Messenger molecules of the immune &
inflammatory system. Often produced
and act on leukocytes (interleukins)
Pleiotrophic (can do more than
one thing)-have effects
simultaneously on more than
one cell or have more than one
action. ie they can act on many
different cells producing many
different effects
Redundancy- several cytokines may have similar
properties, actions and target cells. eg. IL-4 & !L-13/
IL-1a & IL-1b may be to avoid any potential lethal effect
of gene loss or viral evasion of a single cytokine
Locally active- mostly acute medators ie paracrine-cell produces
signal to induce changes in nearby cell not endocrine (in bloodstream).
Act through receptors. Active at very low concs, work in cascade
Often act in vincinity in which they are produced. Are short
lived. If they get into general circ=TROUBLE. IL-1/TNF=
SHOCK. IL-2=vascular leakage. But very short half life in blood
Cytokine receptors
all cellls have receptor for atleast one cytokine/ growth factor
All receptors have an extracellular (cytokine-binding) domain &
an intracellular (signal transduction) domain
signal transduction= cell proliferation, diffentiaton, cell death,
production of cytokines, expression of cell surface molecules
Receptors may be simple eg IL-1R- extracellular & intracellular
portion, transmem portion/ Complex eg IL-4 & IL-13= eg if virus
found way to block IL-4- 2 pathways would still be present
Different cytokines may share receptor chains- IL-3, IL-5 & GM-CSF
receptors share a common beta chain, but have different alpha chain.
Receptors may be shed from cells- cells can secrete cytokine
receptors under certain conditions and bind cytokines
extracellualely. At high level of cytokine, to prevent it from causing
extensive inflammation damage to tissues can produce a soluble
receptor which mop up excess cytokine and block its function. Very
important in controlling cytokine activity in the general circ eg TNFR
produced following stress/ shock STNFR blocks excessive TNF
Networks & cascades
Interferons
Type I: IFNas and IFNb.
Produced by and act on many cell
types. Anti-viral and
immunostimulatory effects. Type
II: IFNy produced by T cells and
NK cells upreg class I & II MHC
and stimulate macrophage function
Virus' trigger release
Some cytokines are heterohimers eg IL-12 is made up of p40 & p35 subunits. Rate
limiting step is production of p35- many cells express p40, need p35.
Pro-inflammatory cytokines
TNFa, IL-1, IL-6 (systemically found
exception). TNF & IL-1 produce a
local inflammatory response. IL-6 is a
serum marker of inflammation used
clinically to detect if patient is
suffering from inflammation
IL-1: 2 forms IL-1a & IL-1b. Only 27% homology but same activities
and bind same receptors (to avoid having virus which can block both
forms). IL-1Receptor type I on T cells, fibroblasts and endos. IL-1R
type II on monocytes & macrophages. Induces IL-2 & IL-2R expression
by T cells. Increases B cell prolif & Ig syn (can switch ona daptive)
leukocyte chemoattraction-attract leukocytes to site of inflammation. Leucocyte
activation/degranulation, angiogenesis/angiostasis, tissue homeostasis/wound healing,
lymphoid organ development, cell growth & metastasis (normal & tumour cells)
Low molecular weight soluble molecules,
some constitutive, involved in migration of
leucocytes through lymphoid tissues.
Other inducible in inflammation attracting
leucocytes to sites of inflammation
Mech: Bind to proteoglycans/GAGs on endothelial cell luminal surface
and form a stable conc gradient. Interact with receptors on 'rolling'
leucocytes and induce activation of integrins (adhesion molecules which
slow down leucocytes)-leads to stimulation of extravasation (move out
of endothelial layer into tissues)
Receptors: 7-pass transmembrane 'serpentine'
receptors. Most specific for one or a few CC, CXC,
C/CX3C chemokines. CXCR4 & CCR5 are
co-receptors for HIV. Chemokines & their receptors
have a major target for immune evasion by many
virus' (they want to block chemokines)
T cell cytokines
Th1: some IL-2, IFNy, TNFb, GM-CSF & IL-3
Th2: some GM-CSF, IL-3, IL-4, 5, 6, 9, 10, 13.
Colony stimulating
factors- CSFs
Act on blood stem cells to
induce their growth.
G-CSF (granulocytes),
M-CSF (monocytes),
GM-CSF (common
precursor for G & M)
Therapeutics
GM-CSF used to speed neutophil
recovery following bone marrow
transplantation, chemo-or radiotherapy.
IL-10: used in psoriasis to dampen down
immune system, IL-4 treats arthritis by
dampening down immune sys
IL-12 used to treat asthma-TH2 mediated
disease therefore if TH1 cytokine restore
balance in asthma=decreased IgE)
IL2, IL12 & IFNa used in cancer immunotherapy
to boost natural cell-mediated response
Anti-TNFa & blocking IL-12 function in rheumatoid arthritis because
proinflammatory switched on excessively in rheumatoid arthritis
Anti TNF a also used in Crohn's disease, asthma & psoriasis
IL-8 & IL-12 blocks used in inflammatory bowel disease