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

What are glucocorticoids?. Class of steroids, adrenal gland Distinguishable other steroids Receptors Target cells Effects Cortisol Important to life Cardiovascular, metabolic, immunologic, Homeostatic functions. What are the effects glucocorticoids?.

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

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  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?

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