Initially, interleukins were thought to be produced by leukocytes and act on other leukocytes, leading to their name. Interleukins stimulate immune cell growth and differentiation and activate effector mechanisms. They are cytokines secreted by activated immune cells like macrophages and lymphocytes. Interleukins modulate immune and inflammatory responses.

2. Initially investigators believed that
interleukins were made chiefly
by leukocytes (white blood cells) to act
primarily on other leukocytes, and for this
reason they named them interleukins,
meaning “between leukocytes”.
• In the activation phase of adaptive Ir, they
stimulate the growth and differentiation of
lymphocytes and in the effector phases of
innate and adaptive immunity they
activate different effector mechanisms to
eliminate microbes and other agents.
• Cytokines proteins secreted by the
mononuclear phagocytes were called
monokines and those produced by

3.  Once activated by a complex of antigen plus major
histocompatibility complex (MHC) and appropriate costimulatory
signals, T lymphocytes release a variety o f biologically active
substances collectively referred to as lymphokines.
 Interleukins are biologically active glycoproteins derived primarily
from activated lymphocytes and macrophages that modulate and
regulate immune and inflammatory reactions.
 Types are molecularly characterized and assigned numbers are IL-1,
IL-2 and so on.

4. General Properties
 Cytokine secretion is brief, self limited event
 The actions of cytokines are often pleiotropic and redundant
 Cytokines often influence the synthesis and actions of other
cytokines
 Cytokines action may be local and systemic (autocrine and paracrine)
 Cytokines initiate their action by binding to specific membrane
receptors on target cells
 External signals regulate the expression of cytokine receptors and
thus the responsiveness of cells to cytokines
 The cellular responses to most cytokines consist of changes in gene
expression of new functions and sometimes in the proliferation of
target cells
 Cellular responses to cytokines are tightly regulated and feedback
inhibitory mechanisms exist to turn down these responses

6. • Based on their principal biologic actions.
– Mediators and regulators of innate immunity
– Mediators and regulators of adaptive immunity
– Stimulators of hematopoiesis

7. Cytokines that mediate and regulate Innate immunity
TNF
IL 1
Chemokines
IL 12
Type I interferons
IL 10
IL 6
IL 15
IL 18
IL 23
IL 27

8. Cytokines that mediate and regulate Adaptive
immunity
 IL 2
 IL 4
 IL 5
 IL 13
 Interferon ɤ
 Transforming growth factor β
 LMPHOTOXIN
 IL 17
 IL 21

9. • Cytokines that stimulate
Hematopoiesis
– Stem cell factor
– IL 7
– IL 3
– GM – CSF
• Granulocyte stimulating factor
• Macrocyte colony stimulating factor
– Erythropoietin
– IL 9
– IL 11

10. Interleukin receptor
An interleukin receptor is a cytokine receptor
for interleukins.
• Types
• There are two main families of Interleukin
receptors, type 1 and type 2 cytokine receptors.
• Type 1
• Type 1 interleukin receptors include:
• Interleukin-2,3,4,5,6,7,9,11,12,13,15,21,23,27
types.

11. • Type 2
• Type 2 interleukin receptors include:
• Interleukin-10 receptor20,22,28
• Other
• Interleukin-1 receptor and interleukin-18
receptor belong to the immunoglobulin super
family
• interleukin -8 receptor, RANTES receptors
belong to the chemokine receptor family.

12.  Type I cytokine receptors are trans membrane receptors expressed on
the surface of cells that recognize and respond to cytokines with
four α-helical strands.
 These receptors are also known under the name hemopoietin
receptors, and share a common amino acid motif (WSXWS) in the
extracellular portion adjacent to the cell membrane.
 Members of the type I cytokine receptor family comprise different
chains,
 some of which are involved in ligand/cytokine interaction and others
that are involved in signal transduction.

13.  Signal transduction chains
 The signal transducing chains are often shared
between different receptors within this receptor
family.
 The IL-2 receptor common gamma chain is shared
between:
 IL-2 4,7,9,13,15 receptor
 The common beta chain is shared between the
following type I cytokine receptors:
 IL-3 ,5 receptor

14. General model of cytokine receptors for
interleukin and interferon types of
cytokines.
See figure 12-6 (b) and (c) p. 308, for
interleukin (“hematopoietin”) and
interferon class of cytokines
STAT = signal transducers and
activators of transcription.
See Table 12-2, p. 313 for STAT
family of transcription factors
associated with different cytokines of
the interleukin and interferon series

15. • Type II cytokine
receptors are transmembrane
proteins that are expressed on the
surface of certain cells, which bind
and respond to a select group
of cytokines.
• Thesereceptors are similar to type
I cytokine receptors except they
do not possess the signature
sequence WSXWS that is
characteristic of type I receptors.
• Typically type II cytokine
receptors are heterodimers or
multimers with a high and a low
affinity component.s
• +3

16. • IL-1 was first described as a protein inducing
fever and was called human leukocytic
pyrogen
• 11 members of the IL-1 family exist
• Genes for IL-1a, IL-1b, and IL-1Ra are closely
associated in the region of 2q12-q13 of human
chromosome 2.
• IL-1R belongs to the Toll–IL-1—receptor (TIR)
superfamily, which is defined by an
intracellular TIR domain that initiates the
signaling cascade.
• TIR receptors can be divided into 2 subgroups
regarding the extracellular domains. One
group contains a leucine-rich repeat motif,
and the other group is characterized by an
immunoglobulin-like domain.

17. • IL-1 is expressed by many cells
including macrophages, monocytes,
lymphocytes, keratinocytes, microglia,
megakaryocytes, neutrophils, fibroblasts,
and synovial lining cells.
• IL-1RI is expressed on all cells
responding to IL-1a and b,
predominantly on T cells, fibroblasts,
epithelial cells, and endothelial cells
• The principal function of IL 1 is as a
mediator of the host inflammatory
response to infections and other stimuli
• IL-1a and b, produced by activated
macrophages and monocytes, are one of
the key players in the innate immune
response.

18. They play an important role in coordination of local
and systemic inflammation by causing inflammation
and inducing the expression of other proinflammatory
genes like COX type II, inducible nitric oxide
synthase, and other cytokines or chemokines
IL-1b plays a major role in a wide range of
autoimmune and inflammatory diseases by initiating
and potentiating inflammatory responses.

19. • IL-1b induces synthesis of chemokines, including IL-8, which is a potent
neutrophil chemo attractant
• Neutrophils can enhance the inflammation by inducing proinflammatory
cytokines and release of neutrophil granule enzymes, which are involved in
tissue damage
• IL-1Ra neutralizes the effects of IL-1. Complete inhibition of IL-1 requires
10-fold to 100-fold molar excess of IL-1Ra over IL-1.
• The fact that IL-1Ra gene deficiency causes autoimmunity and joint-specific
inflammation suggests that the balance between IL-1 and IL-1Ra is
important in maintaining the normal physiology of the joints and
homeostasis of the immune system
• Low concentration: functions as a mediator of local inflammation
• At high concentrations: enters the blood stream and exerts enocrine effects
—induces fever and also neutrophil and platelet production by the bone
marrow

20. IL 2
Mature IL-2 is a peptide 133 amino acids long
Produced mainly by mitogen activated CD4+T-lymphocytes
Originally called T-cell growth factor (TCGF)
Transformed T-cells and B-cells, leukemia cells,LAK cells
(Lymphokine-activated killer cells) and NK-cells also secrete IL-2
 Target cells of IL-2 include CD4+CD8+ T cells, NK cells, and B cells.

21.  The IL-2R consists of 3 subunits,
the ligand-specific a-chain IL-
2Ra (CD25, originally called Tac
for T activation); the b-chain IL-
2Rb (CD122), which is also part
of the IL-15 receptor complex;
and the common gc (CD132),
which is shared by IL-4, IL-7,
IL-9, IL-15, and IL-21

22. Actions and modulations
 Induces cell cycle progression in resting cells
 Allows clonal expansion of activated T-
lymphocytes
 Growth/expansion effect is modulated by
hormones such as prolactin
 IL-2 damages the blood-brain barrier and the
integrity of the endothelium of brain vessels
 IL-2 does not have a saturable transport
system across the blood-brain barrier

23. IL 3
• It is also known as multilineage colony stimulating factor (multi – CSF)
• IL-3, IL-5, and GM-CSF also share the common receptor subunit b-chain
(CD131), resulting in partially overlapping functions of these hematopoietic
cytokines.
• IL-3 is expressed by T cells, macrophages, stromal cells, NK cells, mast cells,
and eosinophils, and its transcription is regulated by 2 nuclear factor of activated
T cells-dependent enhancers that have distinct tissue-specific activity
• IL-3 is a multilineage hematopoietic growth factor, acting on early stages of
hematopoiesis rather than on late differentiation and maturation processes
• In combination with erythropoietin, IL-3 induces erythroid lineages, whereas it
synergizes with GM-CSF or G-CSF to induce the granulocyte-macrophage
lineage.

24. • IL-3 together with TNF-a leads to short-term proliferation of
CD34+ progenitor cells and the differentiation of DCs and
Langerhans cells.
• Besides its function as a hematopoietic growth factor, IL-3 is
responsible for the activation and the survival of different
mature cell types, including basophils.
• IL-3 plays a role in allergic diseases by preventing the
apoptosis of basophils

25. IL 4
• IL 4 is the major stimulus for the production of IgE antibodies and for the
development of Th2 cells from naïve CD4+ helper T cells
• The principal sources are CD4+ T lymphocytes of the TH2 subset as well as
activated mast cells
• IL 4 is the principal cytokine that stimulates B cell Ig heavy chain class
switching to the IgE isotype
• It stimulates the development of TH2 cells from naïve CD4+ T cells and
functions as an autocrine growth factor for differentiated TH2 cells
• together with IL 13 contributes to macrophage activation which promotes the
phagocytosis of microbes

26. IL 5
• IL 5 is an activator of eosinophils and serves as a link
between T cell activation and eosinophillic inflammation
• The major action of IL 5 are to activate mature eosinophils
and stimulate the growth and differentiation of eosinophils
• Eosinophils express Fc receptors specific for IgA and IgG
antibodies and are thereby able to bind to microbes

27. IL 6
• Alternative names are IFN-b2 (IFNB2), B-cell differentiation factor, BSF2, hepatocyte
stimulatory factor, and hybridoma growth factor.
• IL-6 is produced after stimulation by many different cells:T cells, B cells, granulocytes,
smooth muscle cells, eosinophils, chondrocytes, osteoblasts, mast cells, glia cells, and
keratinocytes.
• Endothelial cells, fibroblasts, and monocytes/macrophages triggered by various stimuli
during systemic inflammation are the main source of this cytokine
• IL-6 is involved in a broad spectrum of biological activities, in humoral as well as in cellular
defense, and acts on various target cells.
• Regulation ofT-cell proliferation and differentiation as well as in the induction of B cells to
produce IgM, IgG, and IgA
• A deregulated production of IL-6 affects thepathogenesis of several autoimmune and
inflammatory diseases.

28. IL 7
• IL-7, also known as pre–B-cell growth factor and lymphopoietin- 1, was originally
derived from bone marrow stromal cells and described as a mediator that alone could
support the growth of Bcell progenitors
• The IL-7R is present on most T cells, progenitors of B cells, and bone marrow
macrophages
• IL-7 is a tissue-derived cytokine. It is produced by multiple stromal tissues, including
epithelial cells in thymus and bone marrow.
• Additional sites of IL-7 production include intestinal epithelium, keratinocytes, fetal
liver, adult liver, DCs, follicular DCs, B cells, and monocytes/macrophages

29. • IL-7 is required for the survival of naive T-cell populations and contributes to
homeostatic cycling of naive and memory cells.
• IL-7 is required for the survival of naive T-cell populations and contributes to
homeostatic cycling of naive and memory cells.
• It stimulates the proliferation of thymocytes and is therefore an important
differentiation factor for functionally different subpopulations of T cells.
• IL-7 and its receptor are linked to the development of autoimmune diseases
– IL-7 is capable in vivo of causing CD4+ T-cell–dependent destruction of
tumor cells and shows a potential contribution to allergen-induced
eosinophilic airway inflammation in asthma

30. IL 8
• A wide variety of different cells such as monocytes and macrophages,
neutrophils, lymphocytes, endothelial and epithelial cells, fibroblasts,
keratinocytes, synovial cells, chondrocytes, hepatocytes, and smooth muscle and
skeletal muscle cells as well as several tumor cell types produce IL-8.
• The major effector function of IL-8 is the recruitment of neutrophils to the site of
infection or injury
• Besides neutrophils, IL-8 attracts NK cells, T cells, basophils, and GM-CSF or
IL-3–primed eosinophils.
• In the presence of IL-3, IL-8 activates basophils to release leukotrienes and
histamine. Thus, IL-8 plays an important role in the innate immunity, providing a
first line of defense against invading pathogens

31. • In addition to its chemokine function, IL-8 stimulates the
release of hematopoietic progenitor cells from the bone marrow
into the peripheral blood
• There is no direct importance of IL-8 described in TH2-
mediated allergic diseases. However, repeated injections of IL-
8 lead to neutrophil accumulation in the lung and joints,
resulting in pulmonary inflammation and cartilage damage.

32. IL9
• The main sources of IL-9 are TH2 cells and the recently
discovered TH9 cells
• To a lesser extent, mast cells and eosinophils have been shown
to secrete IL-9
• IL-9 is a multifunctional cytokine. It is a potent growth factor for T
cells and mast cells, promotes proliferation of CD8+ T cells, and
inhibits cytokine production of TH1 cells
• IL-9 is involved in TH2 inflammatory reactions, promotes the
production of IL-4–induced IgE, induces chemokine and mucus
secretion by bronchial epithelial cells, and leads to mast cell
proliferation

33. IL 10
• The IL-10 gene maps to chromosome 1 (1q31-32) in human
• In human beings, IL-10 is mainly produced by monocytes, T cells (mainly
Treg cells), B cells, macrophages, and DCs
• IL-10 is a key regulator of the inflammatory response. Its
immunosuppressive effects protect the host from exaggerated inflammatory
responses to microbial infections as well as autoimmune diseases
• IL-10 inhibits cytokine production and proliferation of CD4+ T cells mainly
indirectly through its effects on APCs
• IL-10 appears to have a protective role in several autoimmune diseases such
as diabetes mellitus.
• IL-9 is important in the protection against helminth infections

34.  It was first isolated from bone marrow–derived stromal cells in 1990
 The human IL-11 gene is located on the long arm of chromosome 19
(19q13.3-13.4) and consists of 5 exons and 4 introns.
 IL-11 is produced by a variety of stromal cells including fibroblast, epithelial
cells, endothelial cells, vascular smooth muscle cells, synoviocytes,
osteoblasts, and several tumor cell lines
 IL-11 increases peripheral platelet counts and was shown to enhance T-cell–
dependent secretion of immunoglobulins by B cells

35.  Produced by activated inflammatory cells (eg, monocytes,
macrophages, neutrophils, microglia, and DCs), and to a lesser
extent B cells
 IL-12–activated cells expressed increased levels of transcripts for
many genes involved in host defense, including IFN-γ
 By inducing IFN- γ production from NK cells and T cells, IL-12
indirectly activates the antimicrobial, antiparasitic, and antitumor
activity of phagocytotic cells and promotes cytolytic activity of NK
cells and lymphokine-activated killer cells

36. General Properties

37.  Cytokines are the family of proteins that mediate many of the
responses of innate and adaptive immunity
 They mediate their action by binding with high affinity to receptors
which belong to a limited number of structural families
 The cytokines that mediate innate immunity are produced mainly by
activated macrophages
 The cytokines that mediate and regulate adaptive immune responses
are produced mainly by antigen stimulated T lymphocytes
 Excessive production or actions of cytokines can lead to pathological
consequences

38. T h a n k y o u