Download (IL-1) Family

Receptors and Signaling:
Cytokines and
Chemokines
Cytokines
Low-molecular weight regulatory
proteins or glycoproteins
 Secreted by WBC and various other
cells
 Assist in regulating development of
immune effector cells
 Referred to as Interleukins

○ IL-1 through IL-37 have been described
Chemokines
subpopulation of cytokines that share the specific
purpose of mobilizing immune cells from one organ, or
indeed, from one part of an organ, to another.
Subpopulation of cytokines
 Mobilize immune cells from one area to
another
 Class of chemoattractants

General Properties of Cytokines and
Chemokines
1. Cytokines Mediate the Activation, Proliferation, and
Differentiation of Target Cells:
Cytokines bind to specific receptors on the
membranes of target cells, triggering signal
transduction pathways that ultimately alter enzyme
activity and gene expression. The susceptibility of a
target cell to a particular cytokine is determined by
the presence of specific membrane receptors and
exhibit very high affinity for one another.
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Cytokines bind to
specific receptors
Trigger signal
transduction pathways
that alter gene
expression in target
cells
Exhibit pleiotropy,
redundancy, synergy,
antagonism, cascade
induction
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A cytokine that induces different biological
effects depending on the nature of the target
cells is said to have a pleiotropic action
Two or more cytokines that mediate similar
functions are said to be redundant
Cytokine synergy occurs when the combined
effect of two cytokines on cellular activity is
greater than the additive effects of the
individual cytokines
The effects of one cytokine inhibit or
antagonize the effects of another
Cascade induction occurs when the action of
one cytokine on a target cell induces that cell
to produce one or more additional cytokines.
2. Cytokines Can Elicit and Support the Activation
of Specific T-Cell Subpopulations;
TH1 cells secrete cytokines that ▬▬▬▬► promote the differentiation
and activity of macrophages and cytotoxic Tcells, (intracellular bacteria
are recognized and destroyed).
How ?? The cytokines IL-12 and interferon (IFN) γ induce TH1
differentiation.

TH2 cells activate B cells to make antibodies, which ▬▬▬▬►
neutralize and bind extracellular pathogens, ▬▬▬►making them
susceptible to phagocytosis and complement-mediated lysis.
How ?? IL-4 and IL-5 support the generation of TH2 cells.
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TH17 cells promote the ▬▬▬▬► differentiation of activated
macrophages and neutrophils, and support the inflammatory state;
How ?? their generation is induced by IL-17 and IL-23.
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3. Cell Activation May Alter the Expression of Receptors
and Adhesion Molecules
What keeps cytokines from activating all T
cells, for example, in a nonspecific fashion
during the immune response?
 In order for a cell to respond to a signaling
molecule, it must express receptors for that
molecule, and responsiveness to a molecular
signal can thus be controlled by signal receptor
expression.
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4. Cytokines Are Concentrated Between Secreting
and Target Cells;
The close nature of the cell-cell interaction and
the directional release of cytokines by the
secretory apparatus.
 effective concentration of cytokines in the region
of the membrane receptors may be more
important than that experienced outside the
contact region of the two cells.
 the half-life of cytokines in the bloodstream or
other extracellular fluids into which they are
secreted is usually very short, ensuring that
cytokines usually act for only a limited time and
over a short distance

5. Signaling Through Multiple Receptors Can
Fine Tune a Cellular Response;

Cytokines can bind to more than one
receptor, & receptors can bind to more than
one signaling molecule.
cytokines can be classifyed on the basis of the distance
between the cell secreting the signaling ligand & the cell
receiving
that
chemical
signal
:
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Cytokines that act on cells
some distance away from
the secreting cell, such
that they must pass
through the bloodstream
before
reaching
their
target, are referred to as
endocrine
Those that act on cells
near the secreting cell,
such that the cytokine
merely has to diffuse a few
Ångstroms through tissue
fluids
or
across
an
immunological
synapse,
are
referred
to
as
paracrine

Sometimes, a cell
needs to receive a
signal through its own
membrane receptors
from a cytokine that it,
itself, has secreted.
This type of signaling
is referred to as
autocrine.

Of note, the T-cell
interleukin IL-2 acts
effectively
in
all
three modes.

Cytokines belong to 6 families
○ Interleukin 1 (IL-1)
○ Hematopoietin family (Class I)
○ Interferon family (Class II)
○ Chemokine family
○ Tumor necrosis family
○ Interleukin 17 (IL-17)
 Based on structural studies
 All have molecular mass less than 30kDa
 All have similarities and few rarely act alone

Interleukin 1 (IL-1) Family
typically secreted very early in the
immune response
ii. by dendritic cells and monocytes or
macrophages.
iii. IL-1 secretion is stimulated by recognition
of viral, parasitic, or bacterial antigens by
innate immune receptors.
iv. IL-1 family members are generally
proinflammatory, (what does this mean)?
i.
they induce an increase in the capillary permeability at
the site of cytokine secretion,
 amplification of the level of leukocyte migration into the
infected tissues.
 IL-1 has systemic (whole body) effects and signals the
liver to produce acute phase
 These proteins further induce multiple protective effects,
including the destruction of viral RNA
 generation of a systemic fever response (which helps to
eliminate many temperature-sensitive bacterial strains).
innate immune response
 IL-1 also activates both T and B cells at the induction of
the adaptive immune response.
 E.X.
IL-1α and IL-1β ,IL-18

The IL-1 Family of Cytokine Receptors;
Two different receptors for IL-1 are known. are
members of the immunoglobulin superfamily:
 Only the type I IL-1R (IL-1RI), which is
expressed on many cell types,
 the type II IL-1R (IL-1RII) is limited to B cells
Note that both the IL-1RI and the IL-1RII receptor
chains exist in both soluble and membrane-bound
forms.
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Hematopoietin (Class I) Family
○ Called Class I because earliest to be
structurally characterized (not first to be
discovered)
○ Not all involved in hematopoietic functions
Their cellular origins and target cells are as
diverse as their ultimate functions, which range
from;
signaling the onset of T- and B-cell proliferation
(e.g., IL-2),
 to signaling the onset of B-cell differentiation to
plasma cells and antibody secretion (e.g., IL-6),
 to signaling the differentiation of a T helper cell
along one particular differentiation pathway versus
another (e.g., IL-4 vs. IL-12)
 and finally, to initiating the differentiation of
particular leukocyte lineages (e.g., GM-CSF, GCSF).
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The Hematopoietin or Class I Receptor Family

The γ-Chain Bearing, or IL-2 Receptor,
Subfamily:
Expression of a common γ chain defines the IL-2
receptor subfamily, which includes receptors for
IL-2, IL-4, …….
The IL-2 receptors are heterotrimers, consisting of
α chain and —β and γ—responsible for both signal
transduction and cytokine recognition.
The IL-2 receptor γ chain also functions as the signaltransducing subunit for the other receptors in this
subfamily, which are all dimers.
The IL-2 receptor occurs in three forms, each
exhibiting a different affinity for IL-2:
the low-affinity monomeric IL-2Rα (which can
bind to IL-2, but is incapable of transducing a
signal from it),
 the intermediate-affinity dimeric IL-2Rβγ
(which is capable of signal transduction),
 and the high-affinity trimeric IL-2Rαβγ
(which is responsible for most physiologically
relevant IL-2 signaling).
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The β Chain Bearing, Receptor Subfamily
which includes the receptors for IL-3, IL-5…..
share the β signaling subunit.
binds with low affinity α subunit of a dimeric
receptor.
All
three
low-affinity
subunits
associate
noncovalently with the common signaltransducing subunit. The resulting αβ dimeric
receptor has a higher affinity for the cytokine
than the specific α chain alone, and is also
capable of transducing a signal across the
membrane upon cytokine binding.
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 Interferon
(Class II)
○ First cytokines to be discovered
○ Type I - Secreted by not only macrophages and
dendritic cells but also by virus infected cells: (1)
Interferons α, and (2) interferon-β,
○ Type II – produced by activate T and NK cells ,
known as interferon-γ & cytokines include IL-10
o Third class, interferon-λ . This type up-regulate
the expression of genes controlling viral replication
and host cell proliferation.
All three interferons
(1) increase the expression of MHC complex
proteins on the surface of cells, thus
enhancing
their
antigen-presentation
capabilities.
(2) Interferon-γ is used medically to bias the
adaptive immune system toward a cytotoxic
response in diseases such as leprosy and
toxoplasmosis, in which antibody responses
are less effective than those that destroy
infected cells.

Interferon Receptors
are heterodimers that share the same with
members of the Hematopoietin receptor
family
The JAK-STAT Signaling
Pathway
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Tumor Necrosis Family (TNF)
○ Can signal development, activation, or death of
certain cells
Cytokines of the TNF Family
○ There are two members having the same name
of the TNF family: TNF-α and TNF-β. Both of these
are secreted as soluble proteins.
TNF Receptors
TNF-R1,
 Fas Receptor:
Which induce apoptosis, or programmed
cell death, is a mechanism of cell death in
which the cell dies from within and is
fragmented into membrane-bound vesicles
that can be rapidly phagocytosed by
neighboring macrophages.
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 IL-17
Family
○ Most recently described cytokines
○ Proinflammatory cytokine cluster
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interleukins 17A, 17B, 17C, 17D, and 17F
T cells secreting IL-17A represent a new lineage,
the TH17 cell subset, IL-17 family share the
property of operating at the interface of innate
and adaptive immunity, serving to coordinate the
release of proinflammatory and neutrophilmobilizing cytokines.
IL-17E promot the differentiation of the antiinflammatory TH2 subclass, suppressing further
TH17 cell responses,
Chemokines Direct the Migration of
Leukocytes Through the Body;
Are
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.
 located on the surfaces of endothelial cells,
enables them to bind to the inner surfaces of
blood vessels and directing leukocyte
movement.
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The grouping of chemokines into the subclasses
has functional, as well as structural,significance.
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The seven human CXC chemokines share the same
receptor (CXCR2), attract neutrophils, are angiogenic
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Members of the two, structurally distinct CC groups are
chemoattractants
that
attract
monocytes
and
macrophages (although not neutrophils) to the site of
infection.
Cytokine Antagonists

Number of proteins can inhibit cytokine
activity
○ Can bind to receptor but fail to activate the
cell, thus blocking the active cytokine from
binding, OR
○ Can bind to cytokine, inhibiting its ability to
bind to the receptors
Cytokine Related Diseases

Sever combined immunodeficiency
(SCID)
 Genetic defects in cytokines, their receptors

Defective receptor for IFN-γ
 Susceptible to mycobacterial infections
Cytokine Related Diseases
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Bacterial Septic Shock
 Certain bacteria: Staphyloccocus aureus, E. coli,
Klebsiella pneumoniae …..
 Symptoms: drop in blood pressure, fever,
diarrhea, blood clotting
 Endotoxins (cell wall) bind TLRs on dendritic
cells and macrophages leading them to produce
○ Over-produce IL-1β and TNF-α
○ Cytokine imbalance causes abnormal temp, abnormal
respiration, capillary leakage, tissue injury, organ failure
○ Neutralization by monoclonal antibodies may help
Cytokine Related Diseases

Bacterial Toxic Shock
 Microorganisms produce toxins that act as
Superantigens
○ Bind simultaneously to Class II MHC and T
cell receptor, activating T cell despite
antigenic specificity ,,induce extremely high
levels of TNF-α and IL-1β
 Symptoms similar to sepsis
Cytokine Related Diseases
Abnormalities in production of cytokines or
receptors are associated with certain types of
cancer (abnormally high levels of IL-6 are
secreted by cardiac myxoma)
 Historical documents detailing the symptoms
of the 1918 Spanish influenza with massive
fatalities resulted from cytokine storms,
unregulated,
immune
cell
cytokine
secretion…..
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Cytokine-Based Therapies;
Soluble TNF-α receptor and monoclonal
antibodies against TNF-α have been used to treat
rheumatoid arthritis and ankylosing spondylitis
in more than a million patients. Which reduce
proinflamatory cytokine cascades; help to alleviate
pain, stiffness, and joint swelling; and promote
healing and tissue repair.
 The recombinant form of IL-1Ra has been shown
to be relatively effective in the treatment of
rheumatoid arthritis.
 Monoclonal antibodies directed against the α chain
of the IL-2R are also in clinical use for the
prevention of transplantation rejection reactions
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Q1//How might a cytokine signal result in the
alteration of the location of a lymphocyte?
A cytokine may induce the expression on the
cell surface of new chemokine receptors
and/or new adhesion molecules that would
cause the cell to move to a new location and,
once present, to be retained there.