Cytokines in health and disease

Question 1

What are the 5 different roles of cytokines?

Answer 1

1. cell growth
2. cell differentiation
3. healing
4. tissue remodeling
5. REGULATE IMMUNE RESPONSES

Question 2

What are the 5 general features of cytokines?

Answer 2

• Pleiotrophic: each cytokine has several different functions
• Redundancy: an animal without IL‐6 can perform all functions ascribed to IL‐6
• Production: inducible, short half life
• Synergy: acts together for enhanced effect
• Antagonism: counteract each other

Question 3

What are the 4 modes of action of cytokines?

Answer 3

1. Endocrine: targets peripheral cells (IL-6, IL-1, TNF,…)
2. Paracrine: immediate proximity (IL-1, TNF,…)
3. Autocrine: acts on producer cell (IL-2,…)
4. Gradient-dependent: in tissue (IL-8)

Question 4

What are the 5 factors that regulates the effect of a cytokine?

Answer 4

1. extracellular abundance
2. receptor concentration
3. signalling cascade activation
4. cell type (response can vary depending on the cell type)
5. decoy receptor (receptor having no effect on the cell => a way to regulate reaction)

Question 5

At first infection, what cytokine is secreted and what other cytokines does it induce?

Answer 5

TNF is first secreted, then IL-1ß and IL-6

Question 6

What is TNF, what does it do, where is it found and which cells produce them?

Answer 6

1. TNF = Tumour necrosis factor
2. Regulation of proliferation & apoptosis + pro-inflammatory (pleiotropic)
3. Membrane‐bound form and soluble form => both active
4. Produced mainly by: mononuclear phagocytes, activated T‐cells, mast cells & NK‐cells
   => TNF is vital for host defense against intracellular bacteria and parasites

Question 7

What are the cell-bound TNF receptors and where can they be found?

Answer 7

1. p55: present on all cell types apart from erythrocytes, constitutive expression
2. p75: more abundant on immune cells, inducible expression
   => both can be shed during inflammation and lead to activation of pro-inflammatory signals

Question 8

What can down-regulate the production of TNF?

Answer 8

TNF production down-regulated by prostaglandins, IL‐ 6, IL‐10 and corticosteroids

Question 9

What cells produce IL-1a & IL-1ß and what induces their production?

Answer 9

IL‐1a & IL‐1ß produced by: mononuclear phagocytes, B‐cells, NK‐cells, neutrophils, keratinocytes, epithelial cells and endothelial cells
Production induced by: DAMPs, PAMPs, TNF and IL‐1 (induced by itself)

Question 10

What are the effects of IL-1?

Answer 10

Local: activates vascular endothelium (adhesion molecules), activates lymphocytes (co-activator), local tissue destruction and macrophage activation
Systemic: fever, corticosteroid production, production of IL‐6 & almost all other cytokines, bone marrow stimulant (for neutrophils) and
does not kill cells! (contrary to TNF)

Question 11

What is proIL-1ß?

Answer 11

It is the inactive form of IL-1ß, needs to be cleaved by ICE to mature into IL-1ß

Question 12

Where and how is IL-6 produced/induced?

Answer 12

Produced by a wide variety of cells
Induced by microbes, TNF and IL‐1
Endocrine function
Pleiotropic

Question 13

How does iL-6 resolve innate immunity and induce adaptive immunity?

Answer 13

Resolving innate immunity: block TNF & IL-1, induce TNF & IL-1 antagonists, promote neutrophil apoptosis, etc.
Inducing adaptive immunity: block T-cell apoptosis, chemokine receptor expression on T-cells, proliferation of T-cells, Ig-production, etc.

Question 14

What up-regulates and down-regulates IL-6?

Answer 14

Up-regulation: TNF, IL‐1 and IFN‐b

Down-regulation: IL‐4, IL‐13 and glucocorticoids

Question 15

What are JAK and STAT?

Answer 15

They are signaling pathways for cytokines

Question 16

What are immune checkpoint inhibitors?

Answer 16

• Suppression of T‐cell activation by PD‐1 and CTLA‐4 is considered one of the major escape mechanisms of cancer cells
• Inhibition of these molecules by immune checkpoint inhibitors can successfully activate the immune system to fight cancer