6. Cytokines - the word cells use to send messages

Question 1

Cytokines and their receptors

Answer 1

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

Question 2

cytokines and their receptors

Answer 2

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

Question 3

Pleiotropy

Answer 3

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

Question 4

Cytokine signalling properties

Answer 4

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

Question 5

Cytokines

Answer 5

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

Question 6

Cytokines control everythign

Answer 6

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)

Question 7

cytokines int he innate immune system

Answer 7

Bacteria induce macrophages to produce IL-6, which acts on hepatocytes to induce synthesis of acute-phase proteins

1. C-reactive protein binds phosphocholine on bacterial surfaces, acting as an opsonin, and also activating complement
2. Mannose - binding lectin binds, mannose residues on bacterial surfaces, acting as an opsonin, and also activating complement

Question 8

IL-1 beta
IL-6
TNF alpha

Answer 8

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

Question 9

on sensing microbial products, macrophages secrete a variety of pro inflammatory cytokines

Answer 9

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)

Question 10

Knock-out animals

Answer 10

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

Question 11

cytokine receptors

Answer 11

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

Question 12

Dimerisation - JAK STAT signalling

Answer 12

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

Question 13

Cytokines and receptors

Answer 13

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