PMID- 10200320
OWN - NLM
STAT- MEDLINE
DCOM- 19990517
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 8
DP  - 1999 Apr 13
TI  - Cyclopentenone prostaglandins suppress activation of microglia: down-regulation
      of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2.
PG  - 4668-73
AB  - Mechanisms leading to down-regulation of activated microglia and astrocytes are
      poorly understood, in spite of the potentially detrimental role of activated glia
      in neurodegeneration. Prostaglandins, produced both by neurons and glia, may
      serve as mediators of glial and neuronal functions. We examined the influence of 
      cyclopentenone prostaglandins and their precursors on activated glia. As models
      of glial activation, production of inducible nitric-oxide synthase (iNOS) was
      studied in lipopolysaccharide-stimulated rat microglia, a murine microglial cell 
      line BV-2, and IL-1beta-stimulated rat astrocytes. Cyclopentenone prostaglandins 
      were potent inhibitors of iNOS induction and were more effective than their
      precursors, prostaglandins E2 and D2. 15-Deoxy-Delta12,14-prostaglandin J2
      (15d-PGJ2) was the most potent prostaglandin among those tested. In activated
      microglia, 15d-PGJ2 suppressed iNOS promoter activity, iNOS mRNA, and protein
      levels. The action of 15d-PGJ2 does not appear to involve its nuclear receptor
      peroxisome proliferator-activated receptor gamma (PPARgamma) because
      troglitazone, a specific ligand of PPARgamma, was unable to inhibit iNOS
      induction, and neither troglitazone nor 15d-PGJ2 could stimulate the activity of 
      a PPAR-dependent promoter in the absence of cotransfected PPARgamma. 15d-PGJ2 did
      not block nuclear translocation or DNA-binding activity of the transcription
      factor NFkappaB, but it did inhibit the activity of an NFkappaB reporter
      construct, suggesting that the mechanism of suppression of microglial iNOS by
      15d-PGJ2 may involve interference with NFkappaB transcriptional activity in the
      nucleus. Thus, our data suggest the existence of a novel pathway mediated by
      cyclopentenone prostaglandins, which may represent part of a feedback mechanism
      leading to the cessation of inflammatory glial responses in the brain.
FAU - Petrova, T V
AU  - Petrova TV
AD  - Department of Cell and Molecular Biology, Northwestern University Medical School,
      Chicago, IL 60611, USA.
FAU - Akama, K T
AU  - Akama KT
FAU - Van Eldik, L J
AU  - Van Eldik LJ
LA  - eng
GR  - GM08061/GM/NIGMS NIH HHS/United States
GR  - AG13939/AG/NIA NIH HHS/United States
GR  - T32 GM008061/GM/NIGMS NIH HHS/United States
GR  - R37 AG013939/AG/NIA NIH HHS/United States
GR  - R01 AG013939/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (15-deoxy-delta(12,14)-prostaglandin J2)
RN  - 0 (Interleukin-1)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Nitrites)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Fusion Proteins)
RN  - DCR9Z582X0 (Epoprostenol)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, rat)
RN  - RXY07S6CZ2 (Prostaglandin D2)
SB  - IM
MH  - Animals
MH  - Astrocytes/drug effects/enzymology
MH  - Cell Line
MH  - Cell Nucleus/drug effects/physiology
MH  - Cloning, Molecular
MH  - Epoprostenol/pharmacology
MH  - Gene Expression Regulation, Enzymologic/*drug effects
MH  - Interleukin-1/pharmacology
MH  - Kinetics
MH  - Lipopolysaccharides/pharmacology
MH  - Microglia/*drug effects/enzymology/physiology
MH  - Nitric Oxide Synthase/biosynthesis/*genetics
MH  - Nitric Oxide Synthase Type II
MH  - Nitrites/metabolism
MH  - Prostaglandin D2/*analogs & derivatives/pharmacology
MH  - Protein Biosynthesis/drug effects
MH  - RNA, Messenger/genetics
MH  - Rats
MH  - Recombinant Fusion Proteins/biosynthesis
MH  - Salmonella typhimurium
MH  - Transcription, Genetic/drug effects
PMC - PMC16390
EDAT- 1999/04/14 00:00
MHDA- 1999/04/14 00:01
CRDT- 1999/04/14 00:00
PHST- 1999/04/14 00:00 [pubmed]
PHST- 1999/04/14 00:01 [medline]
PHST- 1999/04/14 00:00 [entrez]
AID - 10.1073/pnas.96.8.4668 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4668-73. doi: 10.1073/pnas.96.8.4668.