L15 cytokines Flashcards
what are cytokines?
Cytokines are the way in which
the immune system
communicates.
Analogous to hormones of the immune
system.
Produced by a cell usually following a stimulus, travel and bind to a receptor on a target cell and elicit a immunological response.
Diverse group of small proteins (5-
25KDa).
Secreted by a wide range of cells, both
immune cells and non-immune cells
(epithelial cells secrete IL-1, IL-8, IL-6,
TGFb, Stromal cells of bone marrow
secrete growth factors).
Originally termed lymphokines but now
variously called Chemokines,
Interferons and Interleukins, growth
factors – they are all cytokines.
cytokine vs hormones?
Cytokines can be exquisitely sensitive:
* hormones circulate in nanomolar (10 -9 M)
concentrations and usually vary by less than
one order of magnitude.
* In contrast, cytokines (such as IL-6) circulate in
picomolar (10 -12 M) concentrations and can
increase up to 1,000-fold during trauma or
infection. great capacity for changing the magnitude of their response.
Hormones are secreted by specific glands!
Cytokines are secreted by MANY
DIFERENT cells
cytokine families?
Tend to be grouped either functionally or structurally:
interleukins e.g. IL-1, 2, 3… 36, also
includes erythropoietin (EPO) and thrombopoietin. have an alpha chain bundle structure?
inteferons: Structurally diverse and
grouped into type I: IFN a,b,(k,d,e,t) ,and type II: IFN-gamma. Tend to “interfere” with viral replication.
Chemokines: group of cytokines that direct
cell movement. 4 subfamilies classified by the arrangement of their cysteine bonds into CC, CXC, CX3C groups
Colony stimulating factors (CSF): secreted
glycoproteins that act upon haematopoietic cells to regulate proliferation and differentiation, G-CSF, M-CSF, GM-CSF
Tumour necrosis Factors (TNF): Primarily
transmembrane, surface proteins. TNF-a, b but also CD40L, FASL, CD30L. bound to cell surface. cleaved and released upon infection.
Growth factors (GF): cytokines that direct
proliferation (and differentiation) e.g. TGF-β,
VEGF
chemokines?
They all mediate chemotaxis (not the only cytokines to do this).
Contain 2/4 cysteine residues in a conserved
Structural location.
Chemokines are divided into four groups depending on the number of cysteines and their spacing (arrangement)
Functional Classification of
Cytokines
- 5 main groups
- Immunoregulatory: IL-2, IFNg, TGFb, IL-4, IL-12, IL-15
- Pro-inflammatory: TNFa, IL-1a, IL-6, IL-17, IL-23
- Anti-inflammatory: IL-10, IL-1receptor antagonist, IL-4
- Chemotactic: IL-8 (CXCL8), MCP-1 (CCL2),
RANTES (CCL5) - Haematopoietic: GM-CSF, M-CSF, IL-5, IL-3, IL-7
Cytokine-induced responses
Cytokines induce a WIDE range of effects on their target cell
including:
* Proliferation, IL4, IL2 (B cells, T cells)
* Differentiation/Maturation IL7, IL4, GM-CSF (HSC)
* Survival Fas (many cells), IL15 (CD8+ T cells)
*Changes in expression of membrane proteins (including their
receptors) IFNg, TNF (APC – MHC)
* Secretion of effector molecules IL9 (mast cells), IL17 (epitelial
cells)
Modes of cytokine action
autocrine manner: E.g. IL-2 being produced by maturing T cells following APC interaction stimulating their proliferation and maturation.
paracrine action towards mirons up to 1mm apart: E.g. IL-4 being released by Th2
cells to induce B cell class
switching
endocrine action, great distance, in the circulation to another cell: E.g. IL-6 and TNFα
modulate
hypothalamic
production of ACTH
-elevates temperature
and regulates lipid
metabolism
Modes of cytokine action
Cytokines are PLEIOTROPIC – one cytokine can have different (completely unrelated) effects on different target
cells. e.g: IL-4 in th2
Cytokines can be REDUNDANT– different cytokines can have the same effects on their target cells.
Cytokines can be SYNERGISTIC – different cytokines augment the response of each on its own. e.g: IFN-Y by th1 and TNF-alpha by macrophage increasing mhc 1 expression on many cell types.
Cytokines can be ANTAGONISTIC – different cytokines have opposite effects on the target cell. e.g: IL-4 and IFN-Y by th1/th2: il-4 drives class switching to IgE while ifn-y blocks this.
T helper cells are defined by the
cytokines they produce
all in lecture 14
How does a cytokine activate its
target cell?
A cytokine will have no effect on a cell
unless it expresses a receptor for that
cytokine.
* Regulating the expression level of the
receptor is a means of controlling the
effect of the cytokine.
Cytokine receptors are almost as diverse as cytokines themselves
e.g: IL-1 BINDS TO IG-TYPE RECEPTORS
TNF-ALPHA TO TNFR-TYPE
IL-2 CYTOKINE RECEPTOR TYPE 1
IFN, IL-10 TO CYTOKINE RECEPTOR TYPE
Cytokine receptors frequents share subunits
a common chain involved in specifying ligand specificity and a more shared signalling chain/
e.g: IL-4 alpha chain shared by both IL-4R AND IL-13R
Cytokines and Disease
X-linked severe combined
immunodeficiency (X-SCID).
* x-linked recessive trait - mutated IL2-Rg
chain.
* IL-2Rg shared between receptors for IL-
2, IL-4, IL-7, IL-9, IL-15 and IL-21.
* Isolation in a “bubble” was an early
prophylactic treatment.
* BM transplant – standard treatment.
Cytokine storm
- Immune response is normally controlled by feedback mechanisms.
- If these fail, too many cells are recruited and a systemic immune response results, releasing >150 mediators.
- high fever, swelling and redness, extreme fatigue and
nausea - Causes unknown, results from infectious and non-
infectious diseases including (GVHD), acute respiratory
distress syndrome (ARDS), sepsis, Ebola, avian influenza,
Covid 19.
Rheumatoid arthritis
systemic autoimmune disease
Chronic inflammation of joints
Pain, loss of function, invalidity
Multifactorial: gender, age, genetics,
environment
T cells, B cells, DC, macrophages,
neutrophils and fibroblasts
Cytokines: TNF-α, IL-1β, IL-6 and IL-17
Blocking TNF-a can dramatically reduce inflammation and
even reverse some of the cartilage damage (anti-TNF therapy)
Cytokines in T cell proliferation?
Interleukin-2 (T cells)
* Induces T cell proliferation
* Enhances NK cell activity
cytokines in antiviral response?
Interferon α (leukocyte) and interferon β (fibroblast)
* Prevents viral replication
* Increases MHC class I expression
