Pharmacology &Therapeutics-III

M.PHIL
SIR IMRAN ARSHAD

IRAM KHALIQ
Semester:1

SARA

HINA

SIDRA

CHEMICAL MEDIATORS

These are endogenous chemical

substances that are released from cells or
plasma or the damaged tissue itself, to
mediate & partake in various processes of
acute inflammation like vasodilatation,
increased vascular permeability, PMN
chemotaxis, fever, pain, tissue damage
etc

DEFINITION
The term "cytokine" is derived from a
combination of two Greek words - "cyto"
meaning cell and "kinos" meaning
movement.
Cytokines are cell signalling molecules
that aid cell to cell communication in
immune responses and stimulate the
movement of cells towards sites of
inflammation, infection and trauma.

Cytokines exist in peptide, proteinand

glycoprotein (proteins with a sugar
attached) forms.

The cytokines are a large family of

molecules that are classified in various
different ways due to an absence of a
unified classification system.

Functions of cytokines
Stimulation
Inhibition

Differentiation
Cell death
chemoattract

Cytokine actions may be characterized

as:

Autocrine (self modulating)

Paracrine (modulating cells in the

immediate surroundings)

Endocrine (modulating cells through

circulation in the distant area)

Properties of cytokines

Names of Cytokines
Source
e.g.,Lymphokines

Function
e.g.,Chemokines

Intercellular action
e.g., Interleukins

Chain of Cytokine Action

Stimulus>Cytokineproducing cell>
Cytokine>Target
cell>Receptor>
Biological effect(s)

Cytokine-generating Cells
A Variety Of Cells Are
Capable Of Making
Cytokines

However The Biggest

Producers: M and

TH
THI

TH2

Innate immunity
Macrophages
Endothelial cells
Fibroblasts

Adaptive immunity
T lymphocytes
Macrophages
NK cells

FUNCTIONAL CLASSES OF
CYTOKINES
Cytokines classified according to their biologic
actions into three groups:
1) Mediators and regulators of innate immunity

- Produced by activated macrophages and

NK cells in response to microbial infection
- they act mainly on endothelial cells and
leukocytes to stimulate the early
inflammatory response to microbes

2) Mediators and regulators of acquired

immunity
- Produced mainly by T lymphocytes in
response to
specific recognition of foreign antigens
- They include IL-2, IL-4, IL-5,, IL-13, IFN,
Transforming growth factor- (TGF-) and
lymphotoxin (TNF- )

3) Stimulators of haematopoiesis
- Produced by bone marrow, stormal cells,
leukocytes
- Stimulate growth and differentiation of
leukocytes
- Stem cell factor, IL-3, IL-7, GM-CSF

1) Interferons (IFNs)
* Interferons (IFNs): are proteins secreted in
response to viral infections or other stimuli

* They include:

- INF- produced by leucocytes

induced by virus infected
cells
- INF- produced by fibroblasts
- INF- produced by NK cells,TH1 cells, CD8
T-cells

Action of INF- and IFN- :

- Prevent viral replication
- Increase MHC-I expression on viral
infected cells helping their recognition
by CD8 T-cells
- Increase cytotoxic action of Nk cells
- Inhibit cell proliferation and tumor
growth

Action of IFN- :
- Activate Macrophages
- Increase expression of MHC-I and II on
APCs
- Enhance cytotoxic actions of Nk cells

- Promote production of TH1 and inhibits

proliferation of TH2

2) Interleukins
Group of cytokines (secreted proteins/signalling
molecules) that were first seen to be expressed
by white blood cells (leukocytes).
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.

3)Tumor necrosis factors

(TNF)
Group of cytokines which can cause cell
death (Apoptosis).
Family members :- 19 cytokines are
identified as part of the TNF family on the
basis of sequence, functional & structure
similarities.
The first two members of the family to be
identified were;
TNF-
TNF-

4) Transforming growth
factor (TGF)
Sometimes referred to as Tumor Growth
Factor.
Two classes of polypeptide growth factors,
TGF - & TGF .
The two classes of TGFs are not structurally
or genetically related to one another & they
act through different receptor mechanisms.
They dont always induce cellular
transformation, and are not the only growth
factors that induce cellular transformation.

5) Colony stimulating factors

(CSFs)
colony-stimulating factors are soluble,
membrane-bound substances of
the hematopoietic microenvironment.

secreted glycoproteins that bind to

receptor proteins on the surfaces
of hemopoietic stem cells.

6) Growth factor
A naturally occurring substance capable
of stimulating cellular growth,
proliferation & cellular differentiation.

Usually it is a protein or a steroid

hormone.
Growth factors are important for
regulating a variety of cellular processes.

CHEMOKINES
Family of chemoattractants for
inflammatory cells & include;
IL-8 chemotactic for neutrophils

Platelet factor 4 chemotactic for

neutrophils, monocytes & eosinophils
MCP 1 chemotactic for monocytes
Eotaxin chemotactic for eosinophils

Cytokine Receptors

5 Major Families

Immunoglobulin Superfamily
Hematopoietin Receptor Family (Class I)
Interferon Receptor Family (Class II)
TNF Receptor Family
Chemokine Receptor Family

Cytokine Receptors
Multimeric receptors
Common signal-transducing subunits
Unique high affinity subunits
High affinity subunits associated with
activation of target cell

Seven-transmembrane-domain receptors
signal by coupling with trimeric GTPbinding proteins

Signal Transduction
Initiated by cytokine binding
Activates JAK (Janus kinase)
Phosphorylation of tyrosine
Binding of STAT(Signal transducers and
activators of transcription)
Translocation of STAT to cells DNA
Transcription of specific target genes

Ligand Binds Subunit

Ligand Binding Causes
Dimerization of Receptor
JAKs Get Activated
Phosphorylation of tyrosine residues

on receptor
Phosphorylation of JAKs themselves

STATS Dock Receptor

Phosphorylation of STATs by JAKs

Dimerized STATs Translocate To

Nucleus
Gene Expression

Role of Cytokines in Hematopoiesis

SCF (Stem cell factor)
GM-CSF (Granulocyte-macrophage
colony-stimulating factor)
IL-3 (Interleukin 3)
IL-5 (Interleukin 5)
IL-7 (Interleukin 7)
IL-11(Interleukin 11)

Therapeutic Uses of Cytokines

1) Interferon in treatment of viral diseases,
cancer.
2) Several cytokines are used to enhance T-cell
activation in immunofideficincy diseases, e.g.
IL-2, IFN-,TNF-.
3) IL-2 and lymphokine activating killer cells (LAK)
in treatment of cancer.

4) GM-CSF induces increase in white cell count, it is used:

a- To restore leukocytic count after

cytotoxic

chemotherapy induced neutropenia

b- After bon marrow transplantation

C- To correct AIDS-associated leukopenia

5) Anti-cytokines antibodies in management of

autoimmune diseases and transplant rejection:
a- Anti-TNF in treatment rheumatoid arthritis

& Crohns disease.

b- Anti-IL2R to reduce graft rejection

6) Anti-TNF antibodies in treating septic

shock
7) Anti-IL-2R in treating adult T-cell
leukemia
8) Anti-IL-4 is under trial for treatment
of allergies

Cytokines based therapies in clinical

use

REFERANCES
http://en.wikipedia.org/wiki/Cytokine

Pharmacology. H. P. Rang, M. M.
Dale, J. M. Ritter & P. K. Moore

http://www.cytokines.com/
Pathological Basis of
Disease. Robbins & Cotran

Essential of medical
pharmacology. K. D. Tripathi

**(Knowledge is an unending adventure at the edge of

uncertainity) **