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The Role of Aryl Hydrocarbon Receptor (AhR) in the Immune System of Aging Mice

The Role of Aryl Hydrocarbon Receptor (AhR) in the Immune System of Aging Mice. Duy Pham Dr. Nancy I. Kerkvliet Department of Environmental and Molecular Toxicology Oregon State University HHMI Summer 2007. Immune System.

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The Role of Aryl Hydrocarbon Receptor (AhR) in the Immune System of Aging Mice

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  1. The Role of Aryl Hydrocarbon Receptor (AhR) in the Immune System of Aging Mice Duy Pham Dr. Nancy I. Kerkvliet Department of Environmental and Molecular Toxicology Oregon State University HHMI Summer 2007

  2. Immune System Recognizes and responds to antigenic substances associated with microbial pathogens and parasites that can cause disease or allergic reactions Immune response

  3. Aryl Hydrocarbon Receptor (AhR) • Cellular protein • Responses to variety of environmental agents: ► polycyclic aromatic hydrocarbons ► polychlorinated dioxin compound (TCDD) ► Many dietary substances • Alters immune system upon ligand binding bHLH structural motif of the AhR protein http://en.wikipedia.org/wiki/Basic-helix-loop-helix

  4. AhR SignalingThe case of 2,3,7,8-tetrachlorodibenzo-dioxin (TCDD)

  5. AhR SignalingThe case of 2,3,7,8-tetrachlorodibenzo-dioxin (TCDD) • TCDD-induced AhR activation • increases the expression of: • Cytochrome P4501A1 (Cyp1A1) • Cyp1A2 • Cyp1B1 • IL-2 • and many more

  6. Immune System Clinical applications of chemically induced immune suppression • Prevent rejection of tissue and organ transplants • Reduce overactive immune responses associated with allergy and asthma • Treat autoimmune diseases

  7. Natural Role of AhR not yet knownHypothesis The AhR responds to endogenous or exogenous (eg. dietary) ligands that leads to down-regulation of the immunity and inflammatory response over a lifetime. Therefore, older AhR KO mice would be expected to show enhanced immune response and inflammatory response compared to AhR WT mice

  8. Examine Immune parameterApproach 1. Activate AhR KO and WT spleen cells with antigenic stimulation ► Lipopolysaccharide (LPS) + Anti-CD3 ►Anti-CD3 + Anti-CD28 + IL-4 Culture 24,48 & 72hrs CYTOKINES IL-4

  9. Examine Immune parameterApproach 2. Cytokines Measurement Cytokines=

  10. Examine Immune ParametersMethods & Instruments • ELISA • Antibody-Sandwich ELISA • Spectra Max250 • Spectrophotometer • ALS1155

  11. Examine Immune ParameterExperimental Design-Study 1 (female) & 2 (male)

  12. IFN? - Old Mice IL-6 Old mice 1.2 1200 * * * 1000 * 1.0 * 800 0.8 IFN? (Absorbance) pg/ml 600 0.6 400 0.4 200 WT 0.2 Old WT KO Old KO 0 0.0 24 48 72 24 48 72 hours Hours of Culture Cytokines Measurement Study # 2 Male - Results IFN γ & Il-6 levels in culture supernatants from spleen cells stimulated with LPS and anti-CD3 IFN γ IL-6

  13. Cytokines Measurement Study # 2 Male – Results cont’ IL-5 levels in culture supernatants from spleen cells stimulated with anti-CD3, anti-C28 & IL-4

  14. Summary

  15. Good News vs. Bad News • Increase in pro-inflammatory cytokines in old AhR KO (IL6, IL12, IFN γ ) • More inflammatory response • More susceptible to inflammatory diseases Rheumatoid arthritis

  16. Good News vs. Bad News • Increase in IL-5 production in old AhR KO • Increase antibody secretion • More allergic response

  17. ►Challenge mice with LPS in vivo ► Measure the immune response Liver damage Inflammation many more Future Work

  18. Acknowledgements Howard Hughes Medical Institute Dr. Nancy Kerkvliet Dr. Kevin Ahern Kerkvliet Lab William Vorachek Linda Steppan

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