Lecture 17
Cytokines
What are cytokines?
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A collection of polypeptides used for
communications between cells
Play role similar to hormones (messengers of
the endocrine system)
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Hormones usually act at a distance
Cytokines act locally
Differ from growth factors that are produced
constitutively, while cytokine production is
carefully regulated
Play an important role in both innate and
adaptive immunity
Cytokine nomenclature
Interleukins (1-18)
 Interferons (a,b,g)
 Others (common names)
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Cytokine -mediated effects
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Cell growth
Cell differentiation
Cell death
Induce non-responsiveness to other
cytokines/cells
Induce responsiveness to other
cytokines/cells
Induce secretion of other cytokines
How do cytokines tell cells what
to do?
Produced by cells as part of normal
cellular activity and/or the result of
environmental trigger
 Bind to receptors on cells
 Trigger signal transduction pathways
 Initiate synthesis of new proteins
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Properties of cytokines
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Proteins
Low molecular weight
Bind to receptor on either cell which produced
it or another cell
Receptor binding triggers a signal
Signal results in altered pattern of gene
expression
Cytokines can act in three
different manners
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Autocrine
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Paracrine
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Cytokine binds to receptor on cell that
secreted it
Cytokine binds to receptors on near by cells
Endocrine
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Cytokine binds cells in distant parts of the
body
Cytokine Actions
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Pleiotropy
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Redundancy
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More than one cytokine can do the same thing
(IFNa/b and IFNg)
Synergy
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Act on more than one cell type (INFa/b)
Two or more cytokines cooperate to produce an effect
that is different or greater than the combined effect of
the two cytokines when functioning separately (IL-12
and IL-8)
Antagonism
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Two or more cytokines work against each other (IL-4
and IL-12)
How can non-specific
cytokines act specifically?
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Only cells expressing receptors for specific
cytokines can be activated by them
Many cytokines have very short half-lives
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Only cells in close proximity will be activated
High concentrations of cytokines are needed for
activation
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Only cells in close proximity will be activated
May require cell-to cell contact
Five cytokine receptor families
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Immunoglobulin superfamily receptors
Class I cytokine receptor family
(hematopoietin receptors)
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Binds most of the cytokines in the immune
and hematopoietin systems
Class II cytokine receptor family
TNF receptor family
Chemokine receptor family
Cytokines regulate the immune
response
 Cells
with the appropriate
receptors become activated
 To
differentiate
 To express receptors which will
make them receptive to other
cytokines
 To secrete other cytokines
Signal Transduction by cytokine
receptors
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Cytokine receptors on different cell types
trigger different events
How do you get the message from the outside
of the cell to the machinery inside?
Cytokines, growth factors and hormone
signal transduction pathways
The Jak/Stat Signaling Pathway
Involvement of cytokines in the
immune response
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Alert to
infection.tumor/etc.
Recruit cells to site
Specify type of
immune response
Immune effector
phase
Immune downregulation
Immune memory
and resetting the
system
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Early mediators
(IFNa/b)
Chemokines (MIP1a)
Early & late
mediators (IL-2,
IFNg, IL-4, IL-5)
Down-regulators
(IL-10, TNFg)
Maintenance of
cytokines, etc. (GMCSF, IL-3, IL-7,
etc.)
Early mediators
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Interferons a/b
Induced by dsRNA, etc.
 Induced by CD40/CD40L pathway
 IFNs can induce more of themselves
 Directly interferes with viral replication
 Activation of T and NK cells
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Chemokines
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Recruit to sites of infection
MIP-1a (NK and T cells)
MIG, RANTES (CD4+T cells)
IL-8 (neutrophils)
Eotaxin (eosinophils)
Early mediators
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IL-12, IL-15, 1l-18, IFN-g (from NK cells), IL-10
Proinflammatory mediators
Produced by cell associated with innate immunity
(macrophages, NK, etc.)
Mediate direct effects
Promote inflammation
Shape downstream responses
Late mediators
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IL-2, IL-4, IL-5, IFN-g, TNF, IL-6, IL-10
Produced by cells of the adaptive immune
response (T and B cells)
Direct effects
More immunoregulatory functions
Cytokine secretion and
biological activities of TH1 and
TH2 Subsets
Type 1
Cell-mediated
Immune response
(intracellular
Organisms)
IL-2
IFN-g
TNF
Type 2
T cell
IL-4
IL-5
Humoral
response
(parasites)
Down regulators
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IL-10, IL-11, TGF-b
Inhibit proliferation, cytokine
production
Produced by both innate and adaptive
cells
Maintenance cytokines
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GM-CSF, IL-3, IL-7, IL-9, etc.
Induce cell differentiation, cell growth
Cytokine cross-regulation
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In a a given immune response, either
TH1 or TH2 response dominates
Cytokines of one response tend to
down-regulate the other type of
response
Example: TH1 cells secrete IFN-g,
which inhibits proliferation of TH2
subset
Role of TH1/TH2 balance in
determining disease outcomes
Balance of two subset determines
response to disease
 Leprosy
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Tuberculoid (TH1, CMI response, patient
lives)
 Lepromatous (TH2, humoral response,
patient dies)
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Cytokine-related diseases
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Bacterial septic shock
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Blood pressure drops, clots form, hypoglycemia ensues, patient dies
LPS triggers results in TNF release
TNF induces IL-1 which induces IL-6 and IL-8
Bacterial toxic shock and related diseases
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Superantigens trigger large numbers of T cells which release massive
amounts of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell
receptors and the MHC class II molecules on APC’s, bypassing the need for antigen)
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Lymphoid and myeloid cancers
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Some cancer cells secrete cytokines
Chagas’ disease
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Trypanosoma cruzi infection results in sever immune suppression
Depression of IL-2 receptor production
Components of the immune
system
g
T cell
ab
T cell
CD8
ab
T cell
CD4
Help
B cell
Inflammatory
Cytotoxic cytokines
T cells
?
Antibody
Intra- and Extracellular Inflammatory
Mechanisms to Destroy or Inactivate Pathogens
Macrophages
Granulocytes
Interferon &
Non-lymphoid
Cytokines
Complement
Adapted from Marrack and Kappler, 1994
Infectious agents that target cytokines
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Epstein-Barr virus foster the generation of T helper cells
that do not produce IL-2.
EBV produces an analog of IL-10 that favors TH2 cells,
rather than TH1.
Parasites such as tape worms induce high levels of IgE, an
immunoglobulin induced by TH2 cells.
Since TH1 cells mediate inflammation, this may be a
protective ploy to avoid destructive inflammatory
processes.
Immunosuppressive effects of oral
bacteria on immune function
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Impairment of B and T cell function (P. intermedia,
P. asaccharolytica, P. endodontalis, P.
melaninogenica)
Production of specific toxins that kill monocytes (A.
actinomycetemcomitans)
Provoke the release of peroxide, prostaglandins and
other mediators capable of inhibiting lymphocyte
function (T. denticola)
Modulate expression of cytokines
Cytokine-inducing components of
Periodontopathogens
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Taken from Wilson, M., Reddi, K., Henderson, B. 1996.
Cytokine-inducing components of periodontopathogenic
bacteria. J. Periodont. Res. 31:393-407.
Pro-inflammatory cytokines such as interleukin (IL)-1,
IL-6, IL-8 and tumor necrosis factor (TNF) are believed
to be the major pathological mediators of inflammatory
diseases ranging from arthritis to periodontal diseases.
It is believed that components of microorganisms have
the capacity to induce cytokine synthesis in host cells.
Cytokine-inducing components of
Gram-positive bacteria
Cytokine-inducing components of
Gram-negative bacteria
Cytokine-induction by LPS from
periodontopathogens other than P. gingivalis
Cytokines produced by host cells in response to
components/products from periodontopathogens
Interferon Action
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Viral replication stimulates the infected host cell
to produce interferon.
Interferon induces uninfected cells to
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produce antiviral proteins that prevent translation of
viral mRNA
degrade viral nucleic acid
Viral replication is blocked in uninfected cells
Therapeutic uses of cytokines
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Modulation of TH activation
Interfere with receptor function
Interfere with cytokine
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Make it unable to bind to receptor
Make it unable to act
Examples of therapeutic uses
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Soluble T-cell receptor
Anti-IL-2R
Interleukin analogs which bind receptor, but do
not trigger activation (ties up receptor)
Toxins conjugated to cytokines which kill
activated T-cells
Administration of cytokines to enhance immunity
(side effects/ short half lives)
Allergies