Cytokines
n Small (low molecular weight) proteins that
assist in regulating the development of
immune effector cell
n Secreted by activated lymphocytes,
macrophages (white blood cells and some
others)
n Many cytokines exert biological effect by
binding to receptors on target cells and
triggering signal transduction responses
cytokines act locally within a small
microenvironment
high affinity for receptors (10-10 to 10-12 M)
Action of Cytokines
n The action of cytokines may be
autocrine
paracrine
endocrine
n Cytokines action may be
Pleiotropic- any given cytokine may have
different biological effect on different target
cells
Redundant- two or more cytokines that
mediate similar functions
Synergism- combined effect of two cytokines
is greater than the additive effect of each alone
Antagonism- the effects of one cytokine inhibit
or offset the effects of another
1
Cytokine Action
n Short lived
n secreted only when cell is activated, not
constitutively (like growth factors)
n Most act in an autocrine or paracrine
fashion
n Function as intercellular messengers:
Should know the following: cytokine,
secreted by, target cell, and actions of .....:
IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13,
IL-16, IFN- and TGF- , and TNF- and
Cytokine Receptors
n 5 Families of Receptors
Immunoglobulin superfamily receptors
Class I cytokine receptor family
class II cytokine receptor family
Interferon receptor family
TNF receptor family
Chemokine receptor family
n Receptors of different types may have
same signal transduction action
2
IL-2 Receptor
n Trimeric receptor composed of
chains.
n Occurs in 3 forms that exhibit different
affinities for IL-2
low affinity monomeric IL-2R
intermediate affinity dimeric IL-2R
High affinity receptor IL-2R
n the chain is expressed by activated, but
not resting, T cells (TAC=T cell activation antigen)
n Signal transduction by IL-2R requires both
the and chains, but only the trimeric
has high affinity for IL-2
IL-2 Receptor
n The chain is constitutively expressed on
most lymphoid cells
n The chain is expressed on most cells
constitutively, but is expressed in higher
concentration when the cell is activated
n The chain is expressed only on
activated lymphocytes
the receptor- activated CD4+ and CD8+ cells
and in low levels on activated B cells
the receptor- on NK cells and resting T cells
the receptor- activated CD4+, CD8+ and B
cells
3
Cytokine Antagonists
n Act by binding:
directly to a cytokine receptor, but fail to
activate cell (competition for receptor)
bind directly to cytokine inhibiting its binding
" IL-1Ra binds to IL-1 receptor but has no
activity (role in regulating inflammatory
response
soluble cytokine receptors (made from
enzymatic cleavage of the receptor from the
cell membrane) can bind to cytokines
some viruses produce cytokine binding
proteins (Pox- soluble TNF and IL-1 )
TH1 and TH2 Subset Cytokines
n Cytokine secretion by TH subsets help
regulate whether the response is humoral
or cell mediated
Both CD4+ and CD8+ cells secrete IL-3 and GM-
CSF
TH1 responsible for classical cell-mediated
functions (I.e., DTH and activation of TC cells,
viral cell clearance)
" IL-2, IFN- , TNF- , (GM-CSF and IL-3)
TH2 subset responsible as helper for B-cell
activation (clears free living bacteria and
helminthic parasites, and allergic reactions
through IgE class switch by IL-4 and IL-5)
" IL-4, IL-5, IL-10, IL-13, (GM-CSF and IL-3)
4
TH1 and TH2 Cell Development
n IL-4 and IL-12 act on TH cells when TH are
activated by antigen:
IL-4 cells develop into TH2 subset
IL-12 cells develop into TH1 subset
These two subsets develop from a common
TH0 precursor cell that can secrete IL-2, IL-2
and IFN-
n Cytokines secreted by one subset can
block the cytokines secreted by the other
subset
IFN- inhibits proliferation of TH2 cells and
secretion of IL-10
IL-10 down-regulates secretion of IL-2 and IFN-
TH1 and TH2 Cell Development
n Cytokine Cross-Regulation
" IFN- and IL-2 (secreted by TH1 subset)
promote IgG2a production by B cells but
inhibit IgG1 and IgE production
" IL-4 (secreted by TH2 cells) promotes
production of IgG1 and IgE and suppresses
production of IgG2a
" IL-10 does not inhibit TH1 directly but acts
on macrophage and interferes with their
ability to stimulate TH1 cells
n Progression of some diseases may
depend on the balance between TH1 and
TH2 subsets
5
Therapeutic Uses of Cytokines
n Purified Cytokines
regulation of response to alloantigens (organ
transplants)
" try to block activation of TH and TC cells to
prolong transplants
" use of IL-1 soluble receptors to block TH
activation
" Use of anti-TAC antibodies to block IL-2
receptor
" toxin tagged cytokines (IL -2) to kill TH cells
(only responding cells have IL-2R)
" Use in LAK cell stimulation
" Treatment of allergy (block IL-4 using IL-12)
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