title: HIV-1 Tat activates indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures in a p38 mitogen-activated protein kinase-dependent manner.
abstract: BACKGROUND
  We have established that activation of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) mediates the switch from cytokine-induced sickness behavior to depressive-like behavior. Because human immunodeficiency virus type 1 (HIV-1) Tat protein causes depressive-like behavior in mice, we investigated its ability to activate IDO in organotypic hippocampal slice cultures (OHSCs) derived from neonatal C57BL/6 mice.
  
  
  METHODS
  Depressive-like behavior in C57BL/6J mice was assessed by the forced swim test. Expression of cytokines and IDO mRNA in OHSCs was measured by real-time RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays (ELISAs). p38 MAPK phosphorylation was analyzed by western blot.
  
  
  RESULTS
  Intracerebroventricular (i.c.v.) administration of Tat (40 ng) induced depressive-like behavior in the absence of sickness. Addition of Tat (40 ng/slice) to the medium of OHSCs induced IDO steady-state mRNA that peaked at 6 h. This effect was potentiated by pretreatment with IFNγ. Tat also induced the synthesis and release of TNFα and IL-6 protein in the supernatant of the slices and increased expression of the inducible isoform of nitric oxide synthase (iNOS) and the serotonin transporter (SERT). Tat had no effect on endogenous synthesis of IFNγ. To explore the mechanisms of Tat-induced IDO expression, slices were pretreated with the p38 mitogen-activated protein kinase (MAPK) inhibitor SB 202190 for 30 min before Tat treatment. SB 202190 significantly decreased IDO expression induced by Tat, and this effect was accompanied by a reduction of Tat-induced expression of TNFα, IL-6, iNOS and SERT.
  
  
  CONCLUSIONS
  These data establish that Tat induces IDO expression via an IFNγ-independent mechanism that depends upon activation of p38 MAPK. Targeting IDO itself or the p38 MAPK signaling pathway could provide a novel therapy for comorbid depressive disorders in HIV-1-infected patients.
authors.affiliation: Integrative Immunology and Behavior Program, Department of Animal Sciences, College of ACES, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Fu
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Lawson
authors.forename: Keith W
authors.initials: KW
authors.lastname: Kelley
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015897:Comorbidity; D003863:Depression / Q000453:epidemiology / Q000503:physiopathology; D004789:Enzyme Activation; D015658:HIV Infections / Q000453:epidemiology; D015497:HIV-1 / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D057967:Infusions, Intraventricular; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009483:Neuropsychological Tests; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6; D008070:Lipopolysaccharides; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases