Glucocorticoids Flashcards
What are glucocorticoids?
They are steroid hormones produced by adrenal glands. Example cortisol
How was cortisone firstly used?
It was used to treat a young female patient with RA. It was very successful and she went shopping
What are glucocorticoids used for?
Treatment of many inflammatory diseases:
- RA
- Asthma
- SLE
- Crohn’s disease
- IBD
- Eczema
- Immunosuppression after transplantation
- Certain malignancies
What is cortisone?
It is a glucocorticoid synthesised from cholesterol and it can be converted to its active compound cortisol
The hypothalamus-pituitary-adrenal axis (HPA)
- Any type of stress (physical, mental, injury, starvation) acts on hypothalamus
- Hypothalamus produces corticotropin releasing hormone (CRH)
- CRH acts on anterior pituitary
- Anterior pituitary produces adrenocorticotropic hormone (ACTH)
- ACTH acts on adrenal cortex
- Adrenal cortex produces glucocorticoids (e.g. cortisol)
- Glucocorticoids production leads to negative feedback to anterior pituitary and hypothalamus
What glucocorticoids act on?
Metabolism and immune response. Glucocorticoids are stress hormones and their function is to coordinate adaptive physiological responses to stress to ensure survival. Brain requires a lot of glucose and a response to stress is managing glucose consumption to ensure that brain receives adequate supply during stress.
What tissues and cells glucocorticoids act on?
Metabolic tissues:
- Liver
- Adipose tissue (fat)
- Muscle tissue
- T cells
- B cells
- Macrophages
- Osteoblasts and osteoclasts
How do glucocorticoids act?
- Increasing gluconeogenesis (process of assembling glucose in liver)
- Proteolysis (proteins and peptides breakdown into smaller particles that can be used to assemble glucose)
- Lipolysis (triglycerides get broken-down into smaller particles used to assemble glucose)
- Ensuring maintenance of circulation to effectively deliver glucose to the brain by maintaining vascular tone (constriction and dilation of blood vessels) and ensuring salt and water balance
- Dampening immune response (because activated immune cells consume large amount of glucose and we want to keep glucose for the brain)
Expression of which inflammatory mediators are inhibited by glucocorticoids?
- cytokines (IL-1, IL-6, TNFa, IFNy)
- chemokine (IL8, Gro-a)
- adhesion molecules (E-selectin, ICAM)
- proteases (MMP1, MMP3)
- signalling enzymes (COX3, iNOS)
What are the beneficial effects of glucocorticoids?
- Anti-allergic
- Anti-inflammatory
- Decreases endothelial dysfunction and permeability of blood vessels
What are harmful effects of glucocorticoids?
- Increased cardiovascular risk
- Can cause issues with eyes
- Can have negative effects on bones (osteoporosis)
- Can have negative effects on the brain
- Weight gain, obesity, fluid retention
Are glucocorticoids safe?
Not really, patients need to be closely monitored when taking glucocorticoids as they can have very harmful effects even though they help symptoms of inflammation subside
How glucocorticoids cause osteoporosis?
By impairment of bone remodelling process by osteoblasts and osteoclasts. Glucocorticoids increase expression of RANKL which decreases osteoblasts activity leading to osteoporosis
How can you treat osteoporosis caused by glucocorticoids?
Using bisphosphonates which inhibit increased bone turnover
How glucocorticoids signal?
Through glucocorticoid receptor (GR) which is a transcription factor expressed in all cells.
1. Glucocorticoids can get through plasma membrane into the cell
2. GR in inactive form is in the cytoplasm and it activates when glucocorticoid binds to it
3. Activation of GR leads to its dissociation from HSPs (proteins which are bound to it to stop GR from transporting into nucleus)
4. GR transports to the nucleus
5. Inside nucleus GR can either do transactivation or transrepression
- transactivation - in the nucleus GR dimerise and bind to DNA sequence and switch on gene expression
- transrepression - without dimerisation it can bind to another transcription factor and block it, stopping it from working for example NF-kB and this reduces inflammation
Where is GR located?
In inactive form it is in the cytoplasm and in active form in the nucleus
What is transrepression hypothesis?
It is believed that transrepression is desirable as it gives anti-inflammatory effects while transactivation is the one that gives harmful effects. Pharmaceutical companies try to develop glucocorticoid which will lead to transrepression but not transactivation, however, for now all of these did not pass clinical trials as there is no mechanistic separation of GR actions (Clark 2012)
Is transactivation only bad?
No, it has been shown that it also has desirable effects. GCs switch on expression of dual specificity phosphatase 1 (DUSP1) which switches off p38. p38 is needed for turning on inflammatory genes so switching off p38 gives anti-inflammatory effects (Abraham 2006) (Joanny 2012)
What is HIF1a relation to glycolysis?
HIF1a is a master regulator of glycolysis. Dexamethasone has been shown to prevent glycolysis in activated macrophages by preventing activation of HIF1a (Clayton 2023)
