Cytokines

Cytokines
Low-molecular weight (less than 30 kD)
• Regulatory proteins or glycoproteins
 Cytokines
Secreted by
• White blood cells and
• Various other cells in the body

In response to a number of stimuli

 Cytokines
Regulating the development of effector cells
 Properties of Cytokines
Bind to specific receptors on the membrane

Triggering signal-transduction pathways that

• Alter gene expression
 Properties of Cytokines
Susceptibility is determined by
• Specific membrane receptors

Can mediate biological effects at Pico molar

concentrations
 Autocrine action
A particular cytokine may bind to receptors on the
membrane
• The same cell that secreted it
 Paracrine action
It may bind to receptors on a target cell
• In close proximity to the producer cell
 Endocrine action
It may bind to target cells
• In distant parts of the body
 Effects of Cytokines
Stimulating or inhibiting
• Activation
• Proliferation or
• Differentiation of cells

Regulating the secretion of antibodies or other

cytokines
 Effects of Cytokines
Binding stimulates increased expression of
• Cytokine receptors

Secretion of other cytokines

• Affects other target cells
 Effects of Cytokines
• Pleiotropy
• Redundancy
• Synergy
• Antagonism
• Cascade induction
 Pleiotropy
A given cytokine that has
• Different biological effects on different target
cells
 Redundancy
Two or more cytokines that
• Mediate similar functions

Difficult to ascribe a particular activity to a single

cytokine
 Synergism
The combined effect of two cytokines on cellular
activity is
• Greater than the additive effects of the individual
cytokines
 Antagonism
The effects of one cytokine
• Inhibit or offset the effects of another cytokine
 Cascade induction
Action of one cytokine on a target cell induces that
cell to
• Produce one or more other cytokines which

May induce other target cells for same purpose

 Common Names of Cytokines
Interleukins
They are secreted by some leukocytes
• Act upon other leukocytes
 Common Names of Cytokines
• Interferons
• Tumor Necrosis Factors
 Common Names of Cytokines
Chemokines a group of low-molecular-weight
cytokines that affect
• Chemotaxis
• Leukocyte behaviour

Have role in inflammatory

 Cytokines, Hormones and Growth
Factors
Growth factors produced constitutively
Cytokines and hormones are secreted in response
to stimuli
• Secretion is short-lived
• Few hours to a few days
 Cytokines, Hormones and Growth
Factors
Hormones act long range in an endocrine
• Most cytokines act over a short distance in an
autocrine or paracrine
 Cytokines, Hormones and Growth
Factors
Hormones are produced by specialized glands
• Tend to have a unique action on one or a few types
of target cell

Cytokines are often produced by cells and

• Bind to a variety of cells
 Cytokine Family: Four Groups
• Hematopoietin family
• Interferon family
• Chemokine family
• Tumor necrosis factor family
 JAK-STAT Pathway
The cytokine receptor is composed of subunits
• Alpha Chain: Binding with cytokine
• Beta Chain: Signalling
 JAK-STAT Pathway
Different inactive protein tyrosine kinases are
associated with
• Different subunits of the receptor
 JAK-STAT Pathway
Alpha Chain: Associated with Janus Kinase (JAK)
• JAK is associated but lacks activity without
cytokine binding
 JAK-STAT Pathway
Cytokine binding induces
• Association of the two separate cytokine
receptor subunits
 JAK-STAT Pathway
Activation of the receptor-associated JAKs
 JAK-STAT Pathway
Activated JAKs create docking sites for the STAT
transcription factors by
• Phosphorylation of specific tyrosine residues on
cytokine receptor subunits
 JAK-STAT Pathway
STAT: signal transducers and activators of
transcription
 JAK-STAT Pathway
After phosphorylation

STAT transcription factors translocate

• From receptor docking sites at the membrane
• To the nucleus
 JAK-STAT Pathway
They initiate the transcription of specific genes in
nucleus
• Pathway associated with IFN-gamma
 Interferon α (IFN-α)
A family of molecules
• Produced in Macrophages
• Induces an antiviral state in most nucleated cells
• Increases MHC class I expression; activates NK cells
 Interferon β (IFN-β)
Produced in Fibroblasts
• Induces an antiviral state in most nucleated cells
• Increases MHC class I expression
• Activates NK cells
 Interferon  (IFN-)
Produced in TH1 cells; CD8+ cells; NK cells
• Activates macrophages
• Increases expression MHC class I and class II
molecules
• Increases antigen presentation
 Interleukin 2 (IL-2)
Produced in T cells
• T-cell proliferation
• Can promote AICD (activation-induced cell death)
• NK cell activation and proliferation
• B-cell proliferation
 Interleukin 4 (IL-4)
Produced in TH2 cells; mast cells
• Promotes TH2 differentiation
• Isotype switch to IgE
 Interleukin 5 (IL-5)
Produced in TH2 cells
• Eosinophil activation and generation
 Interleukin 12 (IL-12)
Produced in Macrophages, dendritic cells
• NK cells activation
• Influences adaptive immunity (promotes TH1
subset)
 Tumor Necrosis Factor-α (TNF-α)
Produced by Macrophages
• Vasculature (inflammation)
• Liver (induction of acute phase proteins)
• Loss of muscle, body fat (cachexia)
• Induction of death in many cell types
• Neutrophil activation
 Tumor Necrosis Factor- β (TNF-β)
Mediates inflammation

Accounts for the association of TH1 cells with

inflammatory phenomena such as
• Delayed hypersensitivity
 Transforming growth factor β (TGF-β)
Produced in T cells, macrophages, other cell
types
• Inhibits T-cell proliferation and effector functions
• Inhibits B-cell proliferation
• Promotes isotype switch to IgE
• Inhibits macrophages
 Interleukin 1 (IL-1)
Produced in Monocytes, macrophages,
endothelial cells, epithelial cells
• Vasculature (inflammation)
• Hypothalamus (fever)
• Liver (induction of acute phase proteins)
 Interleukin 6 (IL-6)
Produced in Macrophages, endothelial cells
• Liver (induces acute phase proteins);
• influences adaptive immunity (proliferation and
antibody secretion of B cell lineage)
 Interleukin 25 (IL-25)
Unknown source
• Induces secretion of TH2 cytokine profile