Yanett Roman 2/25/09 Biol 520

1. Exprssion of IDO by Activated monocytes lead to the degradation of Tryptophan and the development of depression Yanett Roman 2/25/09 Biol 520

2. Background Information

3. Psychoneuroimmunology • Investigates interaction between behavior and the immune system, mediated by the endocrine system and nervous system • link between bi-directional communication of the immune system with the endocrine an nervous system CNS Cytokines Nps Nps Hormones Neurotransmitters Ziemssen & Kern 2007 Immune system

4. Immune and Nervous System are Closely Linked • Inflammation • neural pathways that mediate pain and the immune regulation of inflammation • Stress • The sympathetic nervous system(SNS) and HPA axis are peripheral limbs of stress • Mood • Recently, there has been a move toward the focus of brain & immune system and how the activation of proinflammatory cytokines can alter mood, cognition, and behavior Ziemssen & Kern 2007

5. Depression • Major depression (clinical depression), and chronic depression, are the most common types of depression • National Institute of Mental Health characterizes major depression by a combination of symptoms that interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities http://www.webmd.com/depression/

6. Some chronic diseases and cancers are treated by proinflammatory cytokines interferon-α (INF-α) and interferon-γ (INF-γ) • Used because of their strong immunomodulatory and antiviral effects • Several neuropsychiatric disorders have been linked to proinflammatory cytokines INF-α and INF-γ • Depression • Anxiety • Psychosis • Cognitive impairment Myint et al 2008

7. INF-α and INF-γ • Type I • IFN-α is produced by leukocytes • Mainly involved in innate immune response against viral infection • Type II • IFN-γ is secreted by Th1 cells, Tc cells, dendritic cells and NK cells • Also known as immune interferon • IFN-γ has antiviral, immunoregulatory, and anti-tumor properties http://en.wikipedia.org/wiki/Interferon#References

8. Indoleamine 2,3-dioxygenase (IDO) • IDO is inducible in different cell types • Fibroblast • Monocytes • Macropages • Dendritic cells • INF-γ and INF-α are they key inducers of IDO • IDO catalyzes cleavage of tryptophan (TRP) to form kynurenine (the first rate limiting step in the Kynurenne pathway) • Depletion of leads to antimicrobial effects, depression, T cell proliferation, & neurotoxic metabolites Kwidzinskinet al 2005

9. Tryptophan • Tryptophan (TRP) is catabolized in mammals by two enzymes • Tryptophan 2,3-dioxygenase • IDO • TPH-1 and TPH-2 • Can pass Blood brain barrier • TRP is the precursor for serotonin Myint & Schwartz 2009

10. Tryptophan Metabolism & Kynurenine Pathway Oxidative Tryptophan Metabolism along the Kynurenine pathway Neuro- exitotoxin Sanni et al1998

11. Kynurenine Pathway • Kynurenine (KYN) is able to pass through the blood brain barrier • 3-hydroxynurenine leads to the production of reactive oxygen species that initiate neural apoptosis • QA • Increased KYN neurotoxic levels have been seen in some neurodegenerative diseases • Huntington's disease • Parkinson's disease • Depression • IDO induced neurotoxicity and may reduce the production of kynurenine acid (KA) Wichers et al 2005

12. QA and KA • KA • Reduces neurotoxicity since it is an antagonist of the glutamate recognition site in the N-methyl-D-aspartate (NMDA) receptor • Has been found to be released by astrocytes for neural protection • KA synthesizing enzyme can not compete with the direct pathway of QA • QA • An endogenous excitatory amino acid neurotransmitter • Potent (NMDA) receptor agonist Sanni et al 2005

13. Serotonin (5-HT) • Neurotransmitter that is involved in a variety of different physiological functions in both the peripheral and nervous system • Synthesized within the brain from tryptophan • Impaired or altered 5-TH neurotransmitters appear to be a central dysfunction that lead to depression

14. Immune activation Proinfalmmatory Cytokines IFNγ, IFN α Virus infection Activated monocyte Microgilia IDO neurotoxicity Tryp QA 3-OH-KYN KYN Kynurenine aminotransferase 5-hydroxyltrytophan KA Seratonin neuroprotection Astrocyte

15. Hypothesis • The upregulation of pro-inflammatory cytokines leads to mood changes and depression through the upregulation of IDO via tryptophan metabolism

16. Overview • We will start by looking at the relationship between INFα and depression • Focus on IDO activity and expression as well as QA and KA activity • Focus on correlation between IDO, TRP, KYN and neurotoxic effects on depression • Lastly, we will look at the correlation between 5-HT, TRP, and depression

17. Experimental Findings

18. Depression Following Pegylated INF-α: Characteristics and Vulnerability BDI: Beck depression inventory INF-α increases depression symptoms in subjects developing major depression ( ) Control was not exposed to INF-α: Lotrich et al 2007

19. Dramatic Changes in Oxidative Tryptophan Metabolism along the Kynurenine Pathway in Experimental Cerebral and Noncerebral Malaria Brain IDO activity PbA: Plasmodium berghei ANKA (infected red blood cells) IFN-γ GKO: IFN-γ gene knockout ** p<.0001 Sanni et al 1998

20. Dramatic Changes in Oxidative Tryptophan Metabolism along the Kynurenine Pathway in Experimental Cerebral and Noncerebral Malaria Sanni et al 1998

21. Indolamine 2.3 –dioxygenase is Expressed in the CNS and Down-regulates Autoimmune Inflammation HPLC analysis of IDO activity during EAE Kyn/trp ratios taken after immunizing mice Kwidzinski et al 2005

22. Indolamine 2.3 –dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation Expression of IDO in the spinal chord of mice Section were taken from an animals in the acute phase of EAE (A-D) and from a nonimmunized control animal (E-H) Kwidzinski et al 2005

23. IDO and Interferon-α-induced Depressive Symptoms: A Shift in Hypothesis from Tryptophan Depletion to Neurotoxicity MARDS: Montagometry Asberg Depression Rating Scale (how the presence of depressive symptoms were assessed) Whichers et al 2005

24. Interferon-Alpha-induced Changes in Tryptophan Metabolism: Relationship to Depression and Paroxetine Treatment Antidepressant-free patients developed major depression during IFN-α therapy remained free of depression during IFN-α therapy • TRP concentration • KYN concentration • KYN/TRP concentration Capuron et al 2003

25. Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants Marble Burying test Detects compounds having an antidepressant effect TPH: tryptophan hydroxylase * p<.05 ** p<.0001 Savelieva et al 2008

26. Conclusion

27. The upregulation of pro-inflammatory cytokines leads to mood changes and depression through the upregulation of IDO via tryptophan metabolism Supports Supports Supports Supports Supports Supports

28. Take Home Message

29. Conclusion • The previous findings support my hypothesis: • The upregulation of pro-inflammatory cytokines leads to mood changes and depression through the upregulation of IDO via tryptophan metabolism • Increased levels of proinflammatory cytokines lead to decreased levels of TRP, which affects mood in two different ways: • By decreasing serotonin • By increasing production of QA

30. Future Direction/Experiments • Measure the serotonin effects in Humans at the development of major depression • Checking IDO activity leading to TRP degradation and measuring the amount of serotonin with/without the overstimulation of IDO

31. References • Lotrich FE, Rabinovitz M, Gironda P, Pollock BG. Depression following pegylated interferon-alpha: characteristics and vulnerability. J Psychosom Res. 2007 Aug;63(2):131-5. • Sanni LA, Thomas SR, Tattam BN, Moore DE, Chaudhri G, Stocker R, Hunt NH. Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and noncerebral malaria. Am J Pathol. 1998 Feb;152(2):611-9. • Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpé S, Maes M. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry. 2005 Jun;10(6):538-44. • Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH. Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry. 2003 Nov 1;54(9):906-14. • Myint AM, Schwarz MJ, Steinbusch HW, Leonard. BENeuropsychiatric disorders related to interferon and interleukins treatment. Metab Brain Dis. 2009 Mar;24(1):55-68. Epub 2008 Dec 10. • Savelieva KV, Zhao S, Pogorelov VM, Rajan I, Yang Q, Cullinan E, Lanthorn TH. Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PLoS ONE. 2008;3(10):e3301. Epub 2008 Oct 15. • Myint AM, Leonard BE, Steinbusch HW, Kim YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord. 2005 Oct;88(2):167-73. • Kwidzinski E, Bunse J, Aktas O, Richter D, Mutlu L, Zipp F, Nitsch R, Bechmann I. Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J. 2005 Aug;19(10):1347-9. Epub 2005 Jun 6. • Xu H, Oriss TB, Fei M, Henry AC, Melgert BN, Chen L, Mellor AL, Munn DH, Irvin CG, Ray P, Ray A. Indoleamine 2,3-dioxygenase in lung dendritic cells promotes Th2 responses and allergic inflammation. Proc NatlAcadSci U S A. 2008 May 6;105(18):6690-5. Epub 2008 Apr 24. • Pascal Feunou, Sophie Vanwetswinkel, Florence Gaudray, Michel Goldman, Patrick Matthys, and Michel Y. Braun2. Foxp3CD25 T Regulatory Cells Stimulate IFN—Independent CD152-Mediated Activation of Tryptophan Catabolism That Provides Dendritic Cells with Immune Regulatory Activity in Mice Unresponsive to Staphylococcal Enterotoxin B1. J Immunother. 2008 Nov-Dec;31(9):806-11.