Class of steroids, adrenal gland Distinguishable other steroids Receptors Target cells Effects

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 • Cell’s 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-γ, TNF-α • 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-γ, TNF-β • 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-γ 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-γ (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?