Download Cytokines and Chemokines

CYTOKINES
What are Cytokines?
• A collection of polypeptides used for
communications between cells
• Play role similar to hormones (messengers of
the endocrine system)
– 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 (alpha,beta,gamma)
• Others (common names)
Cytokine - Mediated Effects
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
Properties of Cytokines
• 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
• Autocrine
– Cytokine binds to receptor on cell that
secreted it
• Paracrine
– Cytokine binds to receptors on near by cells
• Endocrine
– Cytokine binds cells in distant parts of the
body
Cytokine Actions
• Pleiotropy
– Act on more than one cell type (INFa/b)
• Redundancy
– More than one cytokine can do the same thing
(IFNa/b and IFN )
• Synergy
– 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
– Two or more cytokines work against each other
(IL-4 and IL-12)
How Can Non-specific
cytokines act Specifically?
• Only cells expressing receptors for specific
cytokines can be activated by them
• Many cytokines have very short half-lives
– Only cells in close proximity will be activated
• High concentrations of cytokines are needed
for activation
– Only cells in close proximity will be activated
– May require cell-to cell contact
Cytokine Receptor Families
• 5 Major Families
– Immunoglobulin Superfamily
– Hematopoietin Receptor Family (Class I)
– Interferon Receptor Family (Class II)
– TNF Receptor Family
– Chemokine Receptor Family
• Class I and II (Majority Of Receptors)
– Multimeric
– Upon Receptor Engagement, Tyrosine
Phosphorylation
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
Involvement of Cytokines in the
Immune Response
• Alert to
infection.tumor/et
c.
• Recruit cells to site
• Specify type of
immune response
• Immune effector
phase
• Immune downregulation
• Immune memory
and resetting the
system
• 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.
(GM-CSF, IL-3, IL7, etc.)
Early Mediators
• 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
Chemokines
•
•
•
•
•
Recruit to sites of infection
MIP-1alpha (NK and T cells)
MIG, RANTES (CD4+T cells)
IL-8 (neutrophils)
Eotaxin (eosinophils)
Early Mediators
• 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
• 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
Down Regulators
• IL-10, IL-11, TGF-b
• Inhibit proliferation, cytokine
production
• Produced by both innate and
adaptive cells
Maintenance Cytokines
• GM-CSF, IL-3, IL-7, IL-9, etc.
• Induce cell differentiation, cell
growth
Cytokine Cross-Regulation
• 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
Cytokine Therapies
Suppression of TH-cell proliferation and TC-cell activation