Lecture 9 (4b) - Cytokines Flashcards
Receptors transmit signals
from the cell surface to the nucleus to change gene expression and function
• can work locally, at a distance, at low levels
• signals from - CYTOKINES, chemical messengeres, hormones
IL =
interleukin
• called lymphokines
• can sometimes be non-immune cells and target non-immune cells
Cytokines in antigen presentation
IL- 1 16 12 18 23 27
Cytokines from the gut epithelium to the T cell
IL
7
15
Cytokines in costimulation
APC : Tcell
CD40 : CD40L
CX40L : CX40
CD80/86 : CD28
Cytokines in inflammation
from T cell IL 5 13 17 21 22
TNFα IFNγ
- -> macrophage
- -> TNFα IL-6 IL-1
- -> inflammation
(–> Crohn’s disease)
Cytokines for T cell proliferation
IL
2
21
Cytokines are
small proteins secreted by the cells of the innate and adaptive immune systems
Cytokine secretion is
brief, self-limited
transient synthesis
Cytokine are usually not
stored in the cells (except mast cells store it in cells)
• they are synthesized by new gene transcription
Transcription of cytokine genes is
a transient process
• cytokine mRNAs are unstable
Cytokines, like other polypeptide hormones, mediate their effects by
binding to specific receptors on the surface of target cells
• these receptors are often on many cell types
• immunology is context-specific
Cytokines are pleiotrophic
they have many functions • made by many cell types • same cytokine made by different cells • cytokine receptors on many cell types • have many different effects on different cell types
• many cells make them, many cells respond to them, response depends on what it binds
Cytokines produced as a result of activation of the
INNATE IMMUNE SYSTEM
• type 1 interferon • interleukins - IL-1 - IL-6 - IL-12 • TNF
Cytokines produced as a result of activation of the
ADAPTIVE IMMUNE SYSTEM
• IFNγ • interleukins - IL-2 - IL-4 - IL-5 (IL-4 and IL-5 for Th2)
Cytokines that stimulate immature leukocyte growth and differentiation
- IL-3
* colony stimulating factors
Interleukins vs cytokines
- all interleukins are cytokines
* not all cytokines are interleukins
T cells make lots of cytokines when activated
switch on T cell by binding TCR
make nothing –>
activated = lots of transcriptional activation
= mediated by cytokines, lots of different targets
IL-2
T cell growth factor
IL-3
mast cell growth factor
IL-4 and IL-5
B cell growth factor
• made by Th2
• IL-5 = eosinophil growth factor
IL-10
- B cell growth factor
* immunosuppressive cytokine
IFN- γ
- anti-viral
* activates macrophages
IL-2 secretion
cloned as T cell growth factor, does other things:
• induces Th cell, induced by Th cell
• B cell - stimulation of division
• T cell - stimulation of division, IFNγ release (and other mediators)
• NK cell - increase NK cell activity (lymphokine activated killer)
• monocyte activation
IFN-γ
made by T cells, important in cell-mediated immunity
• induced by: NK cells, T cells
• endothelial cells - activation
• NK cells - increase in NK cell activity
• many cell types - induction of Class I or Class II MHC
• B cell - differentiation, stops cell division
• T cell - activation
• many cell types - weak anti-viral activity, stops cell division, hematopoiesis stops
• macrophage - activation
• granulocyte - activation
Toll-like receptors
innate immunity
molecules on the surface of mammalian cells which recognize components of bacteria and viruses to alert the immune system
TLR2
+
TLR6 (/ TLRX)
- lipoproteins
- lipopolysaccharides
- PGN (gram-positive)
- zygomosan (yeast)
- GPI anchor (T. cruzi)
TLR4
+
MD-2
- LPS (Gram-negative)
- Taxol (plant)
- F protein (RS virus)
- hsp60 (host)
- fibronectin (host)
TLR5
flagellin
TLR9
CpG DNA
When bacteria interact with macrophages through TLRs, macrophages release large amounts of cytokines
IL-1 TNFα IL-6 IL-8 nitric oxide IL-12******* MMPS
Actions of IL-12
NK cells
increased cytosolic activity
and
stimulate IFN-γ
- -> IFN-γ
- -> macrophage activation, killing of phagocytosed microbes
Action of IL-12
CD8+ T cell
stimulation of IFN-γ secretion
- -> IFN-γ
- -> macrophage activation, killing of phagocytosed microbes
Action of IL-12
Naive CD4+ T cell
Th1 cell
- -> stimulate IFN-γ secretion
- -> macrophage activation, killing of phagocytosed microbes
Bacteria in skin, Lagerhans recognize via TLR
macrophage makes TNFα and IL-1
–> endothelial cells, makes them sticky
–> neutrophils (in blood) stick to surface and go through
• localize phagocytes where bugs are
Cytokines are important in mobilizing inflammatory cells into tissues
inflammation
–> cytokines increased on endothelial cells (eg ICAM and selectin)
–> neutrophil finds these because it has receptors (LFA1)
–> neutrophil rolls, slows down and anchored by LFA1-ICAM
–> stops
==> through endothelial into tissue
Septic shock
- most common cause of death in ICUs in the US
- dissemination of infections into the vasculature
- caused by systemic microbial infection, most often by gram-negative infection (endotoxic shock) but can also occur with gram-positive and fungal infections
- infection from site into blood
How - septic shock
Cell envelope of gram-negative bacteria
- -> endotoxin (CLPs)
- -> TLR4
- -> macrophage releases cytokines
- -> local inflamation
- -> septic shock
Disseminated intravascular coagulation in small vessels
little clots in small vessels
–> punch holes in sides
–> vessels so sticky can’t get through
(disseminated intravascular coagulation in small vessels)
• lack of oxygen to the extremities because blood vessels are blocked –> tissue dies
• • cytokines here are bad
Chemokine
• a small subgroup or superfamily of cytokines that are released during the initial phase of cell response to injury, antigens, and invading microorganisms
• selectively attract leukocytes to inflammatory foci during both cell migration and activation
(hemotatic - draw cells into body)
Neutrophils move by
chemotaxis
• move up chemokine concentration gradient
There are lots of chemokines, often
binding to the same receptor
• redundancy
• knock out 1 chemokine and another does its function
IL-8
CXCL8
a chemokine that attracts neutrophils into tissues
• macrophage in lung making IL-8, binds CXCR1/2, chemotaxes it through into tissue and causes damage (CXCR1/2 causes damage)
Chemokines in extravasation
- capture
- activation
- adhesion
- transmigration
• ICAM-LFA1
• ICAM2 brings cells through
Anti-inflammatory cytokines
- IL-10 made by T cells, B cells, macrophages
- TNF, IL-1, IL-6 - pro-inflammatory
• transforming growth factor TGFβ (–> Treg)
- inhibits T cell activation
- inhibits antigen presentation
Damaging cytokines vs inhibitor cytokines
damaging - TNF, IL-1, IL-6
inhibitory - IL-10, TGFβ
• balance is anti-inflammatory usually
Cytokine storm
positive feedback loop between cytokines and immune cells –> elevated levels of cytokines
• TGN1412 (anti-CD28) activated all T cells –> cytokine storm
• antibodies to Cd28 usually activating for T cells
• TGN1412 (anti-CD28) meant to induce unresponsiveness in T cells
• given to patient with T cell disease, would switch T cells off
• cytokine storm same as septic shock
Anti-TNFα antibodies
- rheumatoid
- IBD
- asthma
- psoriasis
Anti IL-15 antibodies
rheumatoid
Soluble IL-1R
- rheumatoid
* psoriasis
Summary
- cytokines are critical for immunity
- complex, redundant, wide-ranging
- can kill you in excess
