Cytokines and Chemokines

After reading this lecture, you should be able to:

►Define cytokines and chemokines

►describe
the general properties of cytokines and
chemokines
►Demonstrate and classify the cytokine families
►Explainthe common features of each family that
used by innate and adaptive immune cells and
give examples for each family
►ExplainCytokine antagonists, cytokine related
diseases and cytokine-based therapies.
Dr. Refif S. Al-Shawk
Lec 1
2019-2020
 Cytokines
► Low-molecular weight regulatory proteins or
glycoproteins
► Secreted by WBC and various other cells
► Assist in regulating development of immune
effector cells

Chemokines
Subpopulation of cytokines that share the
specific purpose of mobilizing immune cells
from one organ, or from one part of an
organ, to another.
❖ 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.
Cytokines can act
in several different
ways:
on the basis of the
distance between
the cell secreting
the signaling
ligand & the cell
receiving that
chemical signal

Of note, the T-cell

interleukin IL-2 acts
effectively in all
three modes.
General properties of cytokines
and chemokines

► Cytokines Mediate the Activation, Proliferation, and

Differentiation of Target Cells
► Cytokines regulate the intensity and duration of the immune
response…… by stimulating or inhibiting the activation,
proliferation, and/or differentiation of various cells….. by
regulating the secretion of other cytokines or of antibodies,
or in some cases …… by actually inducing programmed cell
death in the target cell

► Cytokines exhibit the attributes of pleiotropy, redundancy,

synergism, antagonism, and cascade induction
 Cytokines Have
Numerous
Biological Functions

► Table 12-1 summarizes

the biological functions
of some commonly
encountered cytokines.
 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.
 
► 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.
Cytokine classes and
their action
► 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
Cytokines of the IL-1 family promote
inflammation
► IL-1 stimulated by viral, parasitic, or
bacterial antigens after recognition
by innate immune receptors ???
► typically secreted very early in the
immune response by dendritic cells
and monocytes or macrophages.
► IL-1 family members are generally
proinflammatory, (what does that
mean)?
► 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 (CRP) and IL-6
► 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).
► IL-18 stimulate production of the
macrophage-activating cytokine IFN-γ by NK cells and
T cells.
innate immune response
► IL-1 also activates both T and B cells at the induction of
the adaptive immune response.
► Hematopoietin (Class I) Family
► Called Class I because earliest to be structurally
characterized (not first to be discovered)
► Large family of small cytokine molecules with
functional diversity???
► 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., granulocyte
monocyte-colony stimulating factors GM-CSF, G-CSF).
► E.X. IL-2, IL-4, IL-5, IL-7, IL-9,IL-12, IL-15, IL-21 and GM-CSF
 Interferon (Class II) First cytokines to be discovered

○ Type I - Secreted by not only activated

macrophages and dendritic cells but also by virus
infected cells with anti-viral effect: Interferons (INF-
α), and interferon(INF-β),
○ Type II – produced by activate T and NK cells ,
known as interferon(INF-γ) & cytokines include
IL-10
○ Type III – Secreted by plasmacytoid dendritic
cells, and up regulate genes controlling viral
replication and host cell proliferation:
interferon(INF-λ)
► Interferon-γ is used medically to bias the adaptive
immune system toward a cytotoxic response in
diseases such as leprosy and toxoplasmosis
(intracellular pathogens), in which antibody
responses are less effective. BY
► inducing the activation of macrophages, with
subsequent destruction of any intracellular
pathogens
► and the differentiation of cytotoxic T cells.
► All three INFs
(increase the expression of MHC complex proteins on
the surface of cells, thus enhancing their
antigen-presentation capabilities.)
► Tumor Necrosis Family (TNF)
► Can signal development, activation, or death of certain
cells (homeostasis)
► Which induce apoptosis, or programmed cell death
► TNF cytokines may be soluble or membrane bound
► 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
► CD40L (T-cell differentiation signal to B-cell) and FasL (induce
cell death upon ligand binding,)and are membrane bound
► TNF-α is a proinflammatory cytokine, produced primarily by
activated macrophages, and lymphocytes, in response to
infection,or inflammation.
► TNF-β is produced by activated lymphocytes and can deliver a
variety of signals. On binding to neutrophils, endothelial cells lead
to increased expression of MHC and of adhesion molecules.
► IL-17 Family (most recently described cytokines
,proinflammatory cytokine cluster)

► interleukins 17A, 17B, 17C, 17D, and 17F.

Signaling through most members of this family
culminates in the generation of inflammation.
► IL-17 released by activated T cells and
stimulates the production of factors that signal
a proinflammatory state, including IL-6,
chemokines CXCL8, and (G-CSF).
 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
toward the chemokine source.
⦿ This soluble factor-directed cell movement is
known as chemotaxis, and molecules that
can elicit such movement are referred to as
chemoattractants
⦿ located on the surfaces of endothelial cells,
enables them to bind to the inner surfaces of
blood vessels and directing leukocyte
movement.
•CXCLgroup: attract
neutrophils
•CCL group: attract
monocytes and
macrophages (although not
neutrophils) to the site of
infection.
 Cytokine Antagonists
► Number of proteins can ► A naturally occurring cytokine
inhibit cytokine activity antagonists that modulate and refine
the power of particular cytokine
► Can bind to responses, as well as the ways in which
receptor but fail various pathogens have hijacked
to activate the cytokine responses to their own ends.
cell, thus
blocking the ► Regulatory T cells, which express high
active cytokine levels of CD25 on their membrane
from binding, OR surfaces, have been shown to release
► Can bind to sIL-2R upon activation. Since these T
cytokine, cells serve the function of
inhibiting its down-regulating ongoing immune
ability to bind to responses, (soluble IL-2 receptors serve
the cognate the physiological function of soaking up
receptor excess IL-2 ) thus reducing the amount
of the cytokine that is available.
► Epstein-Barr virus (EBV), for example,
produces an IL-10–like molecule (viral
IL-10 or vIL-10) that binds to the IL-10
receptor. Just like host-derived IL-10, this
viral homologue suppresses TH1-type
cell-mediated responses that would
otherwise be effective in fighting a viral
infection.
Cytokine Related Diseases
⦿ 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-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-1R receptor?? has
been shown to be relatively effective in the
treatment of rheumatoid arthritis.
► Monoclonal antibodies directed against the IL-2
Receptors ?? are also in clinical use for the
prevention of transplantation rejection reactions
 
► Referrences :
► Kuby immunology 7th edition, 2013 by W. H.
Freeman and Company
► Kuby immunology 8th edition, 2019
► Cellular and molecular immunology 8th edition ,
2015 by Abul K. Abbas