PMID- 20678226
OWN - NLM
STAT- MEDLINE
DCOM- 20100923
LR  - 20211020
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 7
DP  - 2010 Aug 2
TI  - Central administration of lipopolysaccharide induces depressive-like behavior in 
      vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic 
      hippocampal slice cultures.
PG  - 43
LID - 10.1186/1742-2094-7-43 [doi]
AB  - BACKGROUND: Transient stimulation of the innate immune system by an 
      intraperitoneal injection of lipopolysaccharide (LPS) activates peripheral and 
      central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase 
      (IDO) which mediates depressive-like behavior. It is unknown whether direct 
      activation of the brain with LPS is sufficient to activate IDO and induce 
      depressive-like behavior. METHODS: Sickness and depressive-like behavior in 
      C57BL/6J mice were assessed by social exploration and the forced swim test, 
      respectively. Expression of cytokines and IDO mRNA was measured by real-time 
      RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays 
      (ELISAs). Enzymatic activity of IDO was estimated as the amount of kynurenine 
      produced from tryptophan as determined by high pressure liquid chromatography 
      (HPLC) with electrochemical detection. RESULTS: Intracerebroventricular (i.c.v.) 
      administration of LPS (100 ng) increased steady-state transcripts of TNFalpha, 
      IL-6 and the inducible isoform of nitric oxide synthase (iNOS) in the hippocampus 
      in the absence of any change in IFN gamma mRNA. LPS also increased IDO expression 
      and induced depressive-like behavior, as measured by increased duration of 
      immobility in the forced swim test. The regulation of IDO expression was 
      investigated using in situ organotypic hippocampal slice cultures (OHSCs) derived 
      from brains of newborn C57BL/6J mice. In accordance with the in vivo data, 
      addition of LPS (10 ng/ml) to the medium of OHSCs induced steady-state expression 
      of mRNA transcripts for IDO that peaked at 6 h and translated into increased IDO 
      enzymatic activity within 8 h post-LPS. This activation of IDO by direct 
      application of LPS was preceded by synthesis and secretion of TNFalpha and IL-6 
      protein and activation of iNOS while IFN gamma expression was undetectable. 
      CONCLUSION: These data establish that activation of the innate immune system in 
      the brain is sufficient to activate IDO and induce depressive-like behavior in 
      the absence of detectable IFN gamma. Targeting IDO itself may provide a novel 
      therapy for inflammation-associated depression.
FAU - Fu, Xin
AU  - Fu X
AD  - Integrative Immunology and Behavior Program, Department of Animal Sciences, 
      College of ACES, University of Illinois at Urbana-Champaign, Urbana, Illinois 
      61801, USA.
FAU - Zunich, Samantha M
AU  - Zunich SM
FAU - O'Connor, Jason C
AU  - O'Connor JC
FAU - Kavelaars, Annemieke
AU  - Kavelaars A
FAU - Dantzer, Robert
AU  - Dantzer R
FAU - Kelley, Keith W
AU  - Kelley KW
LA  - eng
GR  - R01 AG029573/AG/NIA NIH HHS/United States
GR  - R01 AG 029573/AG/NIA NIH HHS/United States
GR  - R01 MH 079829/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100802
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (Cytokines)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
RN  - 0 (Lipopolysaccharides)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Behavior, Animal/*drug effects/physiology
MH  - *Brain/enzymology/immunology
MH  - Cytokines/immunology
MH  - Depression/*chemically induced/immunology/physiopathology
MH  - Enzyme Activation
MH  - Hippocampus/cytology/*drug effects/*enzymology/immunology
MH  - Immunity, Innate/*immunology
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics/*metabolism
MH  - Injections, Intraventricular
MH  - Interferon-gamma/metabolism
MH  - Lipopolysaccharides/administration & dosage/*pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nitric Oxide Synthase Type II/genetics/metabolism
MH  - Tissue Culture Techniques
PMC - PMC2921406
EDAT- 2010/08/04 06:00
MHDA- 2010/09/24 06:00
PMCR- 2010/08/02
CRDT- 2010/08/04 06:00
PHST- 2010/07/16 00:00 [received]
PHST- 2010/08/02 00:00 [accepted]
PHST- 2010/08/04 06:00 [entrez]
PHST- 2010/08/04 06:00 [pubmed]
PHST- 2010/09/24 06:00 [medline]
PHST- 2010/08/02 00:00 [pmc-release]
AID - 1742-2094-7-43 [pii]
AID - 10.1186/1742-2094-7-43 [doi]
PST - epublish
SO  - J Neuroinflammation. 2010 Aug 2;7:43. doi: 10.1186/1742-2094-7-43.