title: Desipramine decreases expression of human and murine indoleamine-2,3-dioxygenases.
abstract: Abundant evidence connects depression symptomology with immune system activation, stress and subsequently elevated levels of kynurenine. Anti-depressants, such as the tricyclic norepinephrine/serotonin reuptake inhibitor desipramine (Desip), were developed under the premise that increasing extracellular neurotransmitter level was the sole mechanism by which they alleviate depressive symptomologies. However, evidence suggests that anti-depressants have additional actions that contribute to their therapeutic potential. The Kynurenine Pathway produces tryptophan metabolites that modulate neurotransmitter activity. This recognition identified another putative pathway for anti-depressant targeting. Considering a recognized role of the Kynurenine Pathway in depression, we investigated the potential for Desip to alter expression of rate-limiting enzymes of this pathway: indoleamine-2,3-dioxygenases (Ido1 and Ido2). Mice were administered lipopolysaccharide (LPS) or synthetic glucocorticoid dexamethasone (Dex) with Desip to determine if Desip alters indoleamine-dioxygenase (DO) expression in vivo following a modeled immune and stress response. This work was followed by treating murine and human peripheral blood mononuclear cells (PBMCs) with interferon-gamma (IFNγ) and Desip. In vivo: Desip blocked LPS-induced Ido1 expression in hippocampi, astrocytes, microglia and PBMCs and Ido2 expression by PBMCs. Ex vivo: Desip decreased IFNγ-induced Ido1 and Ido2 expression in murine PBMCs. This effect was directly translatable to the human system as Desip decreased IDO1 and IDO2 expression by human PBMCs. These data demonstrate for the first time that an anti-depressant alters expression of Ido1 and Ido2, identifying a possible new mechanism behind anti-depressant activity. Furthermore, we propose the assessment of PBMCs for anti-depressant responsiveness using IDO expression as a biomarker.
authors.affiliation: Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: akelly10@illinois.edu.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Brooks
authors.affiliation: Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: tjanda2@illinois.edu.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Janda
authors.affiliation: Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: mlawson@illinois.edu.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Lawson
authors.affiliation: Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: jenrytych@gmail.com.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Rytych
authors.affiliation: Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: robinsmith.ras@gmail.com.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Smith
authors.affiliation: Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: cocampo3@illinois.edu.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ocampo-Solis
authors.affiliation: Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Department of Pathology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: rmccuske@illinois.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: McCusker
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D003891:Desipramine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D003891:Desipramine
keywords: Depression; Desipramine; Ido1; Inflammation; Kynurenine pathway; PBMCs