Cell signalling, Cytokines, Inflammation - NMSK

receptor

specialised protein molecules that specific ligands bind to, to trigger a cellular response

ligand

chemical messenger sent by cells

Describe the steps in signal transduction.

1. reception - ligand binds to a specific receptor protein

2. transduction - the activated receptor converts the extracellular signal into an internal molecular message, triggering a multi-step relay pathway

3. response - the transduced signal triggers a specific functional action within the cell.

What is the difference between intracellular signalling and intercellular signalling?

intracellular - a singular cell sends and receives the same signal

intercellular - the transmission of a signal from one cell (signalling cell) to another (target cell)

What are the different types of cell signalling, and describe?

• autocrine - cell targets itself

• paracrine - cell targets nearby cells via short-range diffusion

• synaptic - occurs at a synapse, involving neurotransmitters (specialised type of paracrine)

• endocrine - long distance signalling, e.g. hormones travelling within the bloodstream.

• juxtacrine/direct contact - occurs via gap junctions between cells in direct contact with each other.

What is the structure, function and signalling of cytokines?

• structure - small proteins or glycoproteins

• function - secreted by immune and non-immune cells and act as chemical messengers to coordinate immunity, inflammation and cell growth (type of ligand)

• signalling - can function as autocrine, paracrine or endocrine

Define these terms in relation to cytokines: redundancy, synergy, antagonism, pleiotropism

• redundancy - where multiple different cytokines exert similar or overlapping biological functions on target cells.

• synergy - occurs when the combined effect of 2 or more cytokines on a target cell is exponentially greater than the simple sum of their individual effects

• antagonism - mechanisms or agents that block, inhibit or counteract the biological activity of cytokines

• pleiotropism - the ability of a single cytokine molecule to produce multiple, distinct biological effects, depending on the target cell type, its local environment and its activation state.

What is signal specificity and how is it achieved?

a specific ligand triggers a precise, intended cellular response (without accidentally activating wrong pathways). achieved partly by a ligand being specific to a receptor protein (lock and key). partly achieved by compartmentalisation as it allows specific signalling components to be isolated so that they only interact where and when they are supposed to.

What are the characteristics of the lipid bilayer?

• membranes held together primarily by hydrophobic interactions

• most lipids and some proteins can drift laterally

• phospholipids move rapidly while proteins move slower and in highly directed manner

• fluidity is temperature dependent

• fluid mosaic model - a mosaic of different proteins imbedded in a fluid matrix of the lipid bilayer.

What are lipid rafts and why are they important?

• sections of a membrane (micro domains) that are more stabilised and rigid structures (due to cholesterol and sphingolipids), floating as a raft or island within the membrane

• proteins integrated within the lipid rafts will stay in close proximity to each other

• this is important for signalling events (and other processes) as it is important that the collection of interacting proteins are in close proximity to each other.

What is meant by an inflammatory response?

an innate immune reaction that ensures immune cells and other substances are brought to the affected area so that:

• foreign organisms may be destroyed or inactivated

• injured tissue or cell remnants may be removed

• tissue repair is initiated

What are some causes of inflammation?

• infection

• heat

• chemical substances

• mechanical injury

• other

What are some disorders associated with inflammation?

• asthma

• allergies/hypersensitivities

• obesity

• osteoarthritis

• chronic prostitis

• autoimmune diseases

• diabetes

• inflammatory bowel disease

What is acute inflammation, how long does it last and some example causes?

• the normal response to most forms of injury or infection. repair of damage or removal of infection removes the stimulus

• lasts a matter of days - weeks

• e.g. infection by microorganisms, hypersensitivity, physical (e.g. burns, UV light), chemical corrosives or irritants, tissue necrosis

What is chronic inflammation, how long doe sit last and some example causes?

• progression from acute inflammation if healing process does not occur due to foreign body or continuing infection. may also occur where no obvious foreign body is present.

• lasts weeks, months, years

• e.g. persistent infection (e.g. Mycobacterium tuberculosis), persistent presence of non-living material (e.g. suture material), immune mediated diseases (including hypersensitivity) (eg arthritis)

What are some effects of inflammation?

• redness (rubor) - increased blood supply to area

• heat (calor) - increased blood supply to area

• swelling (tumor) - increased cell no. in area, vessels become leaky leading to excess tissue fluid

• pain (dolor) - can be due to chemical stimulation or due to swelling putting pressure on surrounding tissue

• lack of function

How is inflammation initiated?

• epithelial cells, at site of infection/damaged tissue, produce cytokines and chemokines (a type of cytokine)

• chemokines attract neutrophils to the site (first migratory leukocyte/white blood cell on site) and then followed by macrophages

• neutrophils then produce cytokines/chemokines themselves, attracting more neutrophils to the area (cascade)

Which pro-inflammatory cytokines do both epithelial cells and neutrophils release when stimulated, and what is their function?

• IL1ß - activates vascular endothelium, local tissue destruction which increases access for infiltration of leukocytes, stimulates IL-6

• TNF⍺ - activates vascular endothelium, increases IgG (antibody class) entry, complement and fluid drainage to lymph

• IL-6 - lymphocyte activation, increased antibody production

• IL8/CXCL8 - attracts neutrophils, basophils and T-cells to site of infection

What do all the cytokines previously listed cause overall?

attraction of and infiltration by leukocytes

What pro-inflammatory mediators (not cytokines) are released by epithelial cells when they are stimulated, and what do they cause?

• prostaglandins and leukotrienes - stimulation of vascular smooth muscle cells and neurones

cause: vasodilation and pain

What pro-inflammatory mediators are released by neutrophils when they are stimulated, and what do they cause?

• IL12 - activation of adaptive immunity (a cytokine)

• cytokines released by neutrophils into blood may lead to systemic effects e.g. fever, mobilisation of metabolites, induction of acute phase proteins

Describe the inflammatory cascade.

• inflammatory cell infiltrate produces more cytokines and chemokines

• more resident cells become activated and more cells extravasate (move out of a blood cell and into surrounding tissue), including lymphocytes

• amplification of immune responses leading to clearance of antigen