Langer - Cytokines Flashcards
What does it mean that cytokines are pleitropic? Redundant?
P - 1 cytokine can have many different effects on different cell types
R - different cytokines have the same or overlapping effects, which basically means that we have backup systems for things that are very important.
How were cytokines originally discovered?
They would put cells in a Petri dish with a certain medium and then transfer them to a Petri dish with a different medium and see if they would survive/proliferate/differentiate/die etc. Then they would look to see what in that medium is responsible for it.
How do we discover cytokines now?
“In silico” - you find a cytokine, sequence it, and then look to see if there is anything in the gene that is similar to this either in the human genome or different genome.
What is an interleukin?
Signal between WBCs (usually)
Cytokines vs chemokines
Cytokines are larger, signal through receptors coupled to protein kinases. Signal infection and disease
Chemokines are smaller and signal through G-proteins. They generally function in a chemotactic sense in that they attract inflammatory cells.
Cytokine therapeutics
IFNa/b - antiviral, hepB, hepC, MS
IL-2 - growth of T cells and some cancers
GM-CSF - growth factor for neutrophils after bone marrow transplant
IFN-gamma - chronic granulomatous disease
Erythropoietin - anemia, myelodysplasia
Type I Interferons
Tells your Body that the viruses are present.
- gene cluster on ch. 9
- 13 IFNs
- Receptor is IFNAR
- largely involved in anti-viral response
- Causes: MHC induction, NK cell activation, DC maturation, Th1 biasing, B-cell class switching to IgG
Mechanism of Type I IFN
IFN binds to IFNAR, which is a Heterodimer, which activates Jak-STAT. Jak-STAT then binds to the interferon stimulators response element (ISRE), which is essentially the promoter region of the interferon stimulators genes (ISG). Then they activate mRNAs and make proteins, which exert their cellular effects.
How does Lupus work? Why is there so much IFN??
What happens is that you start making antibodies against your own single stranded DNA and RNA. Then the macrophage takes it in and presents it. It looks just like a virus because it is DNA/RNA with a protein. This causes the immune system to start making a lot of IFN to combat this. This will ramp up the immune response.
IL-2
IL-4, IL-5
IFN-gamma
IL-10
IL-2 - T cell growth factor
IL-4,5 - B cell growth, survival and differentiation
IFN-gamma - activates macrophages (made by T-cells)
IL-10 - inhibits immune response (shuts it down when necessary)
Why might a mutation of a certain chain in a cytokine receptor cause huge problems?
Because many cytokines share the same class of receptor, they also share many of the same chains within the receptor. So, although they bind different cytokines, they share a chain. Therefore, if you have a mutation in one chain of the receptor, it will affect all receptors of that same class that have that chain in it.
What are the inflammatory cytokines?
IL-1 and TNF-alpha (and IL-6)
How does the effects of pro–inflammatory cytokines change with level?
Low - local inflammation
High - can cause shock, blood coagulation, death
Chronic - weight loss, loss of connective tissue
In what order will you start to see pro-inflammatory cytokines after an infection?
TNF-alpha –> IL-1 –> IL-6
IL- pathway
Obviously don’t worry about the details, but just Know that IL-1 binds to the receptor, which causes things to bind intracellularly to the receptor and do to some phosphorylation and other cascade events there is activation of two transcription factors: NFkB and AP-1 that are responsible for the cellular affects
