Class of steroids, adrenal gland

1
What are glucocorticoids?

• Class of steroids, adrenal gland
• Distinguishable other steroids
• Receptors
• Target cells
• Effects
• Cortisol
• Important to life
• Cardiovascular, metabolic, immunologic,
• Homeostatic functions

2
What are the effects glucocorticoids?

• Name derived Glucose Metabolism
• Fasted state, cortisol
• Stimulation of gluconeogenesis
• AA mobilization
• Inhibition glucose uptake
• Stimulation fat breakdown
• Anti-inflammatory
  Immunosuppressive
• Homeostasis

3
What are the effects glucocorticoids?

• Fetal Development
• Cognitive Function
• Stimulates GC secretion
• Influenced by GC
• Fear
• Many other systems (excessive)
• Inhibits bone formation
• Delays wound healing

4
Cortisol and Glucocorticoid Receptors

• Cortisol binds GC in cytoplasm
• Cort-GCR nucleus binds
  DNA response element
  transcription
• Cells phenotype changes
• 10 is free
• Bound CBG (not active)
• Decreases metabolic clearance rate
• Acts as buffer, blunts
  CORT fluctuations

5
Control of Cortisol Secretion

• CNS commander and chief
• Any physical or mental stress
• Suppressed by
  negative feedback loops
• Circadian rhythm

6
QUESTIONS

• Who was Han Selye?
• What were his major scientific contributions?
• Are his concepts still valid?

7
Background -- Wiegers et al.,

• 19th century by Addison
• Adrenalectomy vs. Stress
• Thymic hypertrophy
• Adrenal enlargement and thymus involution
• Adrenalectomized and hypophysectomize
• Effects less pronounced
• Pituitary-adrenal axis CNS and IS

8
Background -- Wiegers et al.,

• Munck et al. 1976 GC evidence
• Anti-inflammatory
• Immunosuppressive
• Hypothesis, 1984
• Increased GC not to protect against stress
  itself but against normal defense reaction
  activated by stress
• GC turn off defense reactions, thus prevents
  overshooting and threatening homeostasis

9
Inhibition of immune responsiveness by GC

• Inject rodents w/antigens increase GC
• Antigenic competition abolished by ADX
• GC prevent overreaction and preserve specificity
  
• Confirmed in study using GC antagonist
• ADX mice died from MCMV
• Studies support GC immunoprotective role

10
QUESTIONS

• What was the proposed initial theory about the
  effects of GC on immune system?
• Who introduced this concept first?
• What piece of scientific evidence validated this
  theory?
• Based on Wiegers Paper what is the primary role
  of GC? Evidence to support.

11
GC and Cytokines

• Activate IS releases cytokines, thus activates
  HPA and release GC
• Negative Regulatory Feedback
• Suppress synthesis
• Suppress release
• Inhibit IL-1, -2, -3, -5, -6, -8, -12, -13,
  IFN-?, TNF-a
• IL-10 is increased, IL-4 is controversial

12
GC and Cytokines

• GC inhibit proinflammatory
• GC induce cytokines with immunosuppressive
  potential
• Thus, would it seem likely that GC inhibit Th1
  or Th2, why?
• GC act synergistically with cytokines
• GC induce receptor expression
• Optimize the course of the biological response

13
GC and Th1/Th2 Differentiation

• Th1
• IL-2, IFN-?, TNF-ß
• T-cell mediated delayed-type hypersensitivity
• Th2
• Il-4, -5, -6, -10, -13
• B-cell proliferate, differentiate, and
  participate in humoral
• GC
• Favor Th2 phenotype

14
GC and Th1/Th2 Differentiation

• Evidence for support
• GC decrease IL-2 and increase IL-4
• Suppress IL-12, decrease IFN-? and increase IL-4
• IL-12 mechanism may be the key to shift

15
GC and Th1/Th2 Balance

• Elenkov paper
• Disease skewed in balance
• GC shift toward Th2, not immunosuppression
• Role of Th1/Th2 cytokines
• Innate APC (MO, DC, NK)
• Adaptive Th1 (IFN, IL-2, TNF) and Th2 (Il-4,
  10, 13)
• IL-12, IL-18, IFN Th1
• IL-12 IFN inhibit Th2
• IL-4 and IL-10 inhibit Th1

16
GC shifts toward Th2

• Elenkov paper
• GC causes shift toward Th2
• GC suppress APC and Th1
• GC upregulate Th2-cytokine production
• Inhibition in IL-12 (major mechanism)
• Inhibition in IFN-? (indirect via IL-12)
• Upregulate Il-4, -10, -13 (Direct on Th2)
• CRH and Mast Cell

17
APC
THP
TH2
TH1
MO
B cell
TC
NK
Plasma
PMN
18
Questions

• Identify cells and cytokines that are the key
  players in Th1/Th2 pathways.
• What is the proposed major mechanism by which
  GC affect the Th1/Th2 balance?
• Does it seem logical that GC would favor a Th2
  response? Why? Provide evidence.

19
Questions

• Design an experiment to support the hypothesis
  Stress-induced Th2 shift via GC has a profound
  effect on susceptibility of an organism to an
  infection.
• Experimental design?
• What will your approach be?
• What pathogen will you use? Why?
• What will you measure?