Innate immunity: Cytokines and Interferons Flashcards
Interferons and Cytokines can be produced by…
Macrophages
What are the 3 main effects of Interferons and Cytokines?
a. Signal neighboring cells to put up barriers
b. Signal infected cells to die (apoptosis)
c. Recruitment of white blood cells to stimulate long-lasting immunity
Cell signaling through cytokine receptors is called…
Jaks and Stats pathway
What is the structure of cytokine receptors?
2 chains
1. Extracellular cytokine binding domain - binding site for cytokine molecules
2. Intracytoplasmic domain (catalytic site) binds Janus Kinases (JAKS) - tyrosine kinase activity
What happens in the absence of cytokine molecules?
2 chains remain dissociated
What happens upon cytokine and cytokine receptor binding?
Stabilises heterodimer
Brings together JAKS bound to cytoplasmic portions of each chain.
What happens when JAKS are activated?
Phosphorylates the tyrosine residue of two cytoplasmic tails of cytokine receptors
What is Stat?
Signal transducer and activator or transcription
Where Stat associated in the signaling?
Bind to the PHOSPHORYLATED cytokine receptor chains
Themselves get phosphorylated by the JAKS
The addition of phosphate to STAT enables…
Dimerization of STAT molecule
Migrates into the nucleus
Directly activated gene transcription
What domain of STAT binds to the phosphorylated tails of cytokine receptors?
SH2 domain
What are the key steps of JAK-STAT pathway?
- Cytokine-mediated receptor dimerization
- JAKS phosphorylates tyrosine residues
- STATs recruitment & JAK mediated phosphorylation
- Dimerization of STATS
- Translocation -> transcription
-> STAT dimer binds to STAT-binding sequences in the promoter
->Transcription of cytokine responsive gene
What is JAKS?
Proteins
What residue is found in the intracellular region of cytokine receptors?
Tyrosine Residue
Why do JAKS trans-phosphorylate each other initially?
Increases activity of tyrosine kinase domains.
This activates JAKS
What happens when JAKS gets activated?
Phosphorylates Tyrosine Kinase on cytokine receptors
What is phosphorylated tyrosine called?
Phosphotyrosine
Phosphotyrosine creates docking sites for what proteins?
STAT proteins by SH2 domain
When do the STAT proteins dissociate from phosphate tyrosine on receptor?
When they phosphorylated
Dimerization of STATs occurs straight after?
The phosphorylation of STAT
What does the dimerization of STAT protein involve?
SH2 domain binds to phosphate tyrosine on another STAT molecule -> homodimer
Where does the STAT homodimer translocate to?
Nucleus
What occurs during translocation of STAT?
DNA binding domain of STAT protein attached to DNA
Transcription
Gene Expression
What residues are found in STAT proteins?
Tyrosine Residues
Inactive STAT proteins are?
Found in cytosol
Unphosphorylated tyrosine residues
What effects do cytokines induce?
Local effects
Systemic effects
Local effects of cytokines target which cell?
Endothelial Cells
The local effects of cytokines that induce an increase in rate of…
Adhesion molecules
Permeability
Chemokine expression
Activation Degranulation
The local effects of cytokines that induce an decrease in rate of…
Flow rate
Why is there an increase in adhesion molecules?
Allows white blood cells to interact
Transmigrate to the site of infection
Why is there an increase in permeability?
Allows fluids to reach the site of infection
Swelling (characteristic of inflammatory response)
Why is there a decrease in flow rate?
Allow white blood cells to adhere to adhesion molecules
Why is there an increase in chemokine expression?
For molecules to attract other cells
What is the collective local effects of cytokine induction?
Increase activation of macrophages
Degranulation of neutrophils ( release enzymes)
What are the systemic effects of cytokine induction on the liver?
Stimulate acute phase proteins (produced in the liver)
What are the systemic effects of cytokine induction on the hypothalamus?
Fever
Inhibits microbial growth
What are the systemic effects of cytokine induction on the bone marrow?
Mobilization of cells in bone marrow
Help in innate immune response
List the 5 cytokines
IL-1B
TNF-alpha
IL-6
CXCL8
IL-12
What are the local effects of cytokine IL-1B?
Activates vascular endothelium
Activates lymphocytes
Local tissue destruction
Increases access of effector cells
What are the local effects of cytokine TNF-alpha?
Activates vascular endothelium
Increases vascular permeability -> leads to increased entry of Ig6, complement and cells to tissues, increased fluid drainage to lymph nodes
What are the local effects of cytokine IL-6?
Lymphocyte activation
Increased antibody production
Which cytokines are involved in the first innate immune response?
IL-1B
TNF-a
IL-6
-> Local destruction
What are the local effects of chemokine CXCL8?
Chemotactic factor recruits neutrophils (elimination of pathogen)
basophils, and T cells to the site of infection
What are the local effects of cytokine IL-12?
Activates NK cells
Induces differentiation of CD4 T cell into Th1 cells
Bind to macrophages
Inflammatory mediators
CD4 function state in the immune response against bacteria and viruses
Prominently expressed
What are the systemic effects of cytokine IL-1B?
Fever
Production of IL-6
What are the systemic effects of cytokine TNF-a?
Fever
Mobilization of metabolites SHOCK
What are the systemic effects of cytokine IL-6?
Fever
Induces acute phase protein production
Cell-mediated immunity mechanism to fight off the virus?
Viral infection- macrophage stimulated
Produces IL-12
This help polarise a T cell response -> TH1 response
Produces IFN-Y
Further activates macrophage
Cell-mediated immunity mechanism to fight off the virus?
Viral infection- macrophage stimulated
Produces IL-12
This help polarise a T cell response -> TH1 response
Produces IFN-Y
Further activates macrophage
Mechanism for allergic responses/ Anti-helminth responses?
TH2 cell
Produce -> IL-4 ,IL-5, IL-6, IL-10, IL-13
B cell -> IgE antibodies
Eosinophil response
How are specialized immune responses generated?
Combination of cytokines
