GV6: Inducible transcription factors

Endogenous corticoids: Mineralocorticoids

Where: Adrenal cortex

Examples: Mineralocorticoids, aldosterone, glucocorticoids

Function: Water and electrolyte balance

Endogenous corticoids: Glucocorticoids

Glucocorticoids  - hydrocortisone and corticosterone

- affect carbohydrate and protein metabolism

 - anti-inflammatory and immunosuppressive effects

Describe the cortisol structure

Hypothalamus

Pituitary

Adrenal axis

Natural circadian rhythm releases cortisol

Also stress e.g. infection, environmental

1.Hypothalamus

2.CRH

3.Pituitary

4.ACTH

5.Adrenals

6.Cortisol

What is an issue with steroids

Weaning patients off slowly

Prone to rebound inflammatory mediators

as the patient hasn’t developed endogenous steroids this will take a few weeks to reinstate

What is a consequence of excessive glucocorticoids

Cushing’s syndrome

• moon face

• high blood pressure

• CVD

• Diabetes

  • Skin thinning

Metabolic side effect: Osteoporosis

Caused by lack of vitamin D (steroid)

reduced calcium absorption

decreased collagen synthesis

Parathyroid hormone then increases Ca⁺⁺ resorption from bone leading to bone thinning

Diabetogenic

Decrease in glucose uptake and utilisation

increase in gluconeogenesis

increased appetite – obesity

Mineralocortocoid effects

Na/ H2O retention, hypertension, oedema and CV events

list 5 steroids

Describe what are steroid transcription factors

Lipophilic hormones

Bind intracellular receptors

Bind as homo (GR) and hetero  (Vit D) dimers

What can steroid TF activate

Can act as transcriptional activators and suppressors

Works for multiple weeks

Regulate gene transcription and mRNA stabilisation

Describe the steroid receptor structure

high homology between family members

not much specificity

doesn’t allow for adjustment

Steroid MOA

steroid

displaces protein

binds to receptor itself

Steroid mOA

Glucocorticoids enter cells and bind to cytoplasmic receptors.

Complex translocates to the nucleus to act as transcription factor

Can bind to response elements and activate anti-inflammatory gene transcription (eg IL-10)

Can bind and repress pro-inflammatory gene activation

(eg COX-2, PLA2)

Can interact and inhibit binding of other transcription factors

(AP-1 and NFkB)

Half site

Will have different spacing between the sequences

Gene control of vitamin D

vitamin D receptor (VDR)

- calcium binding proteins

- osteocalcin (bone development)

Glucocorticoid gene control

•Steroid-activated glucocorticoid receptor

- inhibits expression of IL-1

               - collagenase genes

What anti-inflammatory effects do steroids have

Not very effective

Overall broad spectrum dampening agent which works on many parts of immune system

needs to be controlled to prevent immunosuppression

Decrease vasodilation and extravasation

Inhibit cell activation- TH (inhibit IL-2 and clonal expansion)

Decrease production of inflammatory mediators (ROS, prostanoids and leukotrienes, complement and histamine)

Which patient groups are mostly affected by steroids

SLE: systemic lupus

systemic disorders

immunosuppressed patients

Toxicity of corticosteroids

with high dose, long term

• Immunosuppression can increase risk of infections

• Impaired leucocyte traffic can delay wound healing e.g. ulcers impair blood flow

• Suppress HPA axis through feedback inhibition patient must be weaned while endogenous system reactivates