Cytokines Flashcards
What are the key characteristics of cytokines?
Communication between cells
Mediate their effects by binding to cell-associated receptors on target cells
Usually (not always) secreted
Secretion is brief and self-limited
Act locally within the cellular environment but can also act systemically
Cytokines influence the synthesis and action of other cytokines and immune molecules
Many are ‘interleukins’
What is a PRR?
Pattern recognition receptor
Innate immune receptor expressed on membranes of immune cells that bind specific pathogen patterns
What are Toll-like-receptors?
Type of PRR located on the cell membrane or endosome
TLR2 and TLR4 sense pathogens on cell membrane
- Bind to pathogen proteins/carbohydrates
- Leads to activation of NF-kB and MAPK signalling
- Leading to activation of proinflammatory cytokines and chemokines
TLR 3/7/8 sense pathogen invasion via the endocytic pathways
- Recognise pathogen nucleic acids
- Type 1 INFs
What are some examples of cytoplasmic sensors and what do they recognise?
Foreign nucleic acid
MDA5 - dsRNA
RIG-1 - ss viral RNA
cGAS - dsDNA
What are the interferon receptor signalling pathways?
MOST CELLS:
- Type 1 interferon
- -> ISG (interferon stimulated genes) - make the cell hostile for the virus to grow in
- Inhibits: virus entry, genome replication, translation, virus assembly, release
EPITHELIAL CELLS (and neutrophils)
- INFy type 3 -> more gentle
- -> ISG
What is the action of pro-inflammatory cytokines (IL-1b/IL-6/TNF-a) during infection in different organs
Activates vascular endothelium and increases vascular permeability (leaky)
Activates lymphocytes
Local tissue destruction
Increases access of effector cells
LIVER: acute phase proteins (CRP, MBL) -> activation of complement, opsonisation
BONE MARROW ENDOTHELIUM: neutrophil mobilisation -> phagocytosis
HYPOTHALAMUS: increased body temperature -> decreased viral and bacterial replication, increased antigen processing, increased specific immune response
FAT, MUSCLE: protein and energy mobilisation to allow increased body temperature -> decreased viral and bacterial replication, increased antigen processing, increased specific immune response
DENDRITIC MUSCLE: TNF-a stimulates migration to lymphnodes and maturation -> initiation of adaptive immune response
What are the issues too many cytokines can lead to?
Uncontrolled production -> cell damage
Promotes cellular infiltrates in tissues
High/prolonged fever - seizures
Antimicrobial proteins (e.g. CRP, complement) also cause tissue damage
Uncontrolled immune cell activation = bad
What are the 2 pathways of how TNF either induces cell death or cytokine production
TNF binding trimerises the TNFR, allowing it to bind to the adaptor TRADD
Cell death:
- TRAAD recruits FADD, resulting in caspase 8 activation -> death
Cytokine production:
- TRADD recruits RIP and TRAF2 -> activated NF-kB -> more cytokines
What is the role of TNF-a in a local infection with G-ve bacteria
Macrophages activated to secrete TNF-a in the tissue
Increased release of plasma proteins (complement and antibodies) into tissue
Phagocyte (phagocytosis) and lymphocyte migration into tissue
Increased platelet adhesion to blood vessel wall (clotting process ->limit spread)
Phagocytosis of bacteria
Local vessel occlusion
Plasma and cells drain to local lymph node
What is the role of TNF-a in sepsis with G-ve bacteria
Macrophages activated in the liver and spleen secrete TNF-a into the blood stream
Systemic oedema causing decreased blood volume, hyperproteinaemia, and neutropenia, followed by neutrophilia (lots of neutrophils)
Decreased blood volume causes collapse of vessels
Disseminated intravascular coagulation (platelets) leading to wasting and multiple organ failure
What is the role of IL-2 in clonal selection and proliferation
Once a T cell is activated IL-2 and IL-2 receptors are upregulated in that T cell
IL-2 is a growth factor and causes rapid proliferation of that specific T cell
Signalling via the TCR induces AP-1 activation and increases intracellular Ca2+ concentration
Raised intracellular Ca2+ activates calcineurin
- A phosphatase that activates NFATc family members
Activated NFATc family members migrate to the nucleus and bind to AP-1 and other partner proteins to form active transcription
Activation of specific genes including the IL-2 gene (leading to clonal expansion of the activated T cell)
What does IL-12 stimulate
Differentiation of CD4+ helper T lymphocytes into IFN-y producing Th1 cells
Enhances cytolytic functions of activated NK cells and CD8+ cytotoxic T lymphocytes (CTL)
Promotes Th1 cells development and expansion
Represses Th2 cell development
What does IL-4 stimulate
Induces Th2 development and promotes their expansion
Represses Th1 development
Also acts as B-cell growth factor
Controls class switching to IgE and IgG1 in B-cells
