5, Inflammatory Cytokines Flashcards
Kinetics of Inflammation:
Pathogens drive immune activation and inflammation
Fast, robust response to pathogens
- Response too small = Pathogens escape immune system
- Response too big = Excessive inflammation fives unwanted tissue damage
Following removal of pathogen, immune system must be deactivated
Feedback control of inflammation:
No feedback = Too weak and slow to control infection
Positive feedback = Amplifies response, difficult to turn off once started
Negative feedback = Suppressive response, may turn off before all pathogens are cleared
Positive AND negative feedback: Fast and strong response to initial infection, limits max level of infection, allows deactivation of immune system once pathogen is cleared.
Requirements for positive AND negative feedback:
Ability to produce pro-inflammatory mediators AND anti-inflammatory mediators at the same time
The same signals that induce inflammation must also be able to activate pro-resolution and anti-inflammatory pathways
Chronic inflammation is caused by too many pro-inflammatory molecules or too few anti-inflammatory molecules?
BOTH
Chronic inflammation is caused by too many pro-inflammatory molecules AND too few anti-inflammatory molecules
Anti-inflammatory mechanisms:
Cell-based:
- Immunosuppresive cells: Treg, Breg
- Pro-resolution cells: Alternatively activated/M2b macrophages
Molecule-based:
- Anti-inflammatory Cytokines: IL-10, IL-1ra
- Lipid mediators: Resolvins, Prostaglandins
IL-10 function:
Inhibits production of Th1 cytokines
Suppresses T cells
Inhibits production of pro-inflammatory cytokines by macrophages and dendritic cells.
Promotes differentiation and function of Treg cells
Promotes antibody production by B cells
IL-10 Producing Cells:
CD4 T cells (Th2, Treg) CD8 T cell Regulatory B cells Macrophages Myeloid Dendritic Cells Mast Cells
CD4 and CD8 T cells: TCR activation leads to IL-10 production
Rest: PRR activation (e.g. TLRs, Dectin-1) leads to IL-10 production
Regulation of IL-10 production in T cells:
2 steps:
- Polarisation of CD4 T cells into a phenotype capable of making IL-10
- A 2nd signal to induce IL-10 (e.g. TCR activation)
Regulation of IL-10 production in macrophages:
- Stimulated by TLR agonists (e.g. LPS)
- TLR stimulation leads to activation of ERK1/2 and p38 MAPK pathways
- Leads to activation of kinases MSK1 and 2, which then phosphorylate the transcription factor CREB
- CREB induces transcription of IL-10
IL-10 producing B cells:
Only a small subset of B cells produce IL-10, termed Breg cells (or B10 cells)
TLR stimulation of B cells is required for IL-10 production
IL-10 signalling:
- IL-10 binds to IL10- receptor
- IL-10R is tetrameric (2x IL-10R1, 2x IL-10R2)
IL-10 signalling:
- IL-10 binds to IL10- receptor
- IL-10R is tetrameric (2x IL-10R1, 2x IL-10R2)
- Tyrosine kinases Tyk2 and Jak1 are bound to IL-10R
- Binding of IL-10 to IL-10R activates these tyrosine kinases
- These tyrosine kinases phosphorylate IL-10R1
- This phosphorylation enables recruitment of STAT3, which is then also phosphorylated
- STAT3 dissociates and dimerises
- STAT3 dimer then translocates to nucleus and activates transcription of STAT dependent genes
IL-10R is expressed on BLANK, BLANK, and BLANK
IL-10R is expressed on macrophages, myeloid dendritic cells, and T cells
In macrophages and dendritic cells, IL-10 strongly promotes cytokine production
TRUE OR FALSE
FALSE
In macrophages and dendritic cells, IL-10 strongly SUPPRESSES cytokine production
IL-10 promotes Treg development and function
TRUE OR FALSE
TRUE
