreted very early in the immune response by dendritic cells

and monocytes or macrophages. IL-1 secretion is stimulated

by recognition of viral, parasitic, or bacterial antigens by

innate immune receptors. IL-1 family members are generally

Proinflammatory, meaning that they induce an increase in

the capillary permeability at the site of cytokine secretion,

along with an amplification of the level of leukocyte migration

into the infected tissues.

Those are:

• GM-CSF (Granulocyte-macrophage colony-stimulating factor):

promotes the differentiation of bone marrow

progenitors.

• M-CSF( Monocyte-colony stimulating factor): promotes growth

and differentiation of progenitors into monocytes and

macrophages .

• G-CSF:(also known as pluripoietin): promotes

production of PMNs

• IL-1,IL-3, IL-5, IL-6, IL-7, erythropoietin, Produced by bone marrow cells

and leukocytes

Hematopoietin (Class 1 Cytokine) family

Type I interferon:a family of about 20 related proteins, and

interferon-Beta, which are secreted by activated

macrophages and dendritic cells, as well as by virus-infected

cells. Interferons alpha and beta are also secreted by virally

infected cells after recognition of viral components by

pattern recognition receptors (PRRs) located either at the

cell surface, or inside the cell

Interferon (Class II Cytokine ) family

Type II interferon OR interferon-(gamma), is produced by activated T

and NK cells. Interferon-(gamma) is a powerful modulator of the

adaptive immune response, biasing T cell help toward the TH1 type

and inducing the activation of macrophages, with subsequent

destruction of any intracellular pathogens and the differentiation of

cytotoxic T cells .

All three interferons increase the expression of MHC complex proteins

on the surface of cells, thus enhancing their antigen-presentation

capabilities.

INF-Y

Figure 2

In addition, a third class of interferons, the so-called interferon,-

or type III Interferon family, was discovered in 2003. There

are currently three members of this family: interferon-1

(IL-29 ,)-2 ) -28 (, -3 ) -28 (interferon IL A and interferon IL B.

Like Type I interferons, the Type III interferons up-regulate

the expression of genes controlling viral replication and host

cell proliferation.

• TNF-alpha:is produced by activated macrophages is response to microbes, especially the Lipopolysaccharide (LPS) of Gram negative bacteria.

• It is an important mediator of acute inflammation. • It mediates the recruitment of neutrophils and macrophages to

sites of infection by stimulating endothelial cells to produce adhesion molecules and by producing Chemokines which are chemotactic cytokines.

• TNF- α also acts on the hypothalamus to produce fever and it promotes the production of acute phase proteins

TNF-beta (Lymphotoxin-alpha) : is activited by lymphocytes and bind

to neutrophils,endothelial cells and osteoclasts(bone cells)

CD40L: is a cytokine expressed on the surface of T-cell that is

required to signal for B-cell differentiation.

Fas Ligand (FasL),or CD95: induces apoptosis

Tumor Necrosis Family (TNF)

Interleukin 17 family

The most recently described family of cytokines, the IL-17

family, includes interleukins 17A, 17B, 17C, 17D, and 17F.

IL-17 receptors are found on neutrophils, keratinocytes,

and other non lymphoid cells. Members of the IL-17 family

therefore appear to occupy a location at the interface of

innate and adaptive immunity.IL-17 is produced by Th17 cells and its overexpression has been associated with autoimmune disease including multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

Chemokines family

Chemokines are a structurally related family of small

cytokines that bind to cell-surface receptors and

induce the movement of leukocytes up a

concentration gradient and

toward the chemokine source.

This soluble factor-directed cell movement is known as

chemotaxis, and molecules that can elicit such

movement are referred to as chemoattractants

TGF-β

• Transforming growth factor beta is produced by T cells and many other cell types.• It is primarily an inhibitory

cytokine.• It inhibits the proliferation of T

cells and the activation of macrophages.• It also acts on PMNs and

endothelial cells to block the effects of pro-inflammatory cytokines

Categories of cytokines (IL-2)

Figure 3

each subpopulation can exert inhibitory influences on the other

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