#2 Cytokine Messenger Systems Flashcards
When are cytokines in the bloodstream?
Only when a person is sick
What kind of receptors do cytokines have?
A small number of high-affinity receptors
Signaling uses JAK-STAT or Ras-MAP kinase pathways
What do cytokine receptors do?
Make changes in the pattern of RNA and protein synthesis
Act at very low concentrations
Pathway of Cytokine Signaling
- Cytokine binds to its 2 receptors (at same time) and each has a JAK on it.
- JAKs are activated and auto-phosphorylate
- They then phosphorylate the cytokine receptors (on tyrosine residues)
- STAT proteins bind to these receptors, and then the JAKs phosphorylate them (STATs)
- Once phosphorylated, the STATs bind to one another, go to the nucleus where they bind to the promoter region of cytokine responsive genes
IL-4 effect on differentiation
Can turn T helper cell into 1 of 3 cells:
B cell
Thymocyte (make T cells)
Mast cell
What does redundancy mean in regards to cytokines?
There is overlapping and redundancy between cytokines…i.e. several different types of cytokines can make the same cell
Ex. (starting w/ activated T helper cell)
IL-2,4,5 →B cell proliferation
What does synergy mean in regards to cytokines?
Cytokines can combine/mix each others effects
Ex. (starting w/ activated T helper cell) IL-4 + IL-5 → B cell (induce class switch to IgE)
What does antagonize mean in regards to cytokines?
Cytokines can block each other
Ex. (starting w/ activated T helper cell) IL-4 [IFN γ] blocks→ Blocks class switch to IgE induced by IL-4
Cytokines can induce each other to become different cytokines
True
What are the main pro-inflammatory cytokines?
TNF, IL-1, IL-6
What kind of transcription do pro-inflammatory and anti-inflammatory cytokines have?
Pro: NF-κB dependent transcription
Anti: NF-κB independent
What are the anti-inflammatory cytokines and what do they do?
IL-10
TGF-β
Control inflammation and promote healing
Which of the pro-inflammatory cytokines do you need more of? which less?
IL-1 (need more) and TNF (need less)
When given to humans, they produce fever, systemic inflammation, shock and death
Our body reduces them via neutralizing antibodies, soluble receptors, receptor antagonists
What has been successful in patients with rheumatoid arthritis, inflammatory bowel disease and graft-vs-host disease?
Blocking TNF and IL-1
*NOT successful in treating: sepsis (life-threatening complication of an infection)
What induces TNF?
Endotoxin (LPS)
What does Endotoxin (LPS) do?
It interacts with endothelial cells to induce ICAM 1, VCAM 1 and E-selectin (2nd important is IL-1), which helps get granulocytes to the infection site
What is the primary mediator of septic shock?
TNF
TNF
Activates neutrophils, mediating adherence, chemotaxis, degranulation, respiratory burst
What does TNF bind to?
TNF receptor I (TNFR p75)
TNF receptor II (TNFR p55)
How does TNF induce antitumor immunity?
Via apoptosis of tumors
How does IL-1 induce production of IL-2?
IL-1 induces production of IL-2 by, and proliferation of, CD4 T lymphocytes
What can neutralize IL-1?
IL-1 receptor antagonist, IL-1ra
What is the most important inducer of acute-phase proteins?
IL-6
IL-6 has a primary role in Th17 immune regulation
True
IL-8
Made by MΦ in response to inflammatory stimulus
At the start of inflammation, mast cells release IL-8 form their granules
IL-12
Mostly from DCs and MΦ
Structure of IL-12
Heterodimer with 2 subunits:
IL-12p40 and IL-12p35
IL-12 synergizes with IL-18, also known as IFN-γ-inducing factor, to stimulate IFN-γ release
True
IL-15
Made mostly by mononuclear phagocytic cells
Activates NK cells
Similar to IL-2, IL-15 is a T-cell growth factor
Chemotactic for T lymphocytes
Very important for survival of CD8 memory T cells
What are the major Anti-inflammatory Cytokines?
IL-10, IL-1 receptor antagonist (IL-1ra), TGF-β
What stimulates fibrosis? (for wound healing and scar formation)
TGF-β
Classically activated and alternatively activated Mφ’s
Classically activated Mφ (M1): phagocytosis, inflammation
Alternatively activated Mφ (M2) via IL-4: Anti-inflammatory effects, wound repair, fibrosis
Differentiation of different T-helper subsets is controlled at the transcriptional level
Transcription Factors:
T-bet → Th1 cells
GATA-3 → Th2 cells
RORγT → Th17
FOXP3 → T regulatory cells
IL-2 Controls Proliferation of T-cells
- Naive T cells express the low affinity IL-2 receptor (IL-2R) complex, made up of the β
and γ C chains. - On activation by antigen recognition and co-stimulation, the cells produce IL-2 and
express the α chain of the IL-2R forming the high-affinity IL-2 receptor. - Binding of IL-2 to its receptor initiates proliferation of the T cells that recognized the antigen.
What does IL-2 do?
Stimulates proliferation of T-cells
Stimulates expression of IL-2R (not on naive T cells but synthesized a few hours after activation)
Acts only on cells that have high-affinity IL-2R
Increases # of IL-2R on cells
If Ag is cleared, the # of IL-2R decreases
TGF-β blocks IL-2-induced proliferation is a key mechanism of control of T cells proliferation
Th2 and B cells
Th2 cells activate B-lymphocytes resulting in
upregulation of antibody production.
Role of Th1 cells in Host Defense
Th1 cells make IFN-γ which activates phagocytes (classical pathway of Mφ activation)
Th1 cells stimulate the production of antibodies which promote phagocytosis
IL-12 knockout (KO) mice and IFN-γ KO mice
IL-12 knockout: can’t control infection and die because no Th1-type adaptive immunity in the mice
IFN-γ knockout: die early because Mφ are not activated properly in absence of IFN-γ
*Wild type can control the infection
