6. Cytokines - the word cells use to send messages Flashcards
Cytokines and their receptors
Cytokines – small protein, signalling molecules
Autocrine & paracrine action
- > Stimulus is induced into cytokine gene within a cytokine producing cell
- > these cytokines then attach to receptors on the target cell
- > this sends a signal to activate the gene, causing a biological effect
Autocrine action:
The cytokines from within the cell binds to the cell’s own receptor
Paracrine action:
The cytokines bind to a receptor on a nearby cell
Endocrine action:
The cytokines circulate through a tube before binding to a receptor on a distant cell
cytokines and their receptors
Cytokines – small protein, signalling molecules
Autocrine & paracrine action
5 principal families of cytokine receptors
Cytokines make up ~10% of human genome
Cytokine network have high level of degeneracy
Cells must integrate cytokine signals
before making a decision
Pleiotropy
A cytokine that has different effect on different target cells
B-Cell:
Activation proliferation differentiation
Thymocyte:
proliferation (rapid increase in the number or amount of something)
Mast cell:
proliferation
Cytokine signalling properties
Redundancy:
- > IL 2 / 4 / 5
- > B - cell - proliferation
Synergy:
- > IL 4 + IL 5
- > B - Cell - induces class switch to IgE
Antagonism:
- > IL 4 / IFN gamma
- > B-Cell - blocks class switch to IgE induced by IL 4
Cytokines
Interferons (α, β, γ)
Interleukins (IL-1 to IL-37)
Colony-stimulating factors (CSFs)
- Granulocyte-Macrophage Colony-Stimulating factor
(GM-CSF)
Chemokines
- Stromal-Derived Factor 1(SDF-1) or IL-8
Others
- Tumour Necrosis Factor (TNF α and β)
- Transforming Growth Factor β
Cytokines control everythign
Ponthrombotic action - induction of endothelial dhesion molecules
autokrine activation and differentiation factor (macrophage)
defence against intracellular pathogen (macrophage)
comitogen for T and B cells
regulates haemotopoiesis
induces other cytokines (macrophage)
growth factor (macrophage)
cytokines int he innate immune system
Bacteria induce macrophages to produce IL-6, which acts on hepatocytes to induce synthesis of acute-phase proteins
- C-reactive protein binds phosphocholine on bacterial surfaces, acting as an opsonin, and also activating complement
- Mannose - binding lectin binds, mannose residues on bacterial surfaces, acting as an opsonin, and also activating complement
IL-1 beta
IL-6
TNF alpha
Liver:
- > acute phase proteins (C-reaactive protein, mannose-binding lectin)
- > activation of complement opsonization
Bone marrow endothelium:
- > neutrophil mobilization
- > phagocytosis
Hypothalamus:
- > increased body temperature
- > decreased viral and bacterial replication. increased antigen processing. increased specific immune response.
Fat and muscle:
- > protein and energy mobilization to allow increased body temperature
- > decreased viral and bacterial replication. increased antigen processing. increased specific immune response.
Cencritic cells:
- > TNF alpha stimulates migration to lymph nodes and maturation
- > initiation of adaptive immune response
on sensing microbial products, macrophages secrete a variety of pro inflammatory cytokines
IL-6:
-> fever induces acute phase protein production by hepatocytes (systemic effects)
TNF alpha:
- > activates vascular endothelium and increases vascular permeability, which leads to increased entry of complement and cells to tissues and increased fluid drainage to lymph nodes (local effects)
- > fever mobilization of metabolites shock (systemic effects)
IL-1 beta:
- > activates vascular endothelium. activates lymphocytes. local tissue destruction. increases acces of effector cells. (local effects)
- > fever production of IL-6 (systemic effects)
CXCL8
-> Chemotactic factor recruits neutrophils and basophils to site of infection (local effects)
IL-12:
-> Activates NK cells (local effects)
Knock-out animals
Cytokine KOs
Some embryonic lethal
Others only show effects when stressed
Multi-KO have been made by “crossing” animals
For example:
No IL2Rγ – severe combined immunodeficiency
No IL12 – Impaired Th1 response; enhanced IL4
cytokine receptors
Homodimeric receptor
receptor for erythropoietin and growth hormone
Heterodimeric receptors with a common chain
- > receptors for IL 3 / 5, GM-CSF, share a common chain, CD131 or beta c (common beta chain)
- > recpetors for IL 2 / 4 / 7 / 9 / 15 share a common chain CD132 or gamma c (common gamma chain). IL 2 receptor also has a third chain, a high affinity subunit IL 2R alpha (CD25).
Heterodimeric receptors (no common chain): Receptors for IL-13, IFN alpha / beta / gamma, IL-10
TNF receptor family:
Tumor necrosis factor (TNF) receptor I and II CD40, Fas (Apo1, CD95), CD30, CD27, nerve growth factor receptor
Chemokine receptor family
CCR1-10, CXCR1-5, XCR1, CX3CR1
Dimerisation - JAK STAT signalling
cytokine receptors consistofat least two chains, the cytoplasmic domains of which bind Janus kinases (JAKs)
cytokine binding dimerizes the receptor, bringin together the cytoplasmic JAKs, which activate each other and phosphorylate the receptor
Transcription factors (STATs) bind to the phosphorylated receptors, and are in turn phosphorylated by the activated JAKs
Phosphorylated STATs form dimers that translocate into the nucleus to initiate new game transcription
Cytokines and receptors
Cytokines can only signal if a cell has a receptor
Many act in antagonistic groups
Some factors have natural antagonists
Receptor expression can vary depending on stage of cell maturation and activation
Signal integration occurs in cytosol – 2nd messenger pathways