Zusammenfassung der Ressource
Cytokines
- 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)
- TNF receptors- 2 main
ones: TNFRI (p55)
induces apoptosis &
TNFRII (p75) induces cell
activation & proliferation
- Anti-inflammatory
cytokines
- IL-10 prevents TH1 cytokine production. IL-1RA
(antagonist) inhibits action of IL-1
- Chemokines
- 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
- Families: 1. CXC/a chemokines-
ELR: mainly attract neutrophils/non
ELR: mainly attract monocytes.2.
CC/b chemokines- attract
lymphocytes, monocytes &
eosinophils 3. CX3C chemokine:
attracts lymphocytes & monocytes 4.
C chemokine attracts lymphocytes
- 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
- Blocking TNFa & IL-1 in fever & sepsis (shock)