Core Concepts-L10-Cytokine Signalling

definition of cytokines

• soluble extracellular proteins that regulate innate and inflammatory reactions, cell growth, differentiation, development and repair processes to return homeostasis

what are cytokine families characterised by?

by their receptors

name the 5 cytokine family types and examples

1. Ig Type-processed by cascade-1- IL18,IL-1beta

2. TNFR type

3. cytokine R type 2- leads to JAK/STAT- interferon gamma, alpha, beta

4. cytokineR type I- leads to JAK/STAT- binds IL-2/3/4, GF- control hematopoiesis

5. chemokineR- CXCL8 for neutrophil recruitment and ccl2 for macrophage

discuss TNF- what does it help with and what does it trigger? what happens if its in excess?

tumour necrosis factor

• effector of vascular permeability- helps with immune cell recruitment and activates macrophages and primes the inflammasome(alternative to TLR)

• signals via TNF receptors

• can trigger necropotsis via mitochondrial signalling- fever

in excess

• inflammatory cell death- fever, energy mobilisation, septic shock and basal TNF increases with age due to DAMPs

discuss Ig type cytokine family- key cytokines and their main functions? what controls this signalling?

• IL-1alpha-acts as an alarm and is limited- found in epithelial cells

• IL-1beta found in macrophages- proinflammaory cytokine and regulates adhesion molecules, neutrophil recruitment by CXCL8 and IL-6 production, COX2 induction

• IL-18 found in leukocytes- promotes Th1

• IL-33- Th2 response

IL-1Ra- inhibitor natural- blocks IL-1 receptor

what are eicosanoids and what are their main roles?

• lipid mediators from arachidonic acid

• are signalling molecules

• mediates inflammation- redness, swelling, pain

• recruits immune cells

• NSAIDs inhibit COX2 enzymes

discuss the acute phase response- main cytokine and what is stimulated?

• IL-6 produced by macrophages etc and acts locally and systemically- endocrine and paracrine

• IL-6 to the liver makes acute phase proteins to help control infection: like c reactive protein(binds microbial components and opsonisation), serum amyloid A(recruits immune cells)

• IL6 levels are used clinically and CRP are used clinically to detect inflammation

discuss IL-12 and what it does

helps with T cell polarisation. T cells need 3 signals for activation 1) TCR recognition of antigen, costimulatory signals and cytokines that polarise T cells towards specific T cell subsets

• IL-12 made by DCs, macrophages after PRR. drives naive CD4 into Th1 cells. 

• Th1 cells make IFN-gamma enhancing macrophage antimicrobial activity

discuss IL-10 role- what does it activate, what happens to immune cells when it is made?

• is anti inflammatory- promotes resolution of inflammation

• activates anti inflammatory TF and negatively regulates NF kappa B- signals through JAK/STAT

• made by efferocytes- macrophages that take dead and dying cells- make IL-10 to tone down macrophages M2 response

what triggers Type I interferon response? what’s their main function? what detects these?

IFN alpha/beta- by endosomal TLR’s like TLR3 for dsRNA- ISG and IFN I(TLR3/7/8 and RIG-I )

• shuts down viral mRNA tranlsation

• activates enzymes that edit viral RNA- ADAR1- so it can’t be read by the ribosome

• boosts antigen presentation

how does type II interferons differ from type I interferon production and function?

type II IFN-gamma- made by lymphocytes and activates antimicrobial genes like GAS. increases iNOS to make ROS and promote phago-lyososme maturation in macrophages

what interferons are made by innate vs adaptive?

innate- Type I alpha/beta

adaptive lymphocytes- Type II- gamma