Yanett Roman2/25/09Biol 520

Investigates interaction between behavior and the immune system, mediated by the endocrine system and nervous systemlink between bi-directional communication of the

immune system with the endocrine an nervous system

CNS

Immune system

Nps Hormones

Neurotransmitters

CytokinesNps

Ziemssen & Kern 2007

Ziemssen & Kern 2007

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/depressionhttp://www.webmd.com/depression//

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-γDepressionAnxietyPsychosis Cognitive impairment

Myint et al 2008Myint et al 2008

Type IIFN-α is produced by leukocytesMainly 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 interferonIFN-γ has antiviral, immunoregulatory, and

anti-tumor properties

http://en.wikipedia.org/wiki/Interferon#References

IDO is inducible in different cell typesFibroblastMonocytes

○ 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 2005Kwidzinskinet al 2005

Tryptophan (TRP) is catabolized in mammals by two enzymesTryptophan 2,3-dioxygenaseIDO

TPH-1 and TPH-2 Can pass Blood brain barrier TRP is the precursor for serotonin

Myint & Schwartz 2009

Oxidative Tryptophan Metabolism along the Kynurenine pathway

Sanni et al1998

Neuro- exitotoxin

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 diseasesHuntington's diseaseParkinson's diseaseDepression

IDO induced neurotoxicity and may reduce the production of kynurenine acid (KA)

Wichers et al 2005Wichers et al 2005

KAReduces 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

QAAn endogenous excitatory amino acid

neurotransmitterPotent (NMDA) receptor agonist

Sanni et al 2005

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

Activated monocyte

Proinfalmmatory Cytokines IFNγ, IFN α

IDOIDO

KYN

Immune activation

SeratoninSeratonin

5-hydroxyltrytophan

KAKA

Kynurenine aminotransferase

neuroprotection

Astrocyte

Virus infectionVirus infection

QA

Microgilia

neurotoxicity

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

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

Lotrich et al 2007

BDI: Beck depression inventory

INF-α increases depression symptoms in subjects developing major depression ( )Control was not exposed to INF-α:

Sanni et al 1998Sanni et al 1998

Brain IDO activity PbA: Plasmodium berghei ANKA (infected red blood cells) IFN-γ GKO: IFN-γ gene knockout

** p<.0001

Dramatic Changes in Oxidative Tryptophan Dramatic Changes in Oxidative Tryptophan Metabolism along the Kynurenine Pathway in Metabolism along the Kynurenine Pathway in

Experimental Cerebral and Noncerebral Experimental Cerebral and Noncerebral MalariaMalaria

Sanni et al 1998

HPLC analysis of HPLC analysis of IDO activity during IDO activity during EAEEAEKyn/trp ratios taken after immunizing mice

Expression of IDO in the spinal chord of miceExpression of IDO in the spinal chord of miceSection were taken from an animals in the acute phase of EAE (A-D) and from a nonimmunized control animal (E-H)

MARDS: Montagometry Asberg Depression Rating Scale(how the presence of depressive symptoms were assessed)

Capuron et al 2003Capuron et al 2003

Antidepressant-free patients developed major depression during IFN-α therapy remained free of depression during IFN-α therapy

A. TRP concentrationB. KYN concentrationC. KYN/TRP concentration

Savelieva et al 2008Savelieva et al 2008

Marble Burying testDetects compounds having an antidepressant effect

TPH: tryptophan hydroxylase* p<.05 ** p<.0001

Supports

Supports

Supports

Supports

Supports

Supports

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 serotoninBy increasing production of QA

Future Direction/Experiments

Measure the serotonin effects in Humans at the development of major depressionChecking IDO activity leading to TRP

degradation and measuring the amount of serotonin with/without the overstimulation of IDO

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 Natl Acad Sci 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.