PMID- 15968640
OWN - NLM
STAT- MEDLINE
DCOM- 20051107
LR  - 20220409
IS  - 0360-4012 (Print)
IS  - 0360-4012 (Linking)
VI  - 81
IP  - 3
DP  - 2005 Aug 1
TI  - Agonists for the peroxisome proliferator-activated receptor-alpha and the 
      retinoid X receptor inhibit inflammatory responses of microglia.
PG  - 403-11
AB  - The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) plays a key 
      role in lipid metabolism and inflammation. Recently, we demonstrated that 
      administration of the PPAR-alpha agonists gemfibrozil and fenofibrate, inhibit 
      the clinical signs of experimental autoimmune encephalomyelitis (EAE), the animal 
      model of multiple sclerosis (MS). In the present study we investigated the 
      effects of PPAR-alpha agonists on primary mouse microglia, a cell type implicated 
      in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha 
      agonists ciprofibrate, fenofibrate, gemfibrozil, and WY 14,643 each inhibited NO 
      production by cytokine-stimulated microglia in a dose-dependent manner. However, 
      fenofibrate and WY 14,643 were more potent inhibitors than gemfibrozil and 
      ciprofibrate. In LPS-stimulated microglia, only fenofibrate and WY 14,643 
      significantly suppressed NO production. Additionally, PPAR-alpha agonists 
      inhibited the secretion of the proinflammatory cytokines IL-1beta, TNF-alpha, 
      IL-6, and IL-12 p40 and the chemokine MCP-1 by LPS-stimulated microglia. Retinoid 
      X receptors (RXRs) physically interact with PPAR-alpha receptors, and the 
      resulting heterodimers regulate the expression of PPAR-responsive genes. 
      Interestingly, the RXR agonist 9-cis retinoic acid (9-cis RA) inhibited NO 
      production by LPS-stimulated microglia. Furthermore, a combination of 9-cis RA 
      and the PPAR-alpha agonist fenofibrate cooperatively inhibited NO production by 
      these cells. A combination of these agonists also selectively inhibited the 
      expression of proinflammatory cytokines including IL-1beta, TNF-alpha, and IL-6 
      by LPS-stimulated microglia. Collectively, these results raise the possibility 
      that PPAR-alpha and RXR agonists might have benefit as a therapy in MS, where 
      activated microglia are believed to contribute to disease pathology.
CI  - (c) 2005 Wiley-Liss, Inc.
FAU - Xu, Jihong
AU  - Xu J
AD  - Department of Neurobiology and Developmental Sciences, University of Arkansas for 
      Medical Sciences, Little Rock, AR 72205, USA.
FAU - Storer, Paul D
AU  - Storer PD
FAU - Chavis, Janet A
AU  - Chavis JA
FAU - Racke, Michael K
AU  - Racke MK
FAU - Drew, Paul D
AU  - Drew PD
LA  - eng
GR  - P30 NS047546/NS/NINDS NIH HHS/United States
GR  - P30 NS047546-01A1/NS/NINDS NIH HHS/United States
GR  - NS42860/NS/NINDS NIH HHS/United States
GR  - NS 047546/NS/NINDS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Neurosci Res
JT  - Journal of neuroscience research
JID - 7600111
RN  - 0 (Chemokines)
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (PPAR alpha)
RN  - 0 (Peroxisome Proliferators)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 1UA8E65KDZ (Alitretinoin)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 5688UTC01R (Tretinoin)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EUY85H477I (thiazolyl blue)
SB  - IM
MH  - Alitretinoin
MH  - Analysis of Variance
MH  - Animals
MH  - Animals, Newborn
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology
MH  - Chemokines/metabolism
MH  - Cytokines/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Enzyme-Linked Immunosorbent Assay/methods
MH  - Inflammation
MH  - Interferon-gamma/pharmacology
MH  - Lipopolysaccharides/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microglia/*drug effects
MH  - Nitric Oxide/metabolism
MH  - PPAR alpha/*agonists
MH  - Peroxisome Proliferators/*pharmacology
MH  - Retinoid X Receptors/*physiology
MH  - Tetrazolium Salts
MH  - Thiazoles
MH  - Tretinoin/pharmacology
MH  - Tumor Necrosis Factor-alpha/pharmacology
EDAT- 2005/06/22 09:00
MHDA- 2005/11/08 09:00
CRDT- 2005/06/22 09:00
PHST- 2005/06/22 09:00 [pubmed]
PHST- 2005/11/08 09:00 [medline]
PHST- 2005/06/22 09:00 [entrez]
AID - 10.1002/jnr.20518 [doi]
PST - ppublish
SO  - J Neurosci Res. 2005 Aug 1;81(3):403-11. doi: 10.1002/jnr.20518.