describes classification of cytokines and also its role in brief. you can use this for a quick reference.

1. CYTOKINES
Dr.Vasavi reddy

2. Introduction:
■ Cytokines are diverse group of intercellular signalling low molecular weight
proteins that provide a network controlling local and systemic immune and
inflammatory responses but also wound healing, hematopoiesis and other
biologic process.
■ The term cytokine encompasses those cytokines secreted by lymphocytes
,substances formerly known as LYMPHOKINES, and those secreted by
monocytes& macrophages substances formerly known as MONOKINES

3. Definition:
■ Steve offenbacher 1996 defined cytokines as mediator molecules, which direct and
regulate inflammation and wound healing. The term cytokine meaning the cell protein is
reserved for molecules, which transmit information or signals from one cell to another. It
is part of a fundamental cell-to-cell communication network.
■ Okada and S. Murakami 1998 cytokines are small soluble proteins produced by a cell
that alters the behavior or properties of another cell, locally or systemically.

4. CLASSIFICATION
NISSENGARD NEWMAN
■ First group: cytokines which serve as
mediators of innate immunity e.g α ,β,
interferon, TNF, Il-6
■ Second group: cytokines that regulate the
growth & differentiation of lymphocytes e.g
Il 2,4 TGF β
■ Third group : that regulate hematogenous
activity e.g Gm csf, G csf Il-3,7
■ Fourth group: cytokines that share the
common property of being activation of
inflammatory cell function e.g gamma
interferon
JAN LINDHE
■ Proinflammatory cytokines
E.g. IL-1, IL-6 and TNF
■ Chemotactic cytokines E.g. IL-8
■ Lymphocytes signaling cytokines
E.g. Cytokines released by Th1- IL-2, IFN.
Cytokines released by Th2- IL-4,IL-5,IL-
10 and IL-13.

5. Based on
families
Interleukins (IL)- IL-1a, IL-1b, IL-2 to IL-15
Chemokines- IL-8 and MCP-1
Interferons (IFN) – IFNa, IFNb, IFNy
Cytotoxic cytokines-TNFa,TNFb,TNFy
Growth factors (GF) – Fibroblast GF, platlet
derived GF
Colony stimulating factors (CSF) – G-CSF, GM-
CSF, IL-3, IL-7

6. Receptors :

7. Mechanism of action:
■ cytokine binds to its receptor on the cells and
induces dimerization or polymerization of receptor
polypeptides of the cell surface.
■ This causes activation of intracellular signaling
pathways (e.g. kinase cascades) resulting in the
production of active transcription factors which
migrate to the nucleus and bind to the enhancer
region of gene, induced by that cytokine.

8. Functions:
Basically cytokines interact with cells to cause:
■ Activation (of metabolism, cellular synthesis etc)
■ Proliferation or inhibition of proliferation
■ Apoptosis
■ Differentiation
■ Chemotaxis.

9. General properties:
1) Cytokine secretion brief, self limited, mRNA unstable
2) Actions are pleiotropic and redundant
3) Influence the synthesis and action of other cytokines
4) Bind with high affinity to a specific membrane receptor
5) External signals lead to regulation of receptors
6) Cellular response to these include changes in gene expression
7) Actions can be local or systemic

10. Interleukin 1:
•Interleukin –1 is a very potent multifunctional cytokine that appears to be a central regulator of the
inflammatory and immune responses.
•IL-1 is a Pleotropic cytokine with a variety of activities.
•It includes osteoclast activating factor (OAF) because of stimulation of osteoclasts and lymphocyte
activating factor (LAF) because of its ability to stimulate proliferation of phytohemagglutination-
treatedT-cells.
•It is secreted by monocytes, macrophages, B-cells, fibroblasts, neutrophils, and epithelial cells.
•Bacterial Lipopolysaccharide is a potent commonly used stimulus for IL-1 production.
•IL-1 synthesis is suppressed by several endogenous factors, such as Corticosteroids,
Prostaglandins,Cytokines like IFN-, IL-4.
•Some of the other cytokines share biologic activities with IL-1, most importantly IL-6 andTNF
factor.
•There are 2 principal forms of IL-1 that have agonist activity, IL-1, IL-1, with a third ligand, IL-1
receptor agonist (IL-1ra) that functions as a competitive inhibitor.
•Two IL-1 receptors are found on the surface of the target cells, designated IL-1 receptor-1 and IL-1
receptor 2.

11. Biological activity:
■ Lymphocyte activation, macrophage activation, Natural killer
stimulation, Prostaglandin formation, Fever induction,Anorexia,
Acute phase protein release, Adrenocorticotophin release,
Corticosteroid release, Cytokine gene expression, Plasminogen
activator, Endothelial cell activation,Tumor cell growth inhibition,
and suppression of lipoprotein lipase gene expression.

12. Interleukin 2:
■ IL-2 ( and) was originally calledT-cell growth factor because of its effect on mitogen or
antigen activatingT-cells and is known to play a general role in immune responses.
■ IL-2 also stimulates macrophage functional activity, modulates natural killer function and
induces natural killer proliferation.
■ It is secreted byTh cells and NK cells.
■ Clinical aspects:
■ Used inTumors immunotherapy, either using IL-2 alone or in combination with in-vitro
activated lymphokine-activated killer cells.
■ The potential for IL-2 as a cancer treatment is based on activation of cells, which are cytotoxic
to the tumor.
■ Adverse effects: fever, chills, fatigue, nausea, vomiting, capillary leakage syndrome or vascular
leakage syndrome, characterized by the accumulation of edema fluid in pleural cavities.

13. Interleukin 3:
■ IL-3 is a distinct hematopoietic factor affecting multiple hematopoietic cell lineages.
■ IL-3 also known as burst-promoting factor, B- cells stimulating factor, hemopoietic cell
growth factor and multi colony stimulating factor is produced primarily by activated
helperT type I and II cells.
■ This molecule stimulates the growth of colonies of mast cells, neutrophils,
macrophages, eosinophils, and megakaryocytes.
■ It is secreted by activated helperT cells, NK cells.
■ IL-3 acts as a link between theT- lymphocytes and mast cells of the immune system,
and the hematopoietic system, which generates the accessory cells granulocytes,
phagocytes, and platelets, which carry out repair and defense responses.

14. Interleukin 4:
■ IL-4 originally calledT-cell-derived B-cell growth factor (BCGF-1) because of its activation of B
cells.
■ Also called as migration inhibition factor.
■ It is also play a role in the activation, proliferation and differentiation of B cells,T-cell growth,
macrophage function, and growth of mast cells.
■ IgE synthesis by B cells is also induced by IL-4.
■ It is secreted by helperTcells.
■ Receptors for this cytokine found onT-cells, B-cells, mast cells, myeloid cells, fibroblasts,
neuroblasts, stromal cells, endothelial cells and monocytes.
■ Effects on macrophages:
■ It can activate macrophage cytocidal function and increase macrophage expression of class II
MHC proteins.
■ It suppresses the synthesis of proinflammatory cytokines, such as IL-1, IL-6, IL-8 andTNF-  and
activated monocytes.

15. Interleukin 5
■ Interleukin-5 is the name given to a lymphokine (a cytokine produced by
lymphocytes).
■ Coffman and colleges found that IgA enhancing factor was IL-5 when the protein is
sequenced.
■ Metcalf used the term eosinophil colony stimulatory factor to describe this cytokine.
■ Thus initially known as B- cells growth and differentiation factor, IgA enhancing factor,
eosinophil colony stimulating factor.
■ The major function of IL-5 in humans is to stimulate the production of eosinophils.
■ IL-5 not only increases the number of eosinophils but also has been reported to
increase their function.

16. Interleukin 6:
■ Interleukin-6 is a multifunctional cytokine produced by various cells such as activated
monocytes or macrophages, endothelial cells, activatedT-cells, and fibroblasts.
■ Formerly these molecules were known as B- cells stimulatory factor II, interferon B2
and plasmacytoma growth factor.
■ Its effect on B cells is to promote growth and facilitate maturation of the B cells
causing immunoglobulin secretion.
■ IL-6 increases in sites of gingival inflammation and plays a role in bone resorption.

17. Interleukin 7:
■ Secreted by thymus, spleen and bone marrow stromal cells that functions as a growth
factor forT and B cells precursors.
■ It was formerly known as lymphopoitin 1 based on its capacity to influence early
lymphopoiesis.
■ IL-7 enhances the function of mature activated lymphocytic cells, particularly those
with cytotoxic activity.At higher concentrations, IL-7 also increases macrophage
cytotoxic activity and induces cytokine secretion by monocytes.

18. Interleukin 8:
■ Interleukin-8 is Chemotactic for neutrophils, increases their adherence to the
endothelium.
■ In general these cytokines are produced by:
1. Antigen stimulatedT lymphocytes
2. Mononuclear phagocytes, endothelial and epithelial cells, and fibroblasts that have
been activated by other cytokines or LPS.
3. Platelets.
■ All members of this family stimulate leukocytes and contribute to inflammatory
responses.

19. Interleukin 9:
■ Interleukin-9 is a heavily glycosylated polypeptide lymphokine with an apparent MW of
30000 to 40000.
■ It is secreted by IL-2 activatedT-cells and Hodgkin's lymphoma cells.
■ It is aT cell growth factor, which acts in synergy with other cytokines.

20. Interleukin 10:
■ IL-10 is an 18000 MW protein that is produced late in the activation process byTh2
cells, CD8T cells, monocytes, keratinocytes and activated B cells.
■ It was originally called cytokine synthesis inhibitory factor because of its ability to
inhibit cytokine production by activatedT-lymphocytes i.e.,Th1 cells and NK cells.
■ IL-10 inhibits the antigen presenting capacity of monocytes.
■ IL-10 also synergies with other cytokines to stimulate proliferation of B cells and
mucosal mast cells.
■ Together withTGF beta it causes IgA production by B cells.

21. Interleukin 11:
■ Biologic activities of IL-11:
■ Growth promotion of a plasmacytoma cell line:
■ Originally IL-11 was detected based on its ability to stimulate the proliferation of an IL-6
dependent mouse plasmacytoma cell line.
■ The ability of IL-11 to support the growth of such a plasmacytoma cell line suggest that cytokine
may be removed in the establishment and maintenance of plasmacytomas in vivo and may play
an important role in the tumourogenesis.
■ Hematopoietic colony stimulating activity:
■ Alone, IL-11 cannot support the growth of megakaryocyte colonies but stimulates and increases
in numbers, size of megakaryocyte colonies in combination with IL3.
■ Therefore IL-11 is not a megakaryocyte colony stimulating factor but rather acts like a
megakaryocyte potentiator, their results suggest that IL-11 may play an important role in
megakaryocytopoiesis and possibly in vitro platelet production.

22. Interleukin 12:
■ It was originally called cytotoxic lymphocytes maturation factor (CLMF) or NK cell
stimulatory factors.
■ It is produced predominantly on activation by B cells and macrophages.
■ It acts synergistically with IL-2 to induce IFN- byT-cells and NK cells
■ It is a key factor in the development ofTh1 cells, stimulating both their proliferation
and differentiation.
■ It suppressesTh2 dependent functions, such as the production of IL-4, IL-10, IgE
antibodies.
■ IL-12 also induces the production of GM-CSF,TNF, IL-16, IL-2.

23. Interleukin 13
■ The marked structural homology between
IL-4 and IL-13 and the close juxtaposition of
their genes on the chromosome suggest
that gene duplication occurred.
■ IL-13 is predominantly expressed in
activatedTh2 cells and regulates human B
cell and monocytic activity.
Interleukin 14
■ IL-14 is a 50-60 KD glycosylated cytokine
otherwise known as the high mol wt B cell
growth factor.
■ IL-14 is thought to play a role in the
development of B cell memory.
■ It enhances the proliferation of activated B
cells and inhibits the synthesis of
immunoglobulin.
■ It is produced by follicular dendritic cells and
activatedT cells.
■ IL-14 receptors are found only in cells of the B
cells lineage.
■ IL-14, participates mainly in secondary
humoral immune responses.

24. Interleukin 15
■ IL-15 is widely expressed in kidney, lung,
liver, heart and bone marrow stroma.
■ It is produced most abundantly by
epithelial cells and monocytes, but not
byT lymphocytes.
■ It functions as a signal from non
lymphoid cells for generatingT cell
dependent immune responses.
Interleukin 16
■ IL-16 which was previously known as
lymphocyte chemoattractant factor (LCF) is
produced by lymphocyte and induces the
directional migration of CD4+T cells,
eosinophils and monocytes.
■ The chemoattractant effect of LCF is
blocked by anti CD4 Fab fragments
suggesting that CD4 or CD4 related
molecules are required for the effects of
LCF on target cells.

25. Interferons
Interferons have been divided into two types:Type I an viral interferon
has been further divided into alpha and beta subcategories.Type II or
immune interferon is referred to as gamma interferon.
IFN-alpha is leukocyte derived where as IFN-beta is derived from
fibroblasts. IFN-gamma is however derived from stimulatedT cells of
both CD4+ andCD8+ lineage.
Both IFN-  and  are characterized by their antiviral activity, IFN 
appears to be more integrated part of the immune system.
IFN  is stimulated by IL-2 has a molecular wt of 35 –70 KD and in
addition to its antiviral activity appears to have an important role in the
stimulation of cytotoxicT cells and NK cells activity.
It also plays an important role in B-cells differentiation and in
production of Igs under some conditions

26. Tumour
necrosis
factor:
■ TNF is a principal mediator in the host inflammatory response.
■ The main cell type secretingTNF is the mononuclear phagocyte.
■ The main stimulus for release is the Lipopolysaccharide of bacterial cell
walls.
■ There are two structurally and functionally similar forms ofTNF  and 
but they differ biochemically.
■ TNF  is 17 KD is derived from stimulated macrophages and appears to
have significant stimulatory activity on the cytoxicT lymphocytes (CTL)
responsible for lysing tumor or virally infected cells.
■ TNF- is a 25 KD glycoprotein derived from activatedT cells with a 28%
homology toTNF-
■  Form is occasionally known as lymphotoxin these virtually have
similar actions, which includes CTL stimulation, osteoclast activation of
PMNLs and antiviral activity.
■ TNF also appears however to act synergistically with cytokines and
induces release of IL-1.

27. Transforming
growth factor
β
■ TGF  was initially discovered as a growth factor for fibroblasts
and promotes wound healing.
■ T lymphocytes produceTGF.
■ Humans express at least three forms ofTGF  calledTGF  -1,TGF
 -2,TGF  -3.
■ These are products of separate genes, but they all bind to 5 types
of high affinity cell surface receptors.
■ TGF  has anti proliferative effects on a wide variety of cell types
including macrophages, endothelial cells andT and B-
lymphocytes.
■ TGF is a chemoattractant and promotes many functional activities
of fibroblasts.
■ TGF  is a potential mediator of inflammation because it is a
product of activated macrophages, a potent chemoattractant for
macrophages and can activate macrophages to produce IL-1.
■ It is chemo attractive for neutrophils and monocytes and it
stimulates monocyte expression of adhesion proteins

28. Chemokines:
They generally have low molecular weights, ranging from 7-14 KDa,
and stimulate recruitment of leukocytes.
Chemokines are secondary proinflammatory mediators, i.e., they
are typically induced by primary proinflammatory mediators such
as Interleukin –1 orTNF.
By recruitment of leukocytes, chemokine activity leads to activation
of host defense mechanisms and stimulates the early events of
wound healing.
There are two major chemokine subfamilies based upon the portion
of cystine residues i.e. CXC and CC.
The CXC family members also known as the alpha Chemokines.
They primarily stimulate neutrophils.
C Chemokines are also known as the beta Chemokines.They
stimulate Basophiles, eosinophils,T-lymphocytes and NK cells.

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